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Review Article  |   February 2007
General Anesthetics and Vascular Smooth Muscle: Direct Actions of General Anesthetics on Cellular Mechanisms Regulating Vascular Tone
Author Affiliations & Notes
  • Takashi Akata, M.D., Ph.D.
    *
  • * Assistant Professor.
Article Information
Review Article / Pharmacology
Review Article   |   February 2007
General Anesthetics and Vascular Smooth Muscle: Direct Actions of General Anesthetics on Cellular Mechanisms Regulating Vascular Tone
Anesthesiology 2 2007, Vol.106, 365-391. doi:
Anesthesiology 2 2007, Vol.106, 365-391. doi:
VASCULAR tone is regulated by mechanisms that are intrinsic to the organ, as well as by extrinsic mechanisms, such as the autonomic nervous system and circulating hormones. The vascular endothelium releases a variety of vasoactive mediators in response to various neurohumoral and physicochemical stimuli, contributing to both intrinsic and extrinsic regulation. The intrinsic mechanisms—i.e.  , metabolic and myogenic mechanisms—are considered essential for fine adjustment of regional vascular resistance to meet the ever-changing metabolic needs in regional tissues. On the other hand, extrinsic mechanisms actively regulate vascular tone to maintain arterial pressure and to alter distribution of cardiac output in response to various physiologic and pathologic stresses (e.g.  , hemorrhage). In particular, the sympathetic nervous system plays a major role in regulating vascular tone of both resistance and capacitance vessels in peripheral circulations to sustain systemic vascular resistance and venous return, respectively, and hence systemic arterial pressure. Cardiovascular reflexes (e.g.  , baroreceptor reflex) are essential for short-term regulation of the circulation; namely, in response to moment-to-moment changes in hemodynamics, they rapidly control myocardial contractility, peripheral vascular tone, and heart rate, using the autonomic nervous system. The relative importance of each mechanism varies in different vascular beds.
General anesthetics threaten cardiovascular stability by causing changes in cardiac function, vascular reactivity, and cardiovascular reflexes. Their overall impact is often systemic hypotension, which is attributable to myocardial depression, peripheral vasodilation, and decreased sympathetic nervous system activity; however, one could be more causative than the others, depending on anesthetic agents and cardiovascular factors inherent in patients (e.g.  , heart disease).1–9 General anesthetics also significantly alter blood flow to various organs.1,5,6,10–16 Most general anesthetics are believed to act on multiple sites within the sympathetic nervous system, decreasing its influence on the peripheral vasculature and hence peripheral vascular resistance.17 Indeed, in previous in vivo  studies, during administration of various general anesthetics, vascular resistance or tone was decreased in most peripheral vascular beds, although it was unaffected or increased in some peripheral vascular beds.1,10–13,18–20 General anesthetics may directly influence cellular mechanisms regulating vascular reactivity in various vascular beds, thereby altering total peripheral and/or regional vascular resistance. To gain access to the validity of these hypotheses, to date, numerous studies have investigated direct (i.e.  , nonneural) actions of general anesthetics on vascular smooth muscle cells (VSMCs) and endothelial cells from various vascular beds under in vitro  or in situ  conditions.
This article reviews previous literature evaluating the direct vascular actions of general anesthetics and discusses their underlying mechanisms, their in vivo  relevance, and the future of research for general anesthetic vascular pharmacology. General anesthetics dealt with in this article include halogenated volatile anesthetics, intravenous nonopioid anesthetics (i.e.  , barbiturates, ketamine, propofol, etomidate, benzodiazepines), and intravenous opioid anesthetics (i.e.  , morphine, fentanyl), all of which are currently available for clinical practice.
Cellular Mechanisms Regulating the Contractile State of Vascular Smooth Muscle Cells
This section briefly reviews cellular mechanisms regulating vascular tone, which have been reported to be influenced by various types of general anesthetics as described later.
Role of Calcium
Changes in cytosolic free Ca2+concentration ([Ca2+]c) are the principal mechanisms that regulate contractile state of VSMCs (i.e.  , vascular tone). Namely, an increase and a decrease in [Ca2+]c result in vasoconstriction and vasorelaxation, respectively.21 The Ca2+-dependent activation of myosin light chain kinase (MLCK) and its phosphorylation of 20-kd myosin light chain (MLC20) are the primary mechanisms responsible for the initial development of contractile force.21,22 However, during its subsequent maintenance, the Ca2+sensitivity of MLC20phosphorylation can be secondarily modulated by other signaling pathways.21,23–27 In addition, some regulatory mechanisms that maintain high contractile force at low energy (i.e.  , adenosine 5′-triphosphate [ATP]) cost—i.e.  , low levels of MLC20phosphorylation—may also contribute to its maintenance.28,29 
In response to vasoconstrictor stimuli, Ca2+is mobilized from intracellular stores (i.e.  , sarcoplasmic reticulum [SR]) and/or the extracellular space to increase the [Ca2+]c in VSMCs (fig. 1). The increase in [Ca2+]c, in turn, stimulates the binding of Ca2+to calmodulin (CaM). The Ca2+–CaM complex then activates MLCK to phosphorylate myosin at MLC20on serine 19 (Ser19), allowing myosin ATPase to be activated by actin and the muscle to contract as a result of cyclic interactions between myosin and actin.21,22,30 Ser19 of MLC20also can be phosphorylated by Ca2+/CaM-dependent protein kinase II (CaMKII); however, it occurs only at a very slow rate and probably does not contribute to the initiation of contraction.21 
Fig. 1. Proposed mechanisms of vascular smooth muscle contraction (see text for details). The location of cytosolic molecules or their translocation to the cell membrane or other subcellular sites  (e.g.  , translocation of protein kinase C [PKC], Rho A, Rho kinase, or mitogen-activated protein kinases [MAPKs] to the cell membrane) is not considered in this figure. It is controversial whether Rho kinase functions upstream on, downstream on, or independently of PKC. += Stimulation; −= inhibition; AA = arachidonic acid; APL = arachidonyl phospholipids; CIF = Ca2+-influx factor; CaM = calmodulin; CaMKII = Ca2+/CaM-dependent protein kinase II; CICR = Ca2+-induced Ca2+release; ClCa= Ca2+-activated Clchannel; CPI-17 = PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kd; DAG = 1,2-diacyl-glycerol; G = guanosine-5′-triphosphate–binding protein; IP3= inositol 1, 4, 5-triphosphate; IICR = IP3-induced Ca2+release; KCa= Ca2+-activated K+channel; LG-NSCC = ligand-gated nonselective cation channel; MLC20= regulatory light chain of myosin (20 kd); MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; PC = phosphatidylcholine; PIP2= phosphatidyl-inositol 4,5-bisphosphate; PLA2= phospholipase A2; PLC = phospholipase C; PLD = phospholipase D; RhoA-GDP = GDP-bound RhoA; RhoA-GTP = GTP-bound RhoA; ROCC = receptor-operated Ca2+channel; SMOCC = second messenger–operated Ca2+channel; SOCC = store-operated Ca2+channel (Ca2+release–activated Ca2+channel); SR = sarcoplasmic reticulum; TK = tyrosine kinase; VOCC = voltage-operated Ca2+channel. 
Fig. 1. Proposed mechanisms of vascular smooth muscle contraction (see text for details). The location of cytosolic molecules or their translocation to the cell membrane or other subcellular sites 
	(e.g.  , translocation of protein kinase C [PKC], Rho A, Rho kinase, or mitogen-activated protein kinases [MAPKs] to the cell membrane) is not considered in this figure. It is controversial whether Rho kinase functions upstream on, downstream on, or independently of PKC. += Stimulation; −= inhibition; AA = arachidonic acid; APL = arachidonyl phospholipids; CIF = Ca2+-influx factor; CaM = calmodulin; CaMKII = Ca2+/CaM-dependent protein kinase II; CICR = Ca2+-induced Ca2+release; ClCa= Ca2+-activated Cl−channel; CPI-17 = PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kd; DAG = 1,2-diacyl-glycerol; G = guanosine-5′-triphosphate–binding protein; IP3= inositol 1, 4, 5-triphosphate; IICR = IP3-induced Ca2+release; KCa= Ca2+-activated K+channel; LG-NSCC = ligand-gated nonselective cation channel; MLC20= regulatory light chain of myosin (20 kd); MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; PC = phosphatidylcholine; PIP2= phosphatidyl-inositol 4,5-bisphosphate; PLA2= phospholipase A2; PLC = phospholipase C; PLD = phospholipase D; RhoA-GDP = GDP-bound RhoA; RhoA-GTP = GTP-bound RhoA; ROCC = receptor-operated Ca2+channel; SMOCC = second messenger–operated Ca2+channel; SOCC = store-operated Ca2+channel (Ca2+release–activated Ca2+channel); SR = sarcoplasmic reticulum; TK = tyrosine kinase; VOCC = voltage-operated Ca2+channel. 
Fig. 1. Proposed mechanisms of vascular smooth muscle contraction (see text for details). The location of cytosolic molecules or their translocation to the cell membrane or other subcellular sites  (e.g.  , translocation of protein kinase C [PKC], Rho A, Rho kinase, or mitogen-activated protein kinases [MAPKs] to the cell membrane) is not considered in this figure. It is controversial whether Rho kinase functions upstream on, downstream on, or independently of PKC. += Stimulation; −= inhibition; AA = arachidonic acid; APL = arachidonyl phospholipids; CIF = Ca2+-influx factor; CaM = calmodulin; CaMKII = Ca2+/CaM-dependent protein kinase II; CICR = Ca2+-induced Ca2+release; ClCa= Ca2+-activated Clchannel; CPI-17 = PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kd; DAG = 1,2-diacyl-glycerol; G = guanosine-5′-triphosphate–binding protein; IP3= inositol 1, 4, 5-triphosphate; IICR = IP3-induced Ca2+release; KCa= Ca2+-activated K+channel; LG-NSCC = ligand-gated nonselective cation channel; MLC20= regulatory light chain of myosin (20 kd); MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; PC = phosphatidylcholine; PIP2= phosphatidyl-inositol 4,5-bisphosphate; PLA2= phospholipase A2; PLC = phospholipase C; PLD = phospholipase D; RhoA-GDP = GDP-bound RhoA; RhoA-GTP = GTP-bound RhoA; ROCC = receptor-operated Ca2+channel; SMOCC = second messenger–operated Ca2+channel; SOCC = store-operated Ca2+channel (Ca2+release–activated Ca2+channel); SR = sarcoplasmic reticulum; TK = tyrosine kinase; VOCC = voltage-operated Ca2+channel. 
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In response to vasodilator stimuli or removal of the vasoconstrictor stimuli, the [Ca2+]c decreases mainly as a result of plasmalemmal extrusion and/or uptake into the SR. When the [Ca2+]c decreases to lower than 1 μm, CaM dissociates from MLCK to inactivate MLCK. Under these conditions, myosin light chain phosphatase (MLCP), the activity of which is independent of Ca2+, dephosphorylates MLC20and thereby causes relaxation by inactivating the actomyosin ATPase (i.e.  , actin-activated, ATPase activity of myosin).21,31 
Role of the Phosphatidylinositol Cascade
The majority of vasoconstrictor agonists (e.g.  , norepinephrine, angiotensin II [AT-II], ATP, endothelin 1 [ET-1]), acting on receptors coupled to heterotrimeric guanosine-5′-triphosphate (GTP)–binding protein (G protein), activate phospholipase C (PLC) to hydrolyze the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into two messengers, i.e.  , inositol 1,4,5-triphosphate (IP3) and diacylglycerol (fig. 1).21,32–34 IP3stimulates the SR to release Ca2+(i.e.  , IP3-induced Ca2+release [IICR]) that in turn activates contractile proteins and initiates contraction. This increase in [Ca2+]c may induce further Ca2+release from SR via  the Ca2+-induced Ca2+release (CICR) mechanism.35 In response to the increase in [Ca2+]c and phosphoinositide levels, protein kinase C (PKC) migrates from the cytosol to the cell membrane, where it interacts with diacylglycerol to become activated, possibly increasing the sensitivity of contractile myofilaments to Ca2+(i.e.  , myofilament Ca2+sensitivity).34,36,37 After the initial increase in [Ca2+]c caused by the PLC-mediated Ca2+release, a tonic increase in [Ca2+]c, which is largely dependent on extracellular Ca2+, is normally observed in contractile response to receptor agonists.25–27,34 
Role of Intracellular Calcium Stores
In VSMCs, Ca2+is stored intracellularly in the SR, which contains at least two types of Ca2+-release channels, i.e.  , those sensitive to IP3(IP3receptor [IP3R] channels) and those sensitive to the plant alkaloid ryanodine and caffeine (ryanodine receptor [RyR] channel).38–40 The SR plays a pivotal role in the [Ca2+]c regulation not only as a supply of the activator Ca2+but also as a buffer against VSM activation by Ca2+.21,41 The IP3R channels are believed to play a primary physiologic role in Ca2+mobilization,21,34 whereas the physiologic roles of RyR channels are not fully understood.38,39,42,43 The CICR would occur through the RyR channels and contribute to the amplification of agonist-induced Ca2+signals, cytosolic Ca2+oscillations, and Ca2+waves. In addition, the CICR may play a key role in the superficial buffer barrier mechanism, which is considered essential for cellular Ca2+homeostasis in VSMCs (see review articles40,44 for details).
Role of Plasmalemmal Calcium Influxes
Plasmalemmal Ca2+channels are the major routes by which Ca2+enters the VSMCs. Several types exist in VSMCs, including voltage-operated Ca2+channels (VOCCs), receptor-operated Ca2+channels (ROCCs), and store-operated Ca2+channels (SOCCs) (fig. 1).21,34,45 The open probability of VOCCs increases as the membrane potential becomes more depolarized. The membrane potential of VSMCs measured in vivo  (i.e.  , −40 to −55 mV) falls within the range over which VOCCs are activated.17,46,47 In addition, membrane depolarization occurs during stimulation with norepinephrine, the sympathetic neurotransmitter.46,48 Therefore, the VOCCs are believed to play a crucial role in the physiologic regulation of VSM tone.34,46 
The ROCCs, the opening of which is primarily controlled by receptor stimulation, are further subdivided into ligand-gated Ca2+channels and second messenger–operated Ca2+channels (SMOCCs).34,45 The ligand-gated Ca2+channels are directly activatable by receptor agonists, and have been suggested to be nonselective cation channels, with some degree of selectivity for divalent cations.21,45 On the other hand, the SMOCCs are indirectly activated by diffusible second messengers such as IP3or IP4after receptor activation; however, there is limited evidence for their existence in VSMCs.34,45 
Depletion of the SR activates the SOCCs without continued receptor occupation or generation of related second messengers.49,50 Unlike the nonselective cation channels, the SOCCs are highly selective for Ca2+over other cations.51,52 The cellular mechanisms linking SR depletion to the opening of SOCCs might involve the generation of a diffusible messenger (i.e.  , calcium influx factor) or a direct protein–protein interaction between the SR and the plasmalemma.49,50 Ca2+entry via  SOCCs is considered important not only for the refilling of the depleted SR but also as a source of the activator Ca2+.49 
Mechanisms Reducing the Cytosolic Calcium Level
In VSMCs, there exist several mechanisms that reduce the [Ca2+]c, including plasma membrane Ca2+ATPase (PMCA), SR Ca2+ATPase (SERCA), Na+/Ca2+exchanger, and cytosolic Ca2+-binding proteins. Under physiologic conditions, decreases in the [Ca2+]c result mainly from either PMCA-mediated Ca2+extrusion or SERCA-mediated Ca2+uptake into the SR.53 However, the Na+–Ca2+exchanger may also play a role in the [Ca2+]c regulation, i.e.  , in the superficial buffer barrier mechanism, which has been proposed to maintain the [Ca2+]c at lower levels.40,44 The precise roles of cytosolic Ca2+-binding proteins (e.g.  , S100 proteins) in [Ca2+]c regulation are unknown.34,36 
Cytosolic Calcium Oscillations
Oscillatory changes in [Ca2+]c have been demonstrated in VSMCs during stimulation with receptor agonists; however, its physiologic roles are not clear.54–58 A variety of different mechanisms have been proposed to explain cytosolic Ca2+oscillations, including a periodic release of Ca2+from the SR,58,59 and oscillatory changes in membrane potential due to an interplay between VOCCs and K+channels.58–61 The endothelium, Na+–K+pump, and Clchannels may also play some important roles in the generation of cytosolic Ca2+oscillations.54–58 
Mechanisms Regulating Myofilament Calcium Sensitivity
During receptor stimulation, myofilament Ca2+sensitivity is greatly enhanced through the activation of G proteins21,37; however, its mechanisms are not fully understood (fig. 1). It is currently believed that during receptor stimulation, MLCP activity is inhibited by Rho kinase and/or PKC, leading to the enhanced myofilament Ca2+sensitivity.36,37,62 The activated Rho kinase is believed to phosphorylate MLCP and inhibit its catalytic activity,36,37,62 whereas the activated PKC presumably phosphorylates and activates CPI-17 (an inhibitory protein of MLCP), thereby inhibiting MLCP activity.37,62 The activated Rho kinase is also capable of phosphorylating CPI-17.62 In addition, phosphorylation of the thin filament-associated proteins (e.g.  , caldesmon, calponin), and resultant reversal of their capability to inhibit the actomyosin ATPase activity, may also contribute to this enhancement.31,36,63 PKC, CaMKII, Rho kinase, and mitogen-activated protein kinases (MAPKs) have been reported to have the ability to phosphorylate those proteins, although their physiologic significance remains uncertain.21,31,36,62 
In addition to PLC, phospholipase D (PLD) and cytosolic phospholipase A2are activated after stimulation with receptor agonists (e.g.  , norepinephrine) in VSMCs.64–69 Therefore, after receptor activation, diacylglycerol would be generated not only by PLC-mediated PIP2hydrolysis but also by PLD-mediated hydrolysis of phosphatidylcholine, leading to PKC activation. In addition, arachidonic acid, generated by the phospholipase A2–mediated hydrolysis of arachidonyl phospholipids, has been reported to inhibit MLCP activity, or activate PKC, Rho kinase, and MAPKs, suggesting its involvement in Ca2+sensitization (fig. 1).21,36,37,62,70 Furthermore, arachidonic acid may also be released through PLD activation during receptor stimulation.69 
Myosin light chain kinase activity is primarily regulated by the Ca2+–CaM complex. Phosphorylation of MLCK at a specific serine residue (i.e., site A  ), however, decreases its affinity for the Ca2+–CaM complex.37,71 CaMKII, capable of phosphorylating MLCK at site A  at higher [Ca2+]c, thus may down-regulate Ca2+signals by decreasing myofilament Ca2+sensitivity.36,37,71 
Calcium-independent Contraction
Myosin light chain phosphatase inhibitors, PKC activators, and sphingosylphosphorylcholine (a sphingolipid) have been shown to evoke contraction without an increase in [Ca2+]c in VSMCs.72–75 Depending on the stimulants, the Ca2+-independent contraction was associated with or without an increase in MLC20phosphorylation.73,74,76 Its underlying mechanisms and physiologic roles remain to be clarified.73–75 
Other Important Regulatory Mechanisms
Cyclic Nucleotides.
Increases in cyclic guanosine 3′,5′-monophosphate (cGMP) or cyclic adenosine 3′,5′-monophosphate (cAMP) in VSMCs mediates vasodilator response to various mediators such as nitric oxide, carbon monoxide, or natriuretic peptides.77 The cytosolic cGMP level is increased by activation of soluble or membrane-bound guanylyl cyclase,77–81 or inhibition of various phosphodiesterase subtypes,82,83 leading to activation of cGMP-dependent protein kinase (protein kinase G). Activated protein kinase G causes vasodilation via  multiple mechanisms including activation of SERCA, PMCA, K+channels, and MLCP, as well as inhibition of VOCCs and IP3R channels.53,77 Similarly, increased cytosolic cAMP levels lead to activation of cAMP-dependent protein kinase (protein kinase A), which in turn causes vasodilation via  activation of SERCA, PMCA, and K+channels, as well as inhibition of PLC activation, VOCCs, and MLCK activity.23,53,84–86 Protein kinase G can be cross-activated by cAMP,23,77 whereas protein kinase A can be cross-activated by cGMP77,85; either cross-activation would lead to vasodilation.
Tyrosine Kinases, Mitogen-activated Protein Kinases.
Tyrosine kinases, present abundantly in VSMCs, have been suggested to influence both Ca2+mobilization and myofilament Ca2+sensitivity in VSMCs.87,88 Specifically, tyrosine kinase–catalyzed protein tyrosine phosphorylation has been reported to regulate the activity of VOCCs, SOCCs, K+channels, PLC, PLD, and MAPKs in VSMCs.69,87,89 PLD hydrolyzes phosphatidylcholine to generate diacylglycerol, leading to the activation of PKC, whereas MAPKs phosphorylate caldesmon to attenuate its inhibitory action on actomyosin ATPase activity.36 Therefore, tyrosine phosphorylation might be involved in the regulation of myofilament Ca2+sensitivity through the effects on PLD and/or MAPKs.87 The precise roles of tyrosine kinases and MAPKs in the regulation of vascular tone are not fully understood.
Chloride Channels.
Chloride (Cl) channel, abundantly distributed in the VSMC membrane, would play an important role in the regulation of [Ca2+]c.90 There exist at least two types of Clchannels in VSMCs, i.e.  , Ca2+-dependent Cl(ClCa) and volume-regulated Cl(Clv) channels,90 and their activation leads to the activation of VOCCs and membrane depolarization (ECl=−26 mV). The ClCachannels, activatable by an increase in [Ca2+]c,90,91 may contribute to the contractile response to receptor agonists such as norepinephrine in some vascular beds (e.g.  , portal vein,91 small mesenteric arteries27), whereas the Clv channels, activatable by vascular distension, may play a role in maintaining tissue integrity against mechanical stretch.90 
Potassium Channels.
In VSMCs, potassium (K+) channels play a fundamental role in maintaining the membrane potential, a major determinant of vascular tone.92,93 The blockade of K+channels results in membrane depolarization, leading to increased Ca2+influx through VOCCs and possibly enhanced myofilament Ca2+sensitivity,94,95 whereas their activation induces membrane hyperpolarization, leading to reduced Ca2+influx through VOCCs,92,93 inhibited phosphoinositide metabolism,96,97 and suppressed myofilament Ca2+sensitivity.98,99 The activity of K+channels can be altered by various factors, including intracellular Ca2+, ATP, pH, extracellular K+, G proteins, cyclic nucleotides, and protein kinases (e.g.  , protein kinase A, protein kinase G).86,92 The activation of K+channels has been shown to mediate vasodilator responses to various endogenous mediators such as nitric oxide, prostacyclin (PGI2), endothelium-derived hyperpolarizing factor (EDHF), calcitonin gene–related peptide, or β-adrenergic agonists, as well as vasodilator responses to changes in metabolic activity (i.e.  , hypoxia, reactive hyperemia, acidosis, or shock),92,93,100–104 whereas their inhibition may underlie contractile responses to receptor agonists (e.g.  , phenylephrine, arginine vasopressin [AVP], AT-II, thromboxane A2).86,92,105 At least five distinct types of K+channels exist in VSMCs, including voltage-gated K+(KV), Ca2+-activated K+(KCa), ATP-sensitive K+(KATP), inward rectifying K+(Kir), and cGMP-gated K+channels (see review articles92,93,105,106 for details on each type of K+channels).92 
Vascular Endothelium.
In response to various neurohumoral, physical, and chemical stimuli, vascular endothelial cells produce and release a variety of vasoactive factors, including both relaxing factors (e.g.  , nitric oxide, EDHF, PGI2, adenosine) and contracting factors (e.g.  , prostanoids, ET-1).107,108 Physical force exerted by blood flow (i.e.  , shear stress, pulsatile stretch) serves as a stimulus for the endothelial release of nitric oxide, PGI2, and EDHF.107,109–111 Therefore, continual, basal release of those relaxing factors would keep the vasculature in a dilated state, serving as a primary determinant of resting vascular tone.110,112 In addition, they mediate vasodilator responses to various endogenous substances.109,112,113 
Endothelin 1 is the most potent endogenous vasoconstrictor identified to date.114–116 Its synthesis is enhanced by numerous physicochemical factors such as hypoxia, ischemia, shear stress, or inflammatory cytokines and inhibited by atrial natriuretic peptide, nitric oxide, nitroglycerin, PGE2, PGI2, and heparin.114–116 Besides the vasoconstrictor action, ET-1 exerts vasodilator action by stimulating the release of prostanoids, nitric oxide, and/or EDHF from endothelial cells.114,115,117 The endothelium-derived ET-1 would serve as a local regulator of vascular tone by acting on underlying VSMCs to increase vascular tone in a paracrine manner, as well as on endothelial cells to release those vasodilator factors in an autocrine manner.115 In addition, ET-1 would play some key roles in various disease processes including hypertension, myocardial ischemia, heart failure, cerebral vasospasm, endotoxin shock, and liver failure.114,115 
Anesthetic Actions on Vascular Reactivity or Tone
In previous in vitro  or in situ  studies, most general anesthetics affected vasoconstrictor and vasodilator responses to a wide range of both physiologic and pharmacologic stimuli, as well as basal vascular tone (tables 1 and 2). This section reviews such previously observed direct vascular actions of general anesthetics and discusses their in vivo  relevance.
Table 1. Previously Observed Effects of General Anesthetic Agents on Basal Vascular Tone or Vasoconstrictor Response 
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Table 1. Previously Observed Effects of General Anesthetic Agents on Basal Vascular Tone or Vasoconstrictor Response 
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Table 2. Previously Observed Effects of General Anesthetic Agents on Vasodilator Response 
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Table 2. Previously Observed Effects of General Anesthetic Agents on Vasodilator Response 
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In the following sections, the effective concentrations of anesthetics were not necessarily described if they were clinically relevant. Regarding volatile anesthetics, concentrations up to 1.5 minimum alveolar concentration were considered clinically relevant.
Anesthetic Actions on Vasoconstrictor Response
Previous Observations.
Depending on blood vessels, concentrations, or experimental conditions (e.g.  , the presence of endothelium), the contractile responses were enhanced, inhibited, or unaffected by the anesthetics. However, some tendencies exist in the observed anesthetic actions on vasoconstrictor responses in isolated vessels.
Most volatile and intravenous anesthetics inhibited the contractile response to KCl or norepinephrine in either the presence or the absence of endothelium (KCl response  : halothane,118–130 enflurane,131 isoflurane,27,132–134 sevoflurane,25,135 barbiturates,136,137 ketamine,26,138–142 propofol,143–150 etomidate,151 diazepam,152 morphine153,154; norepinephrine response  : halothane,123,125,128,155–157 enflurane,157–160 isoflurane,27,123,125,128,132,133,157,160–162 sevoflurane,25,135,160,163,164 ketamine,26,138,139,141,165 propofol,144,145,147,166–168 etomidate,151 diazepam,152 midazolam,169,170 morphine,153,154 fentanyl171) (table 1). However, all previously investigated intravenous anesthetics inhibited these responses only at concentrations higher than the clinically relevant free anesthetic concentrations (KCl response  : barbiturates,136,137 ≥ 100 μm; ketamine,26,138–142 ≥ 100 μm; propofol,143–150 ≥ 10 μm; etomidate,151 ≥ 100 μm; diazepam,152 ≥ 30 μm; morphine,153,154 ≥ 30 μm; norepinephrine response  : ketamine,26,138,139,141,165 ≥ 10 μm; propofol,144,145,147,166–168 ≥ 1 μm; etomidate,151 ≥ 100 μm; diazepam,152 ≥ 100 μm; midazolam,169,170 ≥ 1 μm; morphine,153,154 ≥ 10 μm; fentanyl,171 ≥ 1 μm).
Previous in vitro  studies123,133–135,156,172–175 have yielded conflicting results regarding endothelium dependence of the anesthetic actions on vasoconstrictor responses, possibly reflecting species or regional differences, or differences in experimental conditions (e.g.  , test stimulants). However, it has been clearly shown that in some vessels, halothane, enflurane, isoflurane, and sevoflurane all enhanced contractile responses to norepinephrine or phenylephrine in an endothelium-dependent manner,133,135,174,176 although the underlying mechanisms have not yet been clarified. In rat small mesenteric arteries, the enhancement by halothane, isoflurane, or sevoflurane was still observed after inhibition of the nitric oxide, EDHF, cyclooxygenase, and lipoxygenase pathways or after blockade of ET-1, AT-II, or serotonin receptors.133,135,176 Therefore, nitric oxide, EDHF, cyclooxygenase products, lipoxygenase products, ET-1, AT-II, and serotonin all would not be involved in the enhancement by those anesthetics.
In isolated rat small mesenteric arteries exposed to halothane, isoflurane, or sevoflurane, the contractile response to norepinephrine was enhanced in the presence of endothelium, but inhibited or unaffected in its absence.133,135,176 However, regardless of the presence or absence of endothelium, the norepinephrine response was inhibited after the removal of either anesthetic from the extracellular space.133,135,176 Therefore, those anesthetics presumably have opposing actions on the contractile response to norepinephrine, i.e.  , endothelium-dependent enhancing and endothelium-independent inhibitory actions. Namely, the former probably predominates or counteracts the latter during exposure to those anesthetics, whereas only the latter seems to persist after their removal. The experiments using fura-2, a fluorescent Ca2+indicator, further suggested that such prolonged inhibitory action of isoflurane on the norepinephrine response is associated with a reduction in the intracellular Ca2+concentration ([Ca2+]i) in VSMCs, possibly due to inhibition of ClCachannels.27 
In Vivo  Relevance.
Plasmalemmal depolarization of VSMCs by KCl activates the VOCCs, which are active in vivo  ,46 presumably contributing to the maintenance of basal vascular tone as the primary source of Ca2+.91 Norepinephrine plays a central role in the sympathetic maintenance of vascular tone. Thus, the inhibitory action of volatile anesthetics on contractile response to KCl or norepinephrine is consistent with their well-recognized vasodilatory properties. However, it was not consistently observed in systemic resistance arteries, particularly in the presence of endothelium.133,135,160,161,163,176 Therefore, it seems unclear whether the direct action of volatile anesthetics on VSMCs contributes to systemic hypotension during their administration. However, prolonged systemic hypotension observed after anesthesia with halothane, isoflurane, or sevoflurane10,47 might be due, in part, to their direct inhibitory action on the norepinephrine response, i.e.  , the persistent hyporesponsiveness to norepinephrine after their removal from the extracellular space.133,135,176 In addition, the enhanced contractile response to norepinephrine and the inhibited endothelial nitric oxide or EDHF-mediated vasodilator response during exposure to halothane observed in isolated mesenteric resistance arteries176 might contribute to a decrease in intestinal blood flow associated with an increase in intestinal vascular resistance during anesthesia with halothane.177 
The in vivo  relevance of the above-described direct vasodilator actions of intravenous anesthetics is unclear because of their effective concentrations.
Anesthetic Effects on Vasodilator Response
Previous Observations.
In previous in vitro  or in situ  studies, all currently used volatile anesthetics and some intravenous anesthetics inhibited various vasodilator responses, such as those mediated by nitric oxide, EDHF, carbon monoxide, β-adrenoceptor agonists, and KATPchannels (table 2).
In most previous studies, halothane,156,178–183 enflurane,160,178 isoflurane,133,160,178,184 desflurane,177 sevoflurane,135,160,163,180,185,186 thiopental,187 ketamine,188 propofol,189–191 and etomidate188,192–194 inhibited endothelium-dependent, presumed nitric oxide–mediated vasodilator responses (table 2). However, most of those anesthetics did not inhibit the endothelium-independent vasodilator response to nitrovasodilators (table 2) and the associated increases in cGMP level in VSMCs.156,160,163,177,178,180,183,185–187,192,194–196 In addition, most of them inhibited the endothelial nitric oxide–mediated vasodilator response to both receptor agonists and A23187 (i.e.  , Ca2+ionophore) (table 2).178,185,187,194 Therefore, those anesthetics presumably inhibit the nitric oxide–guanylyl cyclase signaling distal to receptor activation in the endothelial cell and proximal to the nitric oxide activation of guanylyl cyclase.78,178,196 This idea is consistent with recent observations that they inhibited Ca2+mobilization induced by nitric oxide–releasing agonists in endothelial cells.188,197–202 However, in some previous studies using isolated aorta,179,203 halothane inhibited the endothelium-independent vasodilator response to nitric oxide and the associated increases in cGMP level in VSMCs. Therefore, halothane may interfere with the nitric oxide activation of guanylyl cyclase, depending on the experimental condition.
In experiments with isolated rat aorta,181,204 halothane inhibited the endothelial nitric oxide–mediated vasodilator response to acetylcholine181,204 and the associated increases in cGMP level in VSMCs,204 but it did not affect the endothelial nitric oxide–mediated vasodilator response to isoproterenol and the associated increases in cGMP level in VSMCs.181 Therefore, halothane may inhibit some mechanisms specifically involved in the cholinergic receptor–mediated nitric oxide production but not in the β-adrenoceptor–mediated nitric oxide production in endothelial cells.181 
Besides the endothelial nitric oxide–mediated vasodilator response, some general anesthetics (halothane,177,182 enflurane,160,177 isoflurane,160,177,192 desflurane,177 sevoflurane,160,177 thiopental,192,193 ketamine,188 etomidate188,192,193) inhibited the EDHF-mediated vasodilator response. However, it has not yet been shown that they inhibit the EDHF-mediated hyperpolarization of the VSMC membrane. Conversely, in rabbit mesenteric arteries, propofol (10 μm) did not influence acetylcholine-induced, EDHF-mediated hyperpolarization, but inhibited acetylcholine-induced, prostanoid-mediated hyperpolarization.190 
Again, the intravenous anesthetics exerted their inhibitory actions on either the nitric oxide–mediated or EDHF-mediated vasodilator response only at the supraclinical concentrations (i.e.  , thiopental,187,192,193 ≥ 30 μm; ketamine,188 ≥ 100 μm; propofol,189 ≥ 1 μm; etomidate,188,192,193 ≥ 30 μm).
Halothane and isoflurane also inhibited vasodilator responses to β-adrenoceptor agonists and the associated increase in cAMP level in VSMCs.205,206 However, both anesthetics had little effect on the decreases in force and [Ca2+]i induced by forskolin (i.e.  , adenylyl cyclase activator) or dibutyryl cAMP (i.e.  , membrane-permeable cAMP analog). They also did not affect the forskolin-induced increases in cAMP levels. Furthermore, they did not affect β-adrenoceptor binding characteristics and affinity for agonists. Therefore, halothane and isoflurane presumably inhibit the β-adrenoceptor–mediated vasodilator response distal to agonist–receptor binding and proximal to adenylyl cyclase activation.206 
The KATPchannels, activatable by depletion of intracellular ATP, mediate vasodilator responses to changes in metabolic activity (i.e.  , hypoxia) and those to various endogenous mediators such as adenosine, nitric oxide, or β agonists.92,100–104 In coronary circulation, the KATPchannels are active under resting conditions, contributing to the maintenance of resting vascular tone.92 Previous in vivo  studies using beating hearts have proposed that volatile anesthetics (i.e.  , halothane,207,208 isoflurane,208,209 enflurane,208 desflurane,210 sevoflurane210) cause coronary vasodilation through activation of KATPchannels. In addition, previous in situ  studies using superperfused mesenteric vascular beds211,212 have proposed that isoflurane hyperpolarizes VSMCs by activating KATPchannels. By contrast, in previous in vivo  and in vitro  studies using pulmonary vessels, halothane,213,214 isoflurane,215 enflurane,213 and desflurane,216 but not sevoflurane,216 attenuated vasodilator responses to lemakalim, a KATPchannel activator. Ketamine (≥ 10 μm) and etomidate (≥ 50 μm) also inhibited the vasodilator response to lemakalim in isolated endothelium-denuded pulmonary arteries.217 However, to my knowledge, there is currently no electrophysiologic evidence indicating that those anesthetics directly influence KATPchannel activity in VSMCs.
In Vivo  Relevance.
Vasodilator responses to nitric oxide, EDHF, carbon monoxide, β-adrenoceptor agonists, and KATPchannels are believed to play important roles in the physiologic regulation of vascular tone. However, in vivo  relevance of the above-described inhibitory actions of general anesthetics on those vasodilator responses remains to be elucidated, as discussed later.
Anesthetic Effects on Basal Vascular Tone
Previous Observations.
Some general anesthetics increased basal vascular tone in vitro  (halothane,125,130,218–220 enflurane,160,218,220 thiopental,221,222 propofol,223,224 morphine225). In isolated small mesenteric arteries, halothane and enflurane caused transient contractions, which were eliminated by ryanodine, which depletes the SR.130,219,220 Therefore, in those arteries, both the anesthetics presumably stimulate Ca2+release from the ryanodine-sensitive SR and cause contraction.130,219,220 However, in conduit arteries, the volatile anesthetic–induced contractions were only partially inhibited by ryanodine.125,218 Some differences may exist in vascular responsiveness to volatile anesthetics between conduit and resistance arteries.
The thiopental (≥ 30 μm)221,222 – and morphine (≥ 30 μm)225 –induced contractions observed in isolated rat aorta and basilar artery, respectively, seemed to be due to increases in [Ca2+]c resulting from either Ca2+release from the SR221 or plasmalemmal Ca2+influx.222,225 
In isolated canine epicardial coronary arteries, propofol increased basal vascular tone at clinical concentrations (i.e.  , < 1 μm) but decreased at higher concentrations (≥ 100 μm).224 The propofol-induced sustained increase in force was independent of endothelium and inhibited by the removal of extracellular Ca2+or verapamil, suggesting that propofol activates VOCCs and thereby increases vascular tone.224 By contrast, in human omental arteries and veins, propofol caused sustained increases in basal vascular tone at a high concentration (1 mm).223 Species or regional differences may exist in vascular sensitivity to propofol.
In Vivo  Relevance.
The vascular tone in vivo  is determined by the net balance between various vasoconstrictor and vasodilator stimuli. Even in the resting condition, the sympathetic vasoconstrictor system is continually active, maintaining a partial state of contraction in the blood vessels. Therefore, in vivo  relevance of the above-described anesthetic actions on basal vascular tone observed in vitro  is unclear. However, they would suggest that besides the vasodilatory actions, some general anesthetics possess vasoconstrictor actions, possibly contributing to the anesthetic-induced changes in vascular tone in vivo  .
Mechanisms behind Direct Actions of General Anesthetics on Vascular Smooth Muscle: Overview
To investigate the mechanisms behind direct vasodilator action of general anesthetics, previous studies25–27,125,140,145,170,220,226–232 evaluated their actions on receptor agonist- or KCl-induced increases in force and [Ca2+]i in VSMCs loaded with Ca2+-sensitive fluorescent dyes (e.g.  , fura-2). Previous studies118,127,159,162,165,230,233,234 also evaluated the anesthetic actions on Ca2+-induced contraction in VSMCs permeabilized with chemical detergents (e.g.  , saponin, β-escin). To summarize the results of those previous studies, the vasodilator action of volatile anesthetics including halothane,118,125,127,226,228–230,232–234 enflurane,127,159 isoflurane,27,162,228,234,235 and sevoflurane25 is presumably due to both a reduction in [Ca2+]c and inhibition of myofilament Ca2+sensitivity, whereas that of ketamine26,140 or midazolam170 is due largely to a reduction in [Ca2+]c. Interestingly, in isolated pulmonary arteries depolarized with KCl, propofol reduced [Ca2+]i while increasing myofilament Ca2+sensitivity, leading to a depressed contractile response to KCl.143 Less information is available regarding the mechanisms behind previously observed direct vasodilator actions of barbiturates, etomidate, diazepam, morphine, and fentanyl (table 1).
Recent studies utilizing fura-2 fluorometry25,27,129 have suggested that the underlying mechanisms may depend on the concentrations of volatile anesthetics. Namely, in isolated small mesenteric arteries, the depressed contractile response to KCl by lower concentrations of halothane (≤ 2.5%, approximately 0.7 mm), isoflurane (3%, approximately 0.6 mm), and sevoflurane (3%, approximately 0.4 mm) seemed to be due to inhibition of the myofilament Ca2+sensitivity, whereas that by higher concentrations of halothane (4.5%, approximately 1.4 mm), isoflurane (5%, approximately 1.0 mm), and sevoflurane (5%, approximately 0.7 mm) seem to arise by both a reduction in [Ca2+]c and inhibition of myofilament Ca2+sensitivity.25,27,129 
The following two sections review the previously observed general anesthetic actions on Ca2+mobilization and myofilament Ca2+sensitivity in VSMCs and discuss the mechanisms underlying the direct inhibitory or excitatory actions of general anesthetics on VSMCs.
Mechanisms behind General Anesthetic–induced Changes in Calcium Mobilization
Previous experiments using VSMCs loaded with fluorescent Ca2+-indicators or 45Ca2+have provided convincing evidence to indicate that various general anesthetics reduce the [Ca2+]c by inhibiting Ca2+release from the SR and/or plasmalemmal Ca2+influx (halothane,125,132,220,226,228,229,236 isoflurane,27,125,132,227,228,232,236 sevoflurane,25,220 pentobarbital,137 ketamine,26,140,237 propofol,143,145,231,238,239 midazolam170) (table 3).
Table 3. Proposed Effects of Anesthetic Agents on Cellular Mechanisms Involved in Vasoconstrictor Response 
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Table 3. Proposed Effects of Anesthetic Agents on Cellular Mechanisms Involved in Vasoconstrictor Response 
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Anesthetic Effects on the Phosphatidylinositol Cascade
Some general anesthetics have been suggested to reduce the [Ca2+]c in VSMCs by inhibiting the phosphatidylinositol cascade.139,140,145,226,227,238–240 
Previous Observations.
Halothane,226 isoflurane,227 and propofol (≥10 μm)238–240 inhibited inositol phosphate (IP) production in cultured rat aortic VSMCs (A7r5, A10) stimulated with AVP or ET-1. Ketamine (≥ 100 μm) and propofol (≥ 30 μm) also inhibited the IP production in arterial VSM tissues stimulated with phenylephrine or norepinephrine.139,140,145 However, in rat aortic VSM tissue, both halothane and isoflurane did not affect the norepinephrine-induced, presumed IP3-induced Ca2+release from SR.132 
Interpretations.
During receptor stimulation, the above anesthetics may interfere with PLC-mediated PIP2hydrolysis (i.e.  , synthesis of IP3and diacylglycerol), thereby inhibiting the IICR from SR and possibly the receptor-operated Ca2+influx through SMOCCs. However, the inability of halothane and isoflurane to inhibit norepinephrine-induced Ca2+release132 suggests that they may inhibit some mechanisms specifically involved in AVP-induced PIP2breakdown but not in norepinephrine-induced PIP2breakdown. Alternatively, the difference may reflect the difference in vascular responsiveness to those anesthetics between cultured VSMCs and intact VSM tissues, or the difference in the experimental condition.
Anesthetic Effects on the Intracellular Calcium Stores (SR)
General anesthetics have been proposed to influence Ca2+mobilization by impairing functional integrity of the SR in VSMCs.118,132,159,162,219,220,230,236 In most previous studies evaluating the anesthetic effects on Ca2+uptake into the SR in VSMCs, the amount of Ca2+in the SR was estimated by vascular responses to caffeine after removal of extracellular Ca2+.
The relative importance of intracellular and extracellular Ca2+pools in the excitation–contraction coupling in VSMCs seems to vary in different vascular beds.91 For example, Ca2+release from the SR seems to be of considerably less importance than plasmalemmal Ca2+influx for development of contractile force in small mesenteric arteries,25–27,91 whereas it presumably plays a central role in contractile responses to agonists in portal veins.91 Therefore, pharmacologic significance of the previously observed general anesthetic actions on SR would depend on the type of blood vessels.
Volatile Anesthetics.
Previous Observations.
In previous contraction and Ca2+measurement experiments with isolated conduit or resistance arteries, halothane118,127,218–220,230,236 and enflurane127,159,218,220 caused transient increases in [Ca2+]i and/or force in the absence of extracellular Ca2+in VSMCs with the SR sensitive to ryanodine and/or caffeine. Similar results were obtained with isoflurane, although the effect was smaller than halothane or enflurane, and observed only at low temperatures (22°–23°C)127,162 but not at a higher temperature (35°C).220 In mesenteric arterial VSMCs,219,220 if the Ca2+-releasing action of halothane or enflurane was blocked by procaine, either anesthetic stimulated Ca2+uptake by the ryanodine-sensitive SR; their overall effects, when applied during Ca2+loading, were to reduce the amount of Ca2+in the SR.219,220 In membrane-permeabilized VSMCs,219 the Ca2+-releasing action of halothane was not blocked by heparin, a specific inhibitor of the IICR.241 
Previous studies also evaluated the effects of various anesthetics on Ca2+-releasing mechanisms (e.g.  , Ca2+release induced by caffeine, receptor agonists, or IP3) in VSMCs. In both conduit or resistance arteries, halothane, enflurane, and isoflurane all enhanced the increase in [Ca2+]i and/or the force induced by caffeine.118,132,159,162,220,230 In addition, in previous contraction studies with conduit arteries, these anesthetics seemed to facilitate the ryanodine depletion of SR.118,159,162 Interestingly, sevoflurane attenuated the caffeine-induced Ca2+release from the SR, whereas it enhanced the norepinephrine-induced Ca2+release from the SR.220 
Interpretations.
The above results118,127,159,218–220,230,236 suggest that both halothane and enflurane stimulate Ca2+release from the ryanodine-sensitive SR in VSMCs. In addition, their ability to stimulate Ca2+uptake into the SR after blockade of their Ca2+releasing action219,220 indicates that both the anesthetics actually have opposing actions on the amount of Ca2+in the SR, i.e.  , the Ca2+-releasing action and a stimulating action on Ca2+uptake. Their overall effects were to reduce the amount of Ca2+in the SR,219,220 which would influence vascular reactivity by decreasing Ca2+availability and enhancing the Ca2+-buffering capacity.
The inability of isoflurane or sevoflurane to stimulate Ca2+release from the SR or Ca2+uptake by the SR at 35°C220suggests that they would not alter the amount of Ca2+stored in the SR under physiologic conditions. The ability of isoflurane to stimulate Ca2+release from the ryanodine-sensitive SR at 22°–23°C127,162 could be due to the increased aqueous concentrations or increased vascular sensitivity to isoflurane at the low temperatures.
The ability of halothane, enflurane, and isoflurane to stimulate Ca2+release from the SR in membrane-permeabilized VSMCs18,127,159,162,219,230 suggests that their Ca2+releasing actions are, at least in part, independent of the intact plasma membrane. Although the Ca2+releasing actions of halothane and enflurane were blocked by procaine,219,220 the nonspecific nature of its blocking action did not allow us to definitely characterize their Ca2+releasing action. However, the lack of effect of heparin on halothane-induced Ca2+release219 indicates that the halothane-induced Ca2+release can occur independently of IP3production.
Because ryanodine depletes the SR by binding to the RYR/Ca2+-release channels in an open state and then locking them open,38 the ability of halothane, enflurane, and isoflurane to facilitate the ryanodine depletion of SR118,159,162 suggests that those anesthetics stimulate the opening of RYR/Ca2+-release channels (i.e.  , CICR). Therefore, their ability to enhance caffeine-induced Ca2+release (i.e.  , Ca2+release from the ryanodine-sensitive SR)118,132,159,162,220,230 could be a result of the activation of the RYR/Ca2+-release channels. By contrast, the ability of sevoflurane to attenuate caffeine-induced Ca2+release and to enhance norepinephrine-induced Ca2+release suggests that it inhibits the CICR, whereas it enhances the IICR.220 There is no definitive evidence to date that those anesthetics directly act on the SR and alter its CICR or IICR channel activity in VSMCs. Further studies using isolated SR vesicles from VSMCs or membrane-permeabilized VSMCs would be necessary to clarify the underlying mechanisms.
In conclusion, halogenated volatile anesthetics would alter the [Ca2+]c and hence vascular reactivity through direct actions on the SR in VSMCs. Indeed, the depletion of SR altered their actions on vascular reactivity (e.g.  , contractile response to norepinephrine).132,176 
Intravenous Anesthetics.
Previous Observations.
Ketamine (≥ 300 μm) inhibited α-adrenergic agonist–induced synthesis of IP or IP3in femoral and mesenteric arterial VSMCs.139,140 However, ketamine (1 mm) did not affect the IICR in membrane-permeabilized VSMCs.165 In addition, in isolated mesenteric arteries, ketamine (1 mm) did not affect caffeine-induced Ca2+release.26,165 
In cultured aortic VSMCs, propofol (≥ 10 μm) also inhibited IP production during stimulation with receptor agonists (i.e.  , ET-1, AVP).239,240 In support of this finding, in VSMCs of isolated mesenteric arteries, propofol (≥ 30 μm) inhibited norepinephrine-induced Ca2+release from the SR; however, it did not affect caffeine-induced Ca2+release even at 100 μm.145 Similarly, in VSMCs of isolated mesenteric arteries, midazolam (≥ 1 μm) inhibited norepinephrine-induced, but not caffeine-induced, Ca2+release from the SR.170 
Interpretations.
The ability of ketamine to inhibit the synthesis of IP or IP3139,140 suggests that ketamine attenuates the IICR by inhibiting PLC-mediated PIP2breakdown. However, its inability to influence IICR in membrane-permeabilized VSMCs165 suggests that ketamine does not directly influence IICR. In addition, its inability to influence the caffeine-induced Ca2+release26,165 indicates the lack of effects of ketamine on the CICR.
The ability of propofol to inhibit IP production239,240 and the norepinephrine-induced Ca2+release145 suggests that propofol also attenuates IICR by inhibiting PLC-mediated IP3production. However, its inability to influence the caffeine-induced Ca2+release suggests that propofol does not affect the CICR.145 The previous result on midazolam170 suggests that midazolam also inhibits IICR but not CICR.
Previous studies have failed to demonstrate that any of the intravenous anesthetics influence functional integrity of the SR at clinically relevant free concentrations, and in vivo  relevance of the above-described intravenous anesthetic actions on SR is currently unclear.
Anesthetic Effects on the Plasmalemmal Calcium Influx through VOCCs
Both volatile and intravenous anesthetics have been suggested to inhibit plasmalemmal Ca2+influx through VOCCs, thereby reducing [Ca2+]c in VSMCs.
Volatile Anesthetics.
Previous Observations.
In earlier studies118,119,121,124,242,243 using isolated aorta or coronary arteries, halothane, enflurane, isoflurane, and sevoflurane all inhibited the contractile response to KCl, suggesting that they inhibit plasmalemmal Ca2+influx through VOCCs. In direct proof of this proposal, by using the whole cell mode of single cell patch clamp technique, Buljubasic et al.  244,245 showed that both halothane and isoflurane inhibited the L-type voltage-dependent Ca2+currents in VSMCs dispersed from cerebral or coronary arteries. This finding was subsequently confirmed in portal venous VSMCs.246,247 In addition, in fura-2–loaded VSMCs of aorta and small mesenteric arteries, halothane, isoflurane, and sevoflurane inhibited KCl-induced increases in [Ca2+]i, mimicking the effects of VOCC blockers.25,27,125,132 
Interpretations.
The above results suggest that most volatile anesthetics inhibit VOCC activity. However, the underlying mechanisms are currently unknown. Because the anesthetic effects have not yet been examined on single-channel activity, it is unclear whether they directly inhibit VOCC activity or indirectly via  diffusible second messengers. Both halothane and isoflurane were previously reported to increase basal cytosolic cAMP or cGMP levels in aortic VSMCs.120,248 Therefore, they may indirectly inhibit VOCC activity by increasing cytosolic cAMP and/or cGMP levels. However, sevoflurane did not increase basal cytosolic cGMP levels in aortic VSMCs.180 
Intravenous Anesthetics.
Previous Observations.
Pentobarbital (≥ 100 μm),137 ketamine (≥ 100 μm),138,141,142,165,249,250 propofol (≥ 10 μm),147,148 diazepam (≥ 30 μm),152 and midazolam (≥ 10 μm)169 inhibited the contractile response to KCl. In patch clamp experiments using VSMCs dispersed from the portal vein,249,251 ketamine (≥ 10 μm) inhibited the whole cell L-type voltage-dependent Ca2+currents. In addition, in experiments with 45Ca2+or Ca2+-sensitive fluorescent dyes, ketamine (≥ 100 μm),26,140 propofol (≥ 10 μm),145,238 and midazolam (≥ 10 μm)170 inhibited plasmalemmal Ca2+influx induced by KCl26,145,170 or that sensitive to VOCC blockers in VSMCs.238 
Interpretations.
These results suggest that some intravenous anesthetics may also inhibit VOCC activity. However, to my knowledge, to date, electrophysiologic studies have not yet been conducted on the above intravenous anesthetics except ketamine to directly prove their inhibitory action on VOCC activity in VSMCs.
Anesthetic Effects on the Plasmalemmal Calcium Influx through ROCCs
General anesthetics have also been suggested to influence plasmalemmal Ca2+influx through ROCCs, thereby altering the [Ca2+]c in VSMCs.
Volatile Anesthetics.
Previous Observations.
In cultured aortic VSMCs loaded with indo-1 or fura-2, both halothane and isoflurane inhibited plasmalemmal Ca2+influx induced by receptor agonists (i.e.  , AVP, platelet-derived growth factor, AT-II).226,227,229,232 Isoflurane and sevoflurane also inhibited norepinephrine-induced plasmalemmal Ca2+influx in fura-2–loaded VSMCs of isolated mesenteric arteries.25,27 By contrast, in contraction and 45Ca2+studies using isolated aorta,252,253 both halothane and isoflurane stimulated plasmalemmal Ca2+influx sensitive to SKF-96365, a putative inhibitor of ROCCs.254,255 
Interpretations.
The ability of halothane, isoflurane, and sevoflurane to inhibit receptor agonist–induced Ca2+influx suggests that they inhibit ROCC activity. However, plasmalemmal Ca2+influx induced by some receptor agonists (e.g.  , norepinephrine) has been shown to be eliminated by VOCC blockers,25,27,170 apparently suggesting that it is mediated exclusively by VOCCs. Therefore, the above results might have simply reflected the anesthetic effects on VOCCs. However, activation of the ligand-gated nonselective cation channels, a type of ROCCs, and resultant membrane depolarization may precede the activation of VOCCs during receptor stimulation.91 Thus, there remains a possibility that the volatile anesthetics inhibit receptor agonist–induced Ca2+influx through VOCCs by inhibiting activity of nonselective cation channels.
On the basis of sensitivity to SKF-96365, both halothane and isoflurane have been proposed to stimulate the Ca2+influx through ROCCs.252,253 However, recent evidence indicates that SKF-96365 does not serve as a selective inhibitor of the ROCCs in VSMCs.27 
At this time, there is no electrophysiologic evidence to indicate that volatile anesthetics alter the ROCC activity in VSMCs. This topic should be the subject of future studies.
Intravenous Anesthetics.
Previous Observations.
In earlier contraction studies, thiamylal (1 mm),136 pentobarbital (≥ 300 μm),136 ketamine (≥ 30 μm),138,165 propofol (≥ 1 μm),147 and midazolam (≥ 30 μm)169 inhibited extracellular Ca2+-dependent responses to receptor agonists (i.e.  , prostaglandin F2α, norepinephrine, histamine). In recent Ca2+measurement studies, pentobarbital (≥ 100 μm),137 ketamine (≥ 300 μm),26 propofol (≥ 10 μm),145,231 and midazolam (≥ 30 μm)170 inhibited the agonist (e.g.  , serotonin, norepinephrine, AT-II)–induced plasmalemmal Ca2+influx.
Interpretations.
These results suggest that intravenous anesthetics may also inhibit ROCC activity, thereby reducing the [Ca2+]c. However, again, to date, electrophysiologic experiments have not yet been conducted definitively to prove these hypotheses.
Anesthetic Effects on the Plasmalemmal Calcium Influx through SOCCs
Less information is available regarding general anesthetic actions on plasmalemmal Ca2+influx through SOCCs. However, some general anesthetics have been suggested to influence activity of SOCCs, thereby altering the [Ca2+]c in VSMCs.
Previous Observations.
In cultured aortic VSMCs loaded with indo-1 or fura-2, isoflurane (≥ 1.5%) inhibited plasmalemmal Ca2+influx activated after depletion of the SR by thapsigargin.227,232 In a previous study with cultured aortic VSMCs loaded with fura-2, propofol (56 μm) did not affect the thapsigargin-induced Ca2+influx.238 However, in recent studies using cultured aortic or pulmonary arterial VSMCs loaded with fura-2, propofol (aorta, ≥ 56 μm; pulmonary artery, ≥ 1 μm) inhibited the thapsigargin-induced Ca2+influx.89,231 By contrast, thiopental (approximately 0.42 mm) was recently proposed to deplete the SR and thereby activate SOCCs, increasing vascular tone in isolated aorta.222 
Interpretations.
These results suggest that the SOCCs are potential targets for general anesthetic agents. However, there is currently no electrophysiologic evidence to support this hypothesis, and this topic also should be the subject to future investigations.
Anesthetic Effects on Mechanisms Reducing the Cytosolic Calcium Level
Stimulation and inhibition of the [Ca2+]c-reducing mechanisms (i.e.  , SERCA-mediated Ca2+uptake into the SR, PMCA-mediated plasmalemmal Ca2+extrusion, Na+–Ca2+exchanger) in VSMCs would lead to vasodilation and vasoconstriction, respectively. Less information is available regarding general anesthetic actions on those mechanisms.
Volatile Anesthetics.
Previous Observations.
In both conduit and resistance arteries, halothane and enflurane, applied during Ca2+loading, decreased the amount of Ca2+loaded in the SR (as judged by the response to caffeine).118,159,162,219,220,256 However, as mentioned above, these anesthetics, applied during Ca2+loading after blockade of their Ca2+-releasing action, conversely increased the amount of Ca2+in SR.219,220 By contrast, in previous experiments performed at 35°–37°C,220,256 neither isoflurane nor sevoflurane, applied during Ca2+loading, affected the amount of Ca2+in SR.
In our recent studies with isolated small mesenteric arteries,176 halothane prolonged vasorelaxation following cessation of stimulation with norepinephrine, and the prolongation was eliminated by treatment with vanadate, a putative inhibitor of the PMCA.
Interpretations.
The ability of halothane and enflurane to inhibit Ca2+loading into the SR118,159,162,219,220,256 apparently suggests that these anesthetics inhibit SERCA activity. However, their ability to conversely increase the Ca2+loading after blockade of their Ca2+-releasing action219,220 indicates that both halothane and enflurane actually stimulate SERCA activity, and that the inhibition of Ca2+uptake by those anesthetics (observed before blockade of their Ca2+-releasing action) was due to their Ca2+-releasing action118,127,159,218–220,230,236 but not due to inhibition of SERCA activity.219,220 The stimulated SERCA-mediated Ca2+uptake into the SR may underlie vascular reactivity during exposure to halothane176 or enflurane. By contrast, the previous results220,256 suggest that neither isoflurane nor sevoflurane affects the SERCA activity at physiologic temperatures. To my knowledge, no direct evidence is currently available to indicate that volatile anesthetics modulate SERCA activity, and further studies using isolated SR vesicles from VSMCs would be essential to clarify this issue.
Volatile anesthetics inhibit PMCA activity in erythrocytes or neuronal cells,257,258 and the Na+–Ca2+exchanger in cardiac cells.259 However, little information is available regarding volatile anesthetic action on those plasmalemmal Ca2+extrusion mechanisms in VSMCs. On the basis of the sensitivity to vanadate, we recently proposed that halothane inhibits PMCA activity in VSMCs.176 However, because of vanadate’s nonspecific nature as a pharmacologic tool,260–262 further investigations are necessary to prove our proposal definitively.
Intravenous Anesthetics.
Previous Observations.
In previous contraction and 45Ca2+studies using isolated mesenteric arteries165 or cultured aortic VSMCs,237 ketamine (1 mm) did not affect Ca2+uptake into the SR under membrane-permeabilized conditions. In addition, in a 45Ca2+study with membrane-intact cultured aortic VSMCs,237 ketamine did not affect plasmalemmal Ca2+extrusion. However, in a contraction study with isolated pulmonary arteries, the vasodilator action of ketamine was attenuated by both ruthenium red (100 μm) and La3+(0.1–10 mm), a putative inhibitor of Ca2+ATPase and ATP-dependent Ca2+extrusion, respectively.250 
In fura-2–loaded mesenteric arterial VSMCs, propofol (≥ 10 μm) increased the resting [Ca2+]i level after depletion of the SR and inhibition of plasmalemmal Ca2+influx.145 
Interpretations.
On the basis of sensitivity to ruthenium red and La3+, ketamine was proposed to enhance PMCA activity in pulmonary arterial VSMCs,250 which is inconsistent with the results obtained in cultured aortic VSMCs.237 However, the nonspecific nature of both ruthenium red and La3+(e.g.  , inhibitions of plasmalemmal Ca2+influx263,264 and RYR/Ca2+release channel activity265) would limit the interpretation of the data obtained with those inhibitors. The ability of propofol to increase the resting [Ca2+]i level in the absence of a functional SR and plasmalemmal Ca2+influx145 suggests that propofol inhibits PMCA activity. Further studies using plasma membrane fractions from VSMCs would be necessary to directly evaluate the anesthetic actions on PMCA activity and definitively prove those previous proposals.145,176,237,250 
Anesthetic Effects on Cytosolic Calcium Oscillations
Rhythmic oscillations have been observed in contractile responses to a wide variety of agonists in isolated vessels.54,55,57,157,266,267 Correspondingly, oscillatory changes in vessel diameter, blood flow, or even oxygen tension have been observed in vivo  .268–272 The oscillatory activity is especially evident in small arteries and arterioles55,56,161; however, its functional importance is still a matter of debate. It might be effective in regulating vascular resistance without disturbing tissue perfusion, minimizing fluid filtration into the extravascular space by reducing hydrostatic pressure, and enhancing lymphatic drainage through the pumping action of closely adjacent arterioles.273–275 The cellular mechanisms behind oscillatory contractile responses have not been fully clarified. However, they would correlate with cytosolic Ca2+oscillations in VSMCs.58,276,277 
Previous Observations.
In previous contraction studies with isolated small mesenteric arteries and veins,130,133,135,157,161 volatile anesthetics (i.e.  , halothane, enflurane, isoflurane, sevoflurane) potently inhibited rhythmic oscillations during the contractile response to norepinephrine. Ketamine (≥ 10 μm), thiopental (≥ 3 μm), lorazepam (≥1 μm), diazepam (0.3 μm), and midazolam (≥100 μm) inhibited the cytosolic Ca2+oscillations in cultured pulmonary arterial VSMCs loaded with fura-2.278,279 Under the same experimental conditions, propofol (≥10 μm), applied in its commercially available 10% Intralipid® emulsion (Kabi Pharmacia AB, Stockholm, Sweden), also inhibited the Ca2+oscillations.278 
Interpretations.
The anesthetic-induced inhibition of oscillatory vasomotion could result in alterations of vascular homeostasis such as fine control of tissue blood flow or vascular permeability. To my knowledge, volatile anesthetics have not yet been shown to inhibit cytosolic Ca2+oscillations in VSMCs. They may inhibit cytosolic Ca2+oscillations through effects on the SR, VOCCs, K+channels, ClCachannels, endothelium, and/or gap junctions, all of which have been proposed to be involved in the generation of cytosolic Ca2+oscillations,54–61 and to be targets for volatile anesthetics.27,118,220,244,245,280,281 The cellular mechanisms of anesthetic-induced inhibition of oscillatory vasomotion or cytosolic Ca2+oscillations in VSMCs remain to be elucidated.
Mechanisms behind General Anesthetic–induced Changes in Myofilament Calcium Sensitivity
General anesthetics have been proposed to significantly influence (either inhibit or enhance) the myofilament Ca2+sensitivity of VSMCs in either absence or presence of receptor stimulation (table 3). However, the underlying mechanisms are not well understood.
Anesthetic Effects on the Myofilament Calcium Sensitivity in the Absence of Receptor Stimulation
There is increasing evidence that volatile anesthetics affect Ca2+activation of contractile proteins (i.e.  , basal myofilament Ca2+sensitivity) in VSMCs. However, data are limited regarding the effects of intravenous anesthetics on the Ca2+activation of contractile proteins.
Volatile Anesthetics.
Previous Observations.
In isolated aorta, pulmonary arteries, and small mesenteric arteries, halothane inhibited the [Ca2+]i–force relation in VSMCs loaded with fura-2, or the Ca2+-induced contractions in VSMCs permeabilized with saponin or β-escin.118,125,127,129,233,234,282 However, in pulmonary arterial, saponin-permeabilized VSMCs, halothane enhanced the Ca2+-induced contraction (at 21°–23°C); however, it was transient and followed by sustained inhibition.230,233 
In rat mesenteric arterial, fura-2–loaded VSMCs, during KCl depolarization, halothane (0.5–4.5%) markedly shifted the [Ca2+]i–force relation as well as the MLC phosphorylation–force relation to the right without altering the MLC phosphorylation level or the [Ca2+]i–MLC phosphorylation relation.129 However, in rat aortic VSMCs loaded with fura PE3 (a fura-2 derivative), halothane did not alter the [Ca2+]i–force relation during KCl depolarization.282 
In isolated small mesenteric arteries, enflurane inhibited the Ca2+-induced contraction in VSMCs permeabilized with β-escin.127 
In isolated aorta, pulmonary arteries, and small mesenteric arteries, isoflurane also inhibited the [Ca2+]i–force relation in fura-2–loaded VSMCs,27,125 or Ca2+-induced contraction in saponin-permeabilized VSMCs.234,235 However, in femoral or pulmonary arterial VSMCs permeabilized with saponin, isoflurane conversely enhanced the Ca2+-induced contraction (at 21°–23°C); it was sustained in the femoral arterial VSMCs,283 whereas it was transient and followed by sustained inhibition in pulmonary arterial VSMCs.235 
In isolated rat small mesenteric arteries, isoflurane and sevoflurane inhibited the [Ca2+]i–force relation only in the fura-2–loaded, membrane-intact VSMCs, but not in the β-escin–membrane-permeabilized VSMCs.25,27 
Interpretations.
The above results suggest that halothane, enflurane, isoflurane, and sevoflurane inhibit the Ca2+activation of contractile proteins. However, the underlying mechanisms are not well understood. In earlier studies, halothane and isoflurane stimulated formation of either cAMP or cGMP in aortic VSMCs,120,248 suggesting that increased cAMP or cGMP levels, which reduce the Ca2+/MLCK-dependent phosphorylation of MLC20,21,23,37,77,85 might be involved in their inhibition of Ca2+activation of contractile proteins. However, more recent studies have failed to confirm their ability (halothane,179,196,204,206,228 isoflurane,172,196,204,206,228 sevoflurane180) to stimulate the formation of either cyclic nucleotide in aortic VSMCs. Because all those results were obtained in rat aortic VSMCs, the discrepancies might be explained by differences in experimental conditions (e.g.  , endothelial intactness, cultured VSMCs vs.  fresh VSM tissue).
Su et al.  230,233,235,283 reported the ability of halothane or isoflurane to enhance the contractile response to Ca2+in pulmonary or femoral arterial, membrane-permeabilized VSMCs. In pulmonary arterial VSMCs, the enhancement was followed by sustained inhibition,230,233,235 but not in femoral arterial VSMCs,283 suggesting differences in vascular responsiveness to volatile anesthetics between vascular beds. On the basis of sensitivity to PKC inhibitors (i.e.  , bisindolylmaleimide 1 [0.1–10 μm], Gö-6976 [0.1–10 μm]) and a CaMKII inhibitor (i.e.  , CKIINtide [0.01–1 μm]), they have proposed involvement of those signaling pathways in either the enhancement or inhibition.230,233,235,283 However, bisindolylmaleimide 1 and Gö-6976 are both capable of inhibiting many other protein kinases with similar potency to PKC isoforms.284,285 In addition, bisindolylmaleimide 1 may exert some other nonspecific actions at micromolar or higher concentrations.286,287 Therefore, further studies would be necessary to prove their proposals on PKC involvement.233–235,283 
By comparing the effects of halothane on [Ca2+]i–force relation, MLC20phosphorylation–force relation, and [Ca2+]i–MLC20phosphorylation relation during KCl depolarization, Tsuneyoshi et al.  129 proposed that the inhibited contractile response to KCl by halothane is due to suppressed myofilament sensitivity to both Ca2+and MLC20phosphorylation, and independent of the Ca2+–CaM–MLCK pathway. Evidence is accumulating that changes in membrane potential alter myofilament Ca2+sensitivity94,95,98,99 or activity of membrane-associated enzymes (e.g.  , PLC,96,97,288–291 adenyl cyclase292,293). Specifically, depolarization and hyperpolarization of VSMC membrane have been shown to increase and decrease myofilament Ca2+sensitivity, respectively.94,95,98,99 Thus, there is a possibility that in the study,129 halothane inhibited the Ca2+sensitizing mechanisms specifically involved in the KCl response. The above-described difference in the effects of halothane on Ca2+–force relation during KCl depolarization between rat aortic282 and mesenteric129 VSMCs might reflect a regional difference in vascular responsiveness to halothane.
The above-mentioned ability of isoflurane and sevoflurane to inhibit the Ca2+activation of contractile proteins only in membrane-intact, but not in membrane-permeabilized, VSMCs25,27 suggests that their inhibitions are mediated by some membrane-associated or intracellular regulatory mechanism of contraction that is impaired as a result of the membrane permeabilization. By contrast, the ability of halothane and enflurane to inhibit the Ca2+activation of contractile proteins under membrane-permeabilized conditions118,127 suggests that their inhibitions would be at least in part independent of the intact plasma membrane.
The above-discussed data suggest a possibility that in spite of their vasodilatory properties in vivo  (as recognized by the dilated cutaneous veins), halothane, enflurane, and isoflurane may constrict vessels by enhancing the Ca2+activation of contractile proteins and/or by stimulating Ca2+release from the SR in VSMCs. However, they also have been shown to have inhibitory actions on VSMCs (tables 3–5), and their overall effects on VSMCs would be determined by the net balance between the excitatory and inhibitory actions on VSMCs. In addition, some of the vasoconstrictor actions were observed only at 21°–23°C after treatment with the chemical detergents.230,233,235,283 Therefore, their in vivo  relevance is currently unclear. However, previous studies1,10–13,18–20 have reported decreases in blood flow associated with increases in vascular resistance or tone in several vascular beds (e.g.  , heart, liver, intestine, and skeletal muscle) during administration of those three anesthetics, possibly reflecting their direct vasoconstrictor actions.
Table 4. Proposed Effects of Anesthetic Agents on Regulatory Mechanisms in Vascular Smooth Muscle Cells 
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Table 4. Proposed Effects of Anesthetic Agents on Regulatory Mechanisms in Vascular Smooth Muscle Cells 
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Table 5. Proposed Effects of General Anesthetic Agents on Regulatory Mechanisms in Vascular Endothelial Cells 
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Table 5. Proposed Effects of General Anesthetic Agents on Regulatory Mechanisms in Vascular Endothelial Cells 
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Intravenous Anesthetics.
Previous Observations.
In VSMCs from systemic resistance arteries,26,165 ketamine (0.3–1 mm) did not affect the [Ca2+]i–force relation in VSMCs from systemic resistance arteries under both fura-2–loaded and membrane-permeabilized conditions.26,165 Similarly, ketamine (0.1 mm) did not affect the [Ca2+]i–force relation in pulmonary venous, fura-2–loaded VSMCs.294 Midazolam (10–30 μm) also did not affect the [Ca2+]i–force relation in mesenteric arterial, fura-2–loaded VSMCs.170 By contrast, propofol (100 μm) modestly, although significantly, shifted the [Ca2+]i–force relation to the left in pulmonary arterial, fura-2–loaded VSMCs.143 
Interpretations.
These results26,143,165,170,294 suggest that both ketamine and midazolam do not affect, whereas propofol enhances, the Ca2+activation of contractile proteins in VSMCs.
Anesthetic Effects on Myofilament Calcium Sensitivity during Stimulation with Receptor Agonists
Volatile anesthetics, in clinical concentrations, have been reported to affect myofilament Ca2+sensitivity in VSMCs stimulated with receptor agonists,25,27,128,282 or some signaling pathways presumed to be involved in the agonist-induced increase in myofilament Ca2+sensitivity (e.g.  , PKC pathway, Rho–Rho kinase pathway). However, information is also limited regarding intravenous anesthetic actions on the myofilament Ca2+sensitivity during receptor stimulation.
Volatile Anesthetics.
Previous Observations.
Halothane and isoflurane inhibited the IP formation induced by receptor agonists (i.e.  , AVP, platelet-derived growth factor) in cultured aortic VSMCs.227,295 Isoflurane also inhibited IP formation induced by acetylcholine in VSMCs of isolated coronary arteries.295 Sevoflurane was recently reported to inhibit phosphorylation of the cPKC-α, an indicator of its activity, in rat aortic VSMCs stimulated with AT-II.296 
In isolated porcine coronary arteries, halothane (1–3%) and isoflurane (1–3%) little affected the contractile response to phorbol ester (PBE), an analog of diacylglycerol.228,295 By contrast, in isolated rat coronary arteries, halothane (0.8–1.5%) inhibited, whereas isoflurane (1.2–2.3%) enhanced, contractile response to PBE.297 In isolated rat aorta, halothane (2–3%) and isoflurane (4%) both inhibited the contractile response to PBE.128 In membrane-permeabilized pulmonary arterial VSMCs, both of them initially enhanced but later inhibited the contractile response to PBE (at 21°C).233,235 
In isolated rat aortic VSMCs, sevoflurane inhibited guanosine-5′-(3-O  -thio) triphosphate (GTPγS, a potent and stable activator of G proteins including RhoA)–induced contraction that was sensitive to 3 μm Y27632 (a Rho-kinase inhibitor), as well as GTPγS-stimulated membrane translocation of RhoA and Rho kinase from the cytosol.298 
Interpretations.
The ability of halothane and isoflurane to inhibit IP formation227,295 suggests that during receptor stimulation, those anesthetics inhibit myofilament Ca2+sensitivity by inhibiting the PLC-mediated formation of diacylglycerol and thereby preventing PKC activation. However, as described above, previous studies128,228,235,295,297 examining the effects of halothane and isoflurane on vascular responses to the physiologic PKC activator PBE have yielded conflicting results. The differences might be due to those in animal species, experimental conditions, and/or vascular bed. Because PBE slightly increases the [Ca2+]c in porcine coronary arterial and rat aortic VSMCs,128,299 the PBE contraction observed in those VSMCs128,228,295 could be mediated not exclusively by increased myofilament sensitivity to the basal [Ca2+]c but in part by an increase in [Ca2+]c. Therefore, the interpretation of results obtained in some of the previous studies128,228,295 would not be straightforward, and it is currently uncertain whether volatile anesthetics interfere with the PKC pathway at steps after the production of diacylglycerol.
The ability of sevoflurane to inhibit the AT-II–induced phosphorylation of PKC296 would suggest that sevoflurane inhibits the activation of PKC during stimulation with AT-II.
Recent evidence suggests that during receptor stimulation, the inhibitory signal to MLCP is communicated by RhoA, a monomeric G protein, to a Rho kinase that phosphorylates MLCP and inhibits its catalytic activity, increasing MLC20phosphorylation (fig. 1).62 Upon activation, both RhoA and Rho kinase are translocated from the cytosol to the membrane in VSMCs.62 The recently reported ability of sevoflurane to inhibit GTPγS-stimulated membrane translocation of RhoA and Rho kinase from the cytosol298 thus suggests that during receptor stimulation, sevoflurane inhibits the Rho–Rho kinase pathway, thereby reducing the myofilament Ca2+sensitivity and causing vasodilation. However, in that study,298 its mechanistic link to the observed vasodilator action seemed unclear because of the nonspecific nature of Y-27632 (3 μm) as a Rho-kinase inhibitor.285 
Volatile anesthetics have been reported to either activate207–210,212 or inhibit244,245,300,301 the K+channel activity in VSMCs. Therefore, they may modulate myofilament Ca2+sensitivity by altering the K+channel activity and thereby causing changes in the membrane potential, which have been suggested to alter the myofilament Ca2+sensitivity in either presence or absence of receptor stimulation.94,95,98,99 
Intravenous Anesthetics.
Previous Observations.
Ketamine (0.3–0.32 mm) inhibited PLC activity in femoral arterial VSMCs,140 as well as phenylephrine (α1-adrenergic agonist)–stimulated IP3production in mesenteric arterial VSMCs139; however, ketamine (0.3–1 mm) did not influence the [Ca2+]i–force relation during stimulation with norepinephrine in mesenteric arterial, fura-2–loaded VSMCs.26 In pulmonary venous, fura-2–loaded VSMCs,294 ketamine (0.1 mm) inhibited the [Ca2+]i–force relation only during stimulation with acetylcholine but not in its absence, mimicking the effect of bisindolylmaleimide 1 (3 μm, the PKC inhibitor). Midazolam (10–30 μm) did not influence the [Ca2+]i–force relation during stimulation with norepinephrine in mesenteric arterial, fura-2–loaded VSMCs.170 
Interpretations.
The ability of ketamine to inhibit PLC activity140 and phenylephrine-stimulated IP3production139 suggests that ketamine may inhibit the agonist-induced increase in myofilament Ca2+sensitivity by inhibiting PLC-mediated PIP2breakdown and preventing subsequent PKC activation. However, its inability to inhibit myofilament Ca2+sensitivity during stimulation with norepinephrine26 suggests that PKC may not play a significant role in the norepinephrine-induced increase in myofilament Ca2+sensitivity. In pulmonary venous VSMCs, ketamine seems to inhibit the acetylcholine-induced, presumed PKC-mediated increase in myofilament Ca2+sensitivity. Midazolam probably does not influence the norepinephrine-induced increase in myofilament Ca2+sensitivity in mesenteric arterial VSMCs.
Future Directions
Investigations with Human Vessels
In previous studies using isolated vascular preparations from various organs, most general anesthetics affected vascular reactivity through direct (i.e.  , nonneural) actions on VSMCs and/or endothelial cells. However, as discussed above, the underlying mechanisms are not entirely clear. In addition, the obtained results on some of them have not been consistent, but conflicting, apparently depending on vascular beds, size of blood vessels, experimental condition, and animal species. General anesthetics, because of their high lipophilicity, would be able to gain access to numerous membranous structures in VSMCs and endothelial cells. Then, they would perturb the functional integrity of membrane proteins by acting either directly on their hydrophobic sites or indirectly through the lipid bilayer surrounding them, and thereby exert multiple actions on VSM reactivity. In addition, general anesthetics would act on various (i.e.  , metabolic, myogenic, neural, humoral, or endothelial) vasoregulatory mechanisms. Therefore, their overall vascular action would represent a balance among their effects on those mechanisms, the relative importance of which varies in different vascular beds. Such a nonspecific nature of general anesthetics would readily lead to the differences in vascular responsiveness between vascular beds, type of blood vessels, experimental conditions, and animal species. Therefore, investigations using human vessels under physiologic conditions would be particularly important to clarify the relevance of direct vascular actions of general anesthetics to their circulatory action observed in the clinical setting. The number of studies using isolated human vessels122,144,146,151,168,183,193,202,223,302–308 is increasing, and they have reported both similarities and differences in vascular responsiveness to general anesthetics between humans and animals. However, our knowledge is still limited.
Investigations with Vessels from Subjects with Cardiovascular Dysfunction
General anesthesia rarely causes cardiovascular collapse in healthy younger patients, but often in patients with cardiovascular dysfunction (e.g.  , aged patients; neonates; patients with heart diseases, atherosclerosis, hypertension, diabetes mellitus, and sepsis). Many of the cellular mechanisms regulating vascular tone—i.e.  , potential targets for general anesthetics—are known to be altered in those susceptible populations (e.g.  , endothelial function, ion channel activity, enzyme activity).309–314 Vascular responsiveness to general anesthetics thus could be altered in those pathologic conditions. Some investigators166,212,231,315,316 have already demonstrated that vascular sensitivity to general anesthetics (i.e.  , propofol, isoflurane, sevoflurane) is indeed altered (either enhanced or attenuated) in hypertensive subjects. However, little information is available regarding direct actions of general anesthetics on VSMCs from atherosclerotic, diabetic, and aged subjects. These topics should be the subjects of future studies.
Investigations on Intravenous Anesthetics
In most previous studies investigating the action of intravenous anesthetics, as mentioned above, their effective concentrations were higher than their clinically relevant free concentrations (table 6). Therefore, intravenous anesthetics may not directly influence VSM reactivity in the normal clinical setting. However, vascular sensitivity could be altered in the in vitro  or in situ  conditions, particularly in cultured VSMCs. In addition, in many previous in vitro  studies, their actions have been evaluated on maximal or near-maximal contractile responses to agonists. However, it must be rare that VSMCs are being maximally contracted under physiologic conditions, and therefore, the anesthetic actions, assessed by percent changes from the control response, could have been underestimated in those studies. Further studies thus would be necessary regarding the intravenous anesthetic actions on submaximal responses to lower concentrations (i.e.  , ≤ EC50) of agonists that are involved in the physiologic regulation of vascular tone.
Table 6. Plasma Concentrations of Intravenous Anesthetics after Bolus Intravenous Injection 
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Table 6. Plasma Concentrations of Intravenous Anesthetics after Bolus Intravenous Injection 
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Investigations with Systemic Resistance and Capacitance Vessels
In previous studies with systemic resistance arteries from rats or rabbits, some general anesthetics (i.e.  , halothane, isoflurane, sevoflurane), despite their hypotensive action in vivo  , did not consistently decrease vascular tone but occasionally increased it.26,130,133,135,160,161,176 Depending on experimental conditions (e.g.  , endothelial intactness) or species (e.g.  , rat vs.  rabbit), they enhanced the contractile response to norepinephrine133,135,176 that plays a central role in the sympathetic maintenance of vascular tone in vivo  . In addition, they attenuated both the nitric oxide–mediated and EDHF-mediated vasodilator responses133,135,160,176 that would be essential in keeping the vasculature in an appropriately dilated state. Therefore, at this time, no definite evidence seems available for any general anesthetic indicating that its direct action on arterial VSMCs contributes to systemic hypotension during its administration. However, as discussed above, the direct action of volatile anesthetics on arterial VSMCs may contribute to the prolonged systemic hypotension observed during the postanesthesia period.10,47 
It has been recognized that venodilation, particularly in the splanchnic region, and a resultant decrease in venous return also underlies systemic hypotension during general anesthesia.2 In previous studies with isolated mesenteric veins,157,158,317 halothane, enflurane, and isoflurane inhibited the contractile response to norepinephrine. In addition, in recent in situ  experiments, propofol hyperpolarized mesenteric venous VSMCs by activating K+channels.318,319 Therefore, systemic hypotension during anesthesia with those anesthetics would be due, in part, to their direct action on venous VSMCs in the splanchnic circulation. Presumably because of the technical difficulty, information about the direct action of general anesthetics on venous VSMCs is still limited.157,158,294,303,305,307,308,317–319 Again, on consideration of possible species differences, further studies using human capacitance vessels, as well as human systemic resistance vessels, would be essential to evaluate a possibility that the direct (i.e.  , nonneural) actions of general anesthetics on VSMCs contribute to systemic hypotension during their administration.
Investigations on Microcirculation
Vasodilator responses to nitric oxide, EDHF, and KATPchannels play a key role in the endothelial and/or metabolic regulation of vascular tone in microcirculation.320 Vasodilator responses via  the β adrenoceptors also would contribute to resting tone of coronary arterial microvessels.321,322 General anesthetics have been shown to inhibit all these vasodilator responses (table 2). In addition, in coronary microvessels, some general anesthetics have been reported to influence myogenic response to changes in intravascular pressure or flow (i.e.  , shear stress)–induced vasomotion,323–325 both of which are essential for fine regulation of blood flow (e.g.  , autoregulation).326 Therefore, general anesthetics may perturb microcirculatory homeostasis, possibly affecting oxygen delivery to the tissues. However, the clinical significance of such anesthetic actions seems unclear at this time, and further studies evaluating anesthetic effects on venular blood oxygen content under various critical conditions (e.g.  , hypoxia, shock) would be helpful for clarification of this issue.
Conducted vasomotor responses—i.e.  , propagation of local vasomotor responses to upstream and downstream along the microvessels—are believed to contribute to functional distribution of blood flow in microcirculation of various organs including the brain and heart.327–329 Specifically, conducted vasodilation could be an important mechanism for increasing blood supply to meet the metabolic demands (i.e.  , functional hyperemia), whereas conducted vasoconstriction would underlie blood flow autoregulation.327 However, data are limited regarding the anesthetic actions on the conducted vasomotor response,330 and this topic should be the subject to future investigations as well.
Conclusions
In previous in vitro  or in situ  experiments using blood vessels from various vascular beds, most general anesthetics affected a wide variety of cellular and molecular mechanisms regulating vascular reactivity. However, in most of them, intravenous anesthetics exerted their vascular actions only at supraclinical concentrations, whereas volatile anesthetics exerted their vascular actions at clinical concentrations. Therefore, direct (i.e.  , nonneural) actions of volatile anesthetics on VSMCs and/or endothelial cells would contribute to the alterations in hemodynamics and organ blood flow during their administration in the clinical setting. On the other hand, most of the previously observed direct vascular actions of intravenous anesthetics might be irrelevant to normal clinical practice.
The previous results on the direct vascular action of general anesthetics have not necessarily been consistent even in experiments with the same blood vessels, possibly reflecting the differences in vascular responsiveness between experimental conditions or species. It is conceivable that such differences exist, because general anesthetics presumably act on multiple sites within VSMCs and endothelial cells and thereby exert multiple actions on vascular reactivity. In addition, general anesthetics would act on multiple vasoregulatory mechanisms, the relative importance of which differs in different vascular beds, leading to the differences in vascular responsiveness to them among vascular beds. On consideration of such a nonspecific nature of general anesthetics, it would be particularly important to evaluate their actions on human vessels under physiologic conditions, as well as on blood vessels from subjects susceptible to their circulatory depressant effects. In addition, electrophysiologic, biochemical, and molecular-biologic techniques would be essential for future studies to clarify the mechanisms behind the direct vascular actions of general anesthetics. Better understanding of the vascular actions of general anesthetics, as well as vascular physiology, would lead to better circulatory management during general anesthesia.
The author thanks Junichi Yoshitake, M.D., Ph.D. (deceased, former Professor of Anesthesiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan), and Shosuke Takahashi, M.D., Ph.D. (Professor of Anesthesiology, Graduate School of Medical Sciences, Kyushu University), for their encouragement, and Kaoru Izumi, M.D., Ph.D. (Staff Anesthesiologist, Iizuka Hospital, Iizuka, Japan), Jun Yoshino, M.D., Ph.D. (Staff Anesthesiologist, Kyushu Medical Center, Fukuoka, Japan), Kazuhiro Shirozu, M.D. (Postgraduate of Anesthesiology, Graduate School of Medical Sciences, Kyushu University), and Tomoo Kanna, M.D. (Research Associate, Department of Advanced Medical Initiatives, Faculty of Medical Sciences, Kyushu University), for their enthusiastic cooperation as a postgraduate or research associate.
References
Thulin L, Andreen M, Irestedt L: Effect of controlled halothane anaesthesia on splanchnic blood flow and cardiac output in the dog. Acta Anaesthesiol Scand 1975; 19:146–53Thulin, L Andreen, M Irestedt, L
Altura BM, Altura BT, Carella A, Turlapaty PDMV, Weinburg J: Vascular smooth muscle and general anesthetics. Federation Proc 1980; 39:1584–91Altura, BM Altura, BT Carella, A Turlapaty, PDMV Weinburg, J
Pavlin EG, Su JY: Cardiopulmonary pharmacology, Anesthesia. Edited by Miller RD. New York, Churchill Livingstone, 1990, pp 105–34Pavlin, EG Su, JY Miller RD New York Churchill Livingstone
Marshall BE, Longnecker DE: General anesthetics, The Pharmacological Basis of Therapeutics. Edited by Gilman AG, Rall TW, Nies AS, Taylor P. New York, Pergamon Press, 1990, pp 285–310Marshall, BE Longnecker, DE Gilman AG, Rall TW, Nies AS, Taylor P New York Pergamon Press
Frink EJ, Morgan SE, Coetzee A, Conzen PF, Brown BR Jr: The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 1992; 76:85–90Frink, EJ Morgan, SE Coetzee, A Conzen, PF Brown, BR
Conzen PF, Vollmar B, Habazettl H, Frink EJ, Peter K, Messmer K: Systemic and regional hemodynamics of isoflurane and sevoflurane in rats. Anesth Analg 1992; 74:79–88Conzen, PF Vollmar, B Habazettl, H Frink, EJ Peter, K Messmer, K
Stevens WC, Kingston HGG: Inhalational anesthesia, Clinical Anesthesia, 3rd edition. Edited by Barash PG, Cullen BF, Stoelting RK. Philadelphia, Lippincott–Raven, 1996, pp 359–83Stevens, WC Kingston, HGG Barash PG, Cullen BF, Stoelting RK Philadelphia Lippincott–Raven
Buhre W, Hoeft A: Anesthesia and cardiovascular system, Cardiovascular Physiology, 2nd edition. Edited by Priebe H-J, Skarvan K. London, BMJ Books, 2000, pp 331–73Buhre, W Hoeft, A Priebe H-J, Skarvan K London BMJ Books
Reves JG, Glass PSA, Lubarsky DA, McEvoy MD: Intravenous nonopioid anesthetics, Miller’s Anesthesia, 6th edition. Edited by Miller RD. Philadelphia, Elsevier Churchill Livingstone, 2004, pp 317–78Reves, JG Glass, PSA Lubarsky, DA McEvoy, MD Miller RD Philadelphia Elsevier Churchill Livingstone
Westermark L: Blood circulation in the skeletal muscles and the skin of the cat under halothane anaesthesia. Acta Anaesthesiol Scand 1969; 13:209–27Westermark, L
Westermark L, Wahlin A: Blood circulation in the intestine of the cat under halothane anaesthesia. Acta Anaesthesiol Scand 1969; 13:47–61Westermark, L Wahlin, A
Seyde WC, Longnecker DE: Anesthetic influences on regional hemodynamics in normal and hemorrhaged rats. Anesthesiology 1984; 61:686–98Seyde, WC Longnecker, DE
Loick HM, Tokyay R, Abdi S, Traber DL, Nichols RJ, Herndon DL: Halothane markedly reduces mesenteric blood flow but does not impair gut mucosal oxygenation in pigs. Eur J Pharmacol 1991; 201:91–6Loick, HM Tokyay, R Abdi, S Traber, DL Nichols, RJ Herndon, DL
Baumgardner JE, Loeb AL, Longnecker DE: Microcirculation, Cardiovascular Physiology, 2nd edition. Edited by Priebe H-J, Skarvan K. London, BMJ Books, 2000, pp 307–30Baumgardner, JE Loeb, AL Longnecker, DE Priebe H-J, Skarvan K London BMJ Books
Kien ND, Reitan JA: Renal, splanchnic, skin, and muscle circulations, Cardiovascular Physiology. Edited by Pierbe H-J, Skarvan K. London, BMJ Books, 2000, pp 278–306Kien, ND Reitan, JA Pierbe H-J, Skarvan K London BMJ Books
Menon DK: Cerebral circulation, Cardiovascular Physiology, 2nd edition. Edited by Priebe H-J, Skarvan K. London, BMJ Books, 2000, pp 244–78Menon, DK Priebe H-J, Skarvan K London BMJ Books
Stekiel TA, Stekiel WJ, Bosnjak ZJ: The peripheral vasculature: Control and anesthetic actions, Anesthesia: Biologic Foundations, 1st edition. Edited by Yaksh TL, Lynch C III Zapol WM, Maze M, Biebuyck JF, Saidman LJ. New York, Lippincott–Raven, 1997, pp 1135–68Stekiel, TA Stekiel, WJ Bosnjak, ZJ Yaksh TL, Lynch C III Zapol WM, Maze M, Biebuyck JF, Saidman LJ New York Lippincott–Raven
Benumof NL, Bookstein JJ, Saidman LJ, Harris R: Diminished hepatic arterial flow during halothane administration. Anesthesiology 1976; 45:545–51Benumof, NL Bookstein, JJ Saidman, LJ Harris, R
Hartman JC, Pagel PS, Proctor LT, Kampine JP, Schmeling WT, Warltier DC: Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs. Can J Anaesth 1992; 39:877–87Hartman, JC Pagel, PS Proctor, LT Kampine, JP Schmeling, WT Warltier, DC
Gatecel C, Losser MR, Payen D: The postoperative effects of halothane versus  isoflurane on hepatic artery and portal vein blood flow in humans. Anesth Analg 2003; 96:740–5Gatecel, C Losser, MR Payen, D
Somlyo AP, Somlyo AV: Signal transduction and regulation in smooth muscle. Nature 1994; 372:231–6Somlyo, AP Somlyo, AV
Itoh T, Ikebe M, Kargacin GJ, Hartshorne DJ, Kemp BE, Fay FS: Effects of modulators of myosin light-chain kinase activity in single smooth muscle cells. Nature 1989; 338:164–7Itoh, T Ikebe, M Kargacin, GJ Hartshorne, DJ Kemp, BE Fay, FS
Rembold CM: Regulation of contraction and relaxation in arterial smooth muscle. Hypertension 1992; 20:129–37Rembold, CM
Morgan KG, Khalil RA, Suematsu E, Katsuyama H: Calcium-dependent and calcium-independent pathways of signal transduction in smooth muscle. Jpn J Pharmacol 1992; 58 (suppl 2):47–53Morgan, KG Khalil, RA Suematsu, E Katsuyama, H
Akata T, Izumi K, Nakashima M: The action of sevoflurane on vascular smooth muscle of isolated mesenteric resistance arteries: II. Mechanisms of endothelium-independent vasorelaxation. Anesthesiology 2000; 92:1441–53Akata, T Izumi, K Nakashima, M
Akata T, Izumi K, Nakashima M: Mechanisms of direct inhibitory action of ketamine on vascular smooth muscle in mesenteric resistance arteries. Anesthesiology 2001; 95:452–62Akata, T Izumi, K Nakashima, M
Akata T, Kanna T, Yoshino J, Takahashi S: Mechanisms of direct inhibitory action of isoflurane on vascular smooth muscle of mesenteric resistance arteries. Anesthesiology 2003; 99:666–77Akata, T Kanna, T Yoshino, J Takahashi, S
Hai C-M, Murphy RA: Ca2+, crossbridge, phosphorylation, and contraction. Annu Rev Physiol 1989; 51:285–98Hai, C-M Murphy, RA
Rembold CM, Murphy RA: Models of the mechanism for crossbridge attachment in smooth muscle. J Muscle Res Cell M 1993; 14:325–34Rembold, CM Murphy, RA
Kamm K, Stull J: Regulation of smooth muscle contractile elements by second messengers. Annu Rev Physiol 1989; 59:299–313Kamm, K Stull, J
Winder SJ, Allen BG, Clement-Chomienne O, Walsh MP: Regulation of smooth muscle actin-myosin interaction and force by calponin. Acta Physiol Scand 1998; 164:415–26Winder, SJ Allen, BG Clement-Chomienne, O Walsh, MP
Hirasawa K, Nishizuka Y: Phosphatidylinositol turnover in receptor mechanism and signal transduction. Annu Rev Pharmacol Toxicol 1985; 25:147–70Hirasawa, K Nishizuka, Y
Berridge MJ, Irvine RF: Inositol phosphates and cell signalling. Nature 1989; 341:197–205Berridge, MJ Irvine, RF
Orallo F: Regulation of cytosolic calcium levels in vascular smooth muscle. Pharmacol Ther 1996; 69:153–71Orallo, F
Wong AY, Klassen GA: A model of calcium regulation in smooth muscle cell. Cell Calcium 1993; 14:227–43Wong, AY Klassen, GA
Horowitz A, Menice CB, Laporte R, Morgan KG: Mechanisms of smooth muscle contraction. Physiol Rev 1996; 76:967–1003Horowitz, A Menice, CB Laporte, R Morgan, KG
Somlyo AP, Somlyo AV: Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol (Lond) 2000; 522:177–85Somlyo, AP Somlyo, AV
Iino M: Calcium release mechanisms in smooth muscle. Jpn J Pharmacol 1990; 54:345–54Iino, M
Lesh RE, Nixon GF, Fleischer S, Airey JA, Somlyo AP, Somlyo AV: Localization of ryanodine receptors in smooth muscle. Circ Res 1997; 82:175–85Lesh, RE Nixon, GF Fleischer, S Airey, JA Somlyo, AP Somlyo, AV
Laporte R, Laher I: Sarcoplasmic reticulum-sarcolemma interactions and vascular smooth muscle tone. J Vasc Res 1997; 34:325–43Laporte, R Laher, I
Chen Q, van Breemen C: Receptor mediated disruption of the smooth muscle SR buffer barrier function. Jpn J Pharmacol 1992; 58 (suppl 2):60–6Chen, Q van Breemen, C
Iino M: Calcium-induced calcium release mechanism in guinea pig taenia caeci. J Gen Physiol 1989; 37:363–83Iino, M
Jagger JH, Wellman GC, Heppner TJ, Porter VA, Perez GJ, Gollasch M, Kleppisch T, Rubart M, Stevenson AS, Lederer WJ, Knot HJ, Bonev AD, Nelson MT: Ca2+channels, ryanodine receptors and Ca2+-activated K+channels: A functional unit for regulating arterial tone. Acta Physiol Scand 1998; 164:577–87Jagger, JH Wellman, GC Heppner, TJ Porter, VA Perez, GJ Gollasch, M Kleppisch, T Rubart, M Stevenson, AS Lederer, WJ Knot, HJ Bonev, AD Nelson, MT
van Breemen C, Chen Q, Laher I: Superficial buffer barrier function of smooth muscle sarcoplasmic reticulum. Trends Pharmacol Sci 1995; 16:98–105van Breemen, C Chen, Q Laher, I
Hughes AD: Calcium channels in vascular smooth muscle cells. J Vasc Res 1995; 32:353–70Hughes, AD
Gollasch M, Nelson MT: Voltage-dependent Ca2+channels in arterial smooth muscle cells. Kidney Blood Press Res 1997; 20:355–71Gollasch, M Nelson, MT
Yamazaki M, Stekiel TA, Bosnjak ZJ, Kampine JP, Stekiel WJ: Effects of volatile anesthetic agents on in situ  vascular smooth muscle transmembrane potential in resistance- and capacitance-regulating blood vessels. Anesthesiology 1998; 88:1085–95Yamazaki, M Stekiel, TA Bosnjak, ZJ Kampine, JP Stekiel, WJ
Nelson MT, Standen NB, Brayden JE, Worley JF III: Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature 1988; 336:382–5Nelson, MT Standen, NB Brayden, JE Worley, JF
Gibson A, McFadzean I, Wallace P, Wayman CP: Capacitative Ca2+entry and the regulation of smooth muscle tone. Trends Pharmacol Sci 1998; 19:266–9Gibson, A McFadzean, I Wallace, P Wayman, CP
Putney JW Jr, McKay RR: Capacitative calcium entry channels. Bioessays 1999; 21:38–46Putney, JW McKay, RR
Hoth M, Penner R: Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 1992; 355:353–6Hoth, M Penner, R
Byron K, Taylor CW: Vasopressin stimulation of Ca2+mobilization, two bivalent cation entry pathways and Ca2+efflux in A7r5 rat smooth muscle cells. J Physiol (Lond) 1995; 485:455–68Byron, K Taylor, CW
Marin J, Encabo A, Briones A, Garcia-Cohen E-C, Alonso MJ: Mechanisms involved in the cellular calcium homeostasis in vascular smooth muscle: Calcium pumps. Life Sci 1999; 64:279–303Marin, J Encabo, A Briones, A Garcia-Cohen, E-C Alonso, MJ
Jackson WF: Oscillations in active tension in hamster aortas: Role of the endothelium. Blood Vessels 1988; 25:144–56Jackson, WF
Gustafsson H, Mulvany MJ, Nilsson H: Rhythmic contractions of isolated small arteries from rat: Influence of the endothelium. Acta Physiol Scand 1993; 148:153–63Gustafsson, H Mulvany, MJ Nilsson, H
Gustafsson H, Nilsson H: Rhythmic contractions in isolated small arteries of rat: Role of K+channels and the Na+,K+-pump. Acta Physiol Scand 1994; 150:161–70Gustafsson, H Nilsson, H
Akata T, Kodama K, Takahashi S: Role of endothelium in oscillatory contractile responses to various receptor agonists in isolated small mesenteric and epicardial coronary arteries. Jpn J Pharmacol 1995; 68:331–43Akata, T Kodama, K Takahashi, S
Lee CH, Poburko D, Kuo KH, Seow CY, van Breemen C: Ca2+oscillations, gradients, and homeostasis in vascular smooth muscle. Am J Physiol 2002; 282:H1571–83Lee, CH Poburko, D Kuo, KH Seow, CY van Breemen, C
Berridge MJ, Galione A: Cytosolic calcium oscillators. FASEB J 1988; 2:3074–82Berridge, MJ Galione, A
Lamb FD, Webb RC: Potassium conductance and oscillatory contractions in tail arteries from genetically hypertensive rats. J Hypertens 1989; 7:457–63Lamb, FD Webb, RC
Knot HJ, de Ree MM, Gahwiler BH, Ruegg UT: Modulation of electrical activity and of intracellular calcium oscillations of smooth muscle cells by calcium antagonists, agonists, and vasopressin. J Cardiovasc Pharmacol 1991; 18:S7–14Knot, HJ de Ree, MM Gahwiler, BH Ruegg, UT
Fukata Y, Amano M, Kaibuchi K: Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 2001; 22:32–9Fukata, Y Amano, M Kaibuchi, K
Gerthoffer WT, Pohl J: Caldesmon and calponin phosphorylation in regulation of smooth muscle contraction. Can J Physiol Pharmacol 1994; 72:1410–4Gerthoffer, WT Pohl, J
Rapoport RM, Campbell AK: Norepinephrine-induced phosphatidylcholine hydrolysis in intact rat aorta. Eur J Pharmacol 1991; 208:89–92Rapoport, RM Campbell, AK
Gu H, Trajkovic S, LaBelle EF: Norepinephrine-induced phosphatidylcholine hydrolysis by phospholipases D and C in rat tail artery. Am J Physiol 1992; 262:C1376–83Gu, H Trajkovic, S LaBelle, EF
LaBelle EF, Fulbright RM, Barsotti RJ, Gu H, Polyak E: Phospholipase D is activated by G-protein and not by calcium ions in vascular smooth muscle. Am J Physiol 1996; 270:H1031–7LaBelle, EF Fulbright, RM Barsotti, RJ Gu, H Polyak, E
LaBelle EF, Polyak E: Norepinephrine stimulates arachidonic acid release from vascular smooth muscle via  activation of cPLA2. Am J Physiol 1998; 274:C1129–37LaBelle, EF Polyak, E
Muthalif MM, Parmentier JH, Benter IF, Karzoun N, Ahmed A, Khandekar Z, Adl MZ, Bourgoin S, Malik KU: Ras/mitogen-activated protein kinase mediates norepinephrine-induced phospholipase D activation in rabbit aortic smooth muscle cells by a phosphorylation-dependent mechanism. J Pharmacol Exp Ther 2000; 293:268–74Muthalif, MM Parmentier, JH Benter, IF Karzoun, N Ahmed, A Khandekar, Z Adl, MZ Bourgoin, S Malik, KU
Parmentier JH, Muthalif MM, Saeed AE, Malik KU: Phospholipase D activation by norepinephrine is mediated by 12(s)-, 15(s)-, and 20-hydroxyeicosatetraenoic acids generated by stimulation of cytosolic phospholipase A2. J Biol Chem 2001; 276:15704–11Parmentier, JH Muthalif, MM Saeed, AE Malik, KU
Feng J, Ito M, Kureishi Y, Ichikawa K, Amano M, Isaka N, Okawa K, Iwamatsu A, Kaibuchi K, Hartshorne DJ, Nakano T: Rho-associated kinase of chicken gizzard smooth muscle. J Biol Chem 1999; 274:3744–52Feng, J Ito, M Kureishi, Y Ichikawa, K Amano, M Isaka, N Okawa, K Iwamatsu, A Kaibuchi, K Hartshorne, DJ Nakano, T
Stull JT, Tansey MG, Tang DC, Word RA, Kamm KE: Phosphorylation of myosin light chain kinase: A cellular mechanism for Ca2+desensitization. Mol Cell Biochem 1993; 127-128:229–37Stull, JT Tansey, MG Tang, DC Word, RA Kamm, KE
Walker LA, Gailly P, Jensen PE, Somlyo AV, Somlyo AP: The unimportance of being (protein kinase C) epsilon. FASEB J 1998; 12:813–21Walker, LA Gailly, P Jensen, PE Somlyo, AV Somlyo, AP
Kureishi Y, Ito M, Feng J, Okinaka T, Isaka N, Nakano T: Regulation of Ca2+-independent smooth muscle contraction by alternative staurosporine-sensitive kinase. Eur J Pharmacol 1999; 376:315–20Kureishi, Y Ito, M Feng, J Okinaka, T Isaka, N Nakano, T
Weber LP, Van Lierop JE, Walsh MP: Ca2+-independent phosphorylation of myosin in rat caudal artery and chicken gizzard myofilaments. J Physiol (Lond) 1999; 516:805–24Weber, LP Van Lierop, JE Walsh, MP
Shirao S, Kashiwagi S, Sato M, Miwa S, Nakao F, Kurokawa T, Todoroki-Ikeda N, Mogami K, Mizukami Y, Kuriyama S, Haze K, Suzuki M, Kobayashi S: Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca2+sensitization in the bovine cerebral artery: Unimportant role for protein kinase C. Circ Res 2002; 91:112–9Shirao, S Kashiwagi, S Sato, M Miwa, S Nakao, F Kurokawa, T Todoroki-Ikeda, N Mogami, K Mizukami, Y Kuriyama, S Haze, K Suzuki, M Kobayashi, S
Walsh MP, Horowitz A, Clement-Chomienne O, Andrea JE, Allen BG, Morgan KG: Protein kinase C mediation of Ca2+-independent contractions of vascular smooth muscle. Biochem Cell Biol 1996; 74:485–502Walsh, MP Horowitz, A Clement-Chomienne, O Andrea, JE Allen, BG Morgan, KG
Vaandrager AB, de Jonge HR: Signalling by cGMP-dependent protein kinases. Mol Cell Biochem 1996; 157:23–30Vaandrager, AB de Jonge, HR
Johns RA: The nitric oxide-guanylyl cyclase signaling pathway, Anesthesia: Biologic Foundations, 1st edition. Edited by Yaksh TL, Lynch C III, Zapol WM, Maze M, Biebuyck JF, Saidman LJ. New York, Lippincott–Raven, 1997, pp 131–43Johns, RA Yaksh TL, Lynch C III, Zapol WM, Maze M, Biebuyck JF, Saidman LJ New York Lippincott–Raven
Wang R: Resurgence of carbon monoxide: An endogenous gaseous vasorelaxing factor. Can J Physiol Pharmacol 1998; 76:1–15Wang, R
Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med 1998; 339:321–8Levin, ER Gardner, DG Samson, WK
Schulz S, Waldman SA: The guanylyl cyclase family of natriuretic peptide receptors. Vitam Horm 1999; 57:123–51Schulz, S Waldman, SA
Sonnenburg WK, Beavo JA: Cyclic GMP and regulation of cyclic nucleotide hydrolysis. Adv Pharmacol 1994; 26:87–114Sonnenburg, WK Beavo, JA
Polson JB, Strada SJ: Cyclic nucleotide phosphodiesterases and vascular smooth muscle. Annu Rev Pharmacol Toxicol 1996; 36:403–27Polson, JB Strada, SJ
Minami K, Fukuzawa K, Nakaya Y, Zeng XR, Inoue I: Mechanism of activation of the Ca(2+)-activated K+ channel by cyclic AMP in cultured porcine coronary artery smooth muscle cells. Life Sci 1993; 53:1129–35Minami, K Fukuzawa, K Nakaya, Y Zeng, XR Inoue, I
Takuwa Y: Regulation of vascular smooth muscle contraction. Jpn Heart J 1996; 37:793–813Takuwa, Y
Bonev AD, Nelson MT: Vasoconstrictors inhibit ATP-sensitive K+channels in arterial smooth muscle through protein kinase C. J Gen Physiol 1996; 108:315–23Bonev, AD Nelson, MT
Hughes AD, Wijetunge S: Role of tyrosine phosphorylation in excitation-contraction coupling in vascular smooth muscle. Acta Physiol Scand 1998; 164:457–69Hughes, AD Wijetunge, S
Murphy TV, Spurrell BE, Hill MA: Cellular signalling in arteriolar myogenic constriction: Involvement of tyrosine phosphorylation pathways. Clin Exp Pharmacol Physiol 2002; 29:612–9Murphy, TV Spurrell, BE Hill, MA
Horibe M, Kondo I, Damron DS, Murray PA: Propofol attenuates capacitative calcium entry in pulmonary artery smooth muscle cells. Anesthesiology 2001; 95:681–8Horibe, M Kondo, I Damron, DS Murray, PA
Kitamura K, Yamazaki J: Chloride channels and their functional roles in smooth muscle tone in the vasculature. Jpn J Pharmacol 2001; 85:351–7Kitamura, K Yamazaki, J
Nilsson H: Interactions between membrane-potential and intracellular calcium concentration in vascular smooth muscle. Acta Physiol Scand 1998; 164:559–66Nilsson, H
Brayden JE: Potassium channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 1996; 23:1069–76Brayden, JE
Clapp LH, Tinker A: Potassium channels in the vasculature. Curr Opin Nephrol Hy 1998; 7:91–8Clapp, LH Tinker, A
Okada Y, Yanagisawa T, Taira N: KCl-depolarization potentiates the Ca2+sensitization by endothelin-1 in canine coronary artery. Jpn J Pharmacol 1992; 60:403–5Okada, Y Yanagisawa, T Taira, N
Yanagisawa T, Okada Y: KCl depolarization increases Ca2+sensitivity of contractile elements in coronary arterial smooth muscle. Am J Physiol 1994; 267:H614–21Yanagisawa, T Okada, Y
Itoh T, Seki N, Suzuki S, Ito S, Kajikuri J, Kuriyama H: Membrane hyperpolarization inhibits agonist-induced synthesis of inositol 1,4,5-triphosphate in rabbit mesenteric artery. J Physiol (Lond) 1992; 451:307–28Itoh, T Seki, N Suzuki, S Ito, S Kajikuri, J Kuriyama, H
Yamagishi T, Yanagisawa T, Taira N: K+channel openers, cromakalim and Ki4032, inhibit agonist-induced Ca2+release in canine coronary artery. Naunyn Schmiedebergs Arch Pharmacol 1992; 346:691–700Yamagishi, T Yanagisawa, T Taira, N
Okada Y, Yanagisawa T, Taira N: E4080 has a dual action, as a K+channel opener and a Ca2+channel blocker, in canine coronary artery smooth muscle. Eur J Pharmacol 1992; 218:259–64Okada, Y Yanagisawa, T Taira, N
Okada Y, Yanagisawa T, Taira N: BRL 38227 (levcromakalim)-induced hyperpolarization reduces the sensitivity to Ca2+of contractile elements in canine coronary artery. Naunyn Schmiedebergs Arch Pharmacol 1993; 347:438–44Okada, Y Yanagisawa, T Taira, N
Daut J, Maier-Rudolph W, von Becherath N, Mehrke G, Gunther K, Goedel-Meinen L: Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science 1990; 247:1341–4Daut, J Maier-Rudolph, W von Becherath, N Mehrke, G Gunther, K Goedel-Meinen, L
Aversano T, Ouyang P, Silverman H: Blockade of the ATP-sensitive potassium channel modulates reactive hyperemia in the canine coronary circulation. Circ Res 1991; 69:618–22Aversano, T Ouyang, P Silverman, H
Randall MD, McCulloch AI: The involvement of ATP-sensitive potassium channels in beta-adrenoceptor-mediated vasorelaxation in the rat isolated mesenteric arterial bed. Br J Pharmacol 1995; 115:607–12Randall, MD McCulloch, AI
Standen NB, Quayle JM: K+channel modulation in arterial smooth muscle. Acta Scand Physiol 1998; 164:549–57Standen, NB Quayle, JM
Ishizaka H, Gudi SR, Frangos JA, Kuo L: Coronary arteriolar dilation to acidosis: Role of ATP-sensitive potassium channels and pertussis toxin-sensitive G proteins. Circulation 1999; 99:558–63Ishizaka, H Gudi, SR Frangos, JA Kuo, L
Waldron GJ, Cole WC: Activation of vascular smooth muscle K+channels by endothelium-derived relaxing factors. Clin Exp Pharmacol Physiol 1999; 26:180–4Waldron, GJ Cole, WC
Cole WC, Clement-Chomienne O, Aiello EA: Regulation of 4-aminopyridine-sensitive, delayed rectifier K+channels in vascular smooth muscle by phosphorylation. Biochem Cell Biol 1996; 74:439–47Cole, WC Clement-Chomienne, O Aiello, EA
Griendling KK, Alexander RW: Endothelial control of the cardiovascular system: Recent advances. FASEB J 1996; 10:283–92Griendling, KK Alexander, RW
Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH: EDHF: Bringing the concepts together. Trends Pharmacol Sci 2002; 23:374–80Busse, R Edwards, G Feletou, M Fleming, I Vanhoutte, PM Weston, AH
Quilley J, Fulton D, McGiff JC: Hyperpolarizing factors. Biochem Pharmacol 1997; 54:1059–70Quilley, J Fulton, D McGiff, JC
Popp R, Fleming I, Busse R: Pulsatile stretch in coronary arteries elicits release of endothelium-derived hyperpolarizing factor: A modulator of arterial compliance. Circ Res 1998; 82:696–703Popp, R Fleming, I Busse, R
Ballermann BJ, Dardik A, Eng E, Liu A: Shear stress and the endothelium. Kidney Int Suppl 1998; 67:S100–8Ballermann, BJ Dardik, A Eng, E Liu, A
Just A: Nitric oxide and renal autoregulation. Kidney Blood Press Res 1997; 20:201–4Just, A
Mombouli J-V, Vanhoutte PM: Endothelium-derived hyperpolarizing factor(s): Updating the unknown. Trends Pharmacol Sci 1997; 18:252–6Mombouli, J-V Vanhoutte, PM
Gandhi CR, Berkowitz DE, Watkins D: Endothelins. Anesthesiology 1994; 80:892–905Gandhi, CR Berkowitz, DE Watkins, D
Kanaide H: Endothelin regulation of vascular tonus. Gen Pharmacol 1996; 27:559–63Kanaide, H
Douglas SA, Ohlstein EH: Signal transduction mechanisms mediating the vascular actions of endothelin. J Vasc Res 1997; 34:152–64Douglas, SA Ohlstein, EH
Cohen RA, Vanhoutte PM: Endothelium-dependent hyperpolarization. Circulation 1995; 92:3337–49Cohen, RA Vanhoutte, PM
Su JY, Zhang CC: Intracellular mechanisms of halothane’s effect on isolated aortic strips of the rabbit. Anesthesiology 1989; 71:409–17Su, JY Zhang, CC
Blaise GA, Hughes JM, Sill JC, Buluran JN, Caille G: Attenuation of contraction of isolated canine coronary arteries by enflurane and halothane. Can J Anaesth 1991; 38:111–5Blaise, GA Hughes, JM Sill, JC Buluran, JN Caille, G
Nakamura K, Hatano Y, Toda H, Nishiwada M, Baek WY, Mori K: Halothane-induced relaxation of vascular smooth muscle: A possible contribution of increased cyclic GMP formation. Jpn J Pharmacol 1991; 55:165–8Nakamura, K Hatano, Y Toda, H Nishiwada, M Baek, WY Mori, K
Marijic J, Buljubasic N, Coughlan MG, Kampine JP, Bosnjak ZJ: Effect of K+channel blockade with tetraethylammonium on anesthetic-induced relaxation in canine cerebral and coronary arteries. Anesthesiology 1992; 77:948–55Marijic, J Buljubasic, N Coughlan, MG Kampine, JP Bosnjak, ZJ
Bollen BA, McKlveen RE, Stevenson JA: Halothane relaxes previously constricted human epicardial coronary artery segments more than isoflurane. Anesth Analg 1992; 75:4–8Bollen, BA McKlveen, RE Stevenson, JA
Jensen NF, Todd MM, Kramer DJ, Leonard PA, Warner DS: A comparison of the vasodilating effects of halothane and isoflurane on the isolated rabbit basilar artery with and without intact endothelium. Anesthesiology 1992; 76:624–34Jensen, NF Todd, MM Kramer, DJ Leonard, PA Warner, DS
Bollen BA, McKlveen RE, Stevenson JA: Halothane relaxes preconstricted small and medium isolated porcine coronary artery segments more than isoflurane. Anesth Analg 1992; 75:9–17Bollen, BA McKlveen, RE Stevenson, JA
Tsuchida H, Namba H, Yamakage M, Fujita S, Notsuki E, Namiki A: Effects of halothane and isoflurane on cytosolic calcium ion concentrations and contraction in vascular smooth muscle of the rat aorta. Anesthesiology 1993; 78:531–40Tsuchida, H Namba, H Yamakage, M Fujita, S Notsuki, E Namiki, A
Yamazaki M, Momose Y, Ito Y: Effects of sevoflurane or halothane on contractile responses of isolated canine basilar artery. Jpn J Anesth 1994; 43:672–9Yamazaki, M Momose, Y Ito, Y
Akata T, Boyle WA III: Volatile anesthetic actions on contractile proteins in membrane-permeabilized small mesenteric arteries. Anesthesiology 1995; 82:700–12Akata, T Boyle, WA
Namba H, Tsuchida H: Effect of volatile anesthetics with and without verapamil on intracellular activity in vascular smooth muscle. Anesthesiology 1996; 84:1465–74Namba, H Tsuchida, H
Tsuneyoshi I, Zhang D, Boyle WA III: Ca2+- and myosin phosphorylation-independent relaxation by halothane in K+-depolarized rat mesenteric arteries. Anesthesiology 2003; 99:656–65Tsuneyoshi, I Zhang, D Boyle, WA
Boyle WA III, Maher GM: Endothelium-independent vasoconstricting and vasodilating actions of halothane on rat mesenteric resistance blood vessels. Anesthesiology 1995; 82:221–35Boyle, WA Maher, GM
Kobayashi Y, Freas W, Muldoon SM: Effects of enflurane on adrenergic function in canine mesenteric artery and vein. Anesth Analg 1995; 81:265–71Kobayashi, Y Freas, W Muldoon, SM
Tsuchida H, Namba H, Seki S, Fujita S, Tanaka S, Namiki A: Role of intracellular Ca2+pools in the effects of halothane and isoflurane on vascular smooth muscle contraction. Anesth Analg 1994; 78:1067–76Tsuchida, H Namba, H Seki, S Fujita, S Tanaka, S Namiki, A
Izumi K, Akata T, Takahashi S: Role of endothelium in the action of isoflurane on vascular smooth muscle of isolated mesenteric resistance arteries. Anesthesiology 2001; 95:990–8Izumi, K Akata, T Takahashi, S
Blaise G, Sill JC, Nugent M, Van Dyke RA, Vanhoutte PM: Isoflurane causes endothelium-dependent inhibition of contractile responses of canine coronary arteries. Anesthesiology 1987; 67:513–7Blaise, G Sill, JC Nugent, M Van Dyke, RA Vanhoutte, PM
Izumi K, Akata T, Takahashi S: The action of sevoflurane on vascular smooth muscle of isolated mesenteric resistance arteries: I. Role of endothelium. Anesthesiology 2000; 92:1426–40Izumi, K Akata, T Takahashi, S
Moriyama S, Nakamura K, Hatano Y, Harioka T, Mori K: Responses to barbiturates of isolated dog cerebral and mesenteric arteries contracted with KCl and prostaglandin F2 alpha. Acta Anaesthesiol Scand 1990; 34:523–9Moriyama, S Nakamura, K Hatano, Y Harioka, T Mori, K
Sanchez-Ferrer CF, Marin J, Benitez J, Herrera N, Rico I, Salaices M: Effect of pentobarbital on the contraction and calcium movements in cat cerebral and peripheral arteries. Brain Res 1987; 411:304–9Sanchez-Ferrer, CF Marin, J Benitez, J Herrera, N Rico, I Salaices, M
Kang BS, Lee YH, Nam TS, Yeon DS, Hwang SK, Park KS: Effects of ketamine on contractile responses in vascular smooth muscle. Yonsei Med J 1990; 31:325–32Kang, BS Lee, YH Nam, TS Yeon, DS Hwang, SK Park, KS
Kanmura Y, Kajikuri J, Itoh T, Yoshitake J: Effects of ketamine on contraction and synthesis of inositol 1,4,5-triphosphate in smooth muscle of the rabbit mesenteric artery. Anesthesiology 1993; 79:571–9Kanmura, Y Kajikuri, J Itoh, T Yoshitake, J
Ratz PH, Callahan PE, Lattanzio FA Jr: Ketamine relaxes rabbit femoral arteries by reducing [Ca2+]i and phospholipase C activity. Eur J Pharmacol 1993; 236:433–41Ratz, PH Callahan, PE Lattanzio, FA
Yamazaki M, Ito Y, Momose Y: Effects of ketamine on K+-contracture in isolated vascular smooth muscle from rabbit. Jpn J Anesth 1989; 38:751–9Yamazaki, M Ito, Y Momose, Y
Yamazaki M, Momose Y, Shakunaga K, Kamitani K, Ito Y: The vasodilatory effects of ketamine on isolated rabbit portal veins. Pharmacol Toxicol 1995; 76:3–8Yamazaki, M Momose, Y Shakunaga, K Kamitani, K Ito, Y
Tanaka S, Kanaya N, Homma Y, Damron DS, Murray PA: Propofol increases pulmonary artery smooth muscle myofilament calcium sensitivity: Role of protein kinase C. Anesthesiology 2002; 97:1557–66Tanaka, S Kanaya, N Homma, Y Damron, DS Murray, PA
Wallerstedt SM, Reinstrup P, Uski T, Bodelsson M: Effects of propofol on isolated human pial arteries. Acta Anaesthesiol Scand 1999; 43:1065–8Wallerstedt, SM Reinstrup, P Uski, T Bodelsson, M
Imura N, Shiraishi Y, Katsuya H, Itoh T: Effect of propofol on norepinephrine-induced increases in [Ca2+]i and force in smooth muscle of the rabbit mesenteric resistance artery. Anesthesiology 1998; 88:1566–78Imura, N Shiraishi, Y Katsuya, H Itoh, T
Wallerstedt SM, Bodelsson M: Effect of propofol on isolated human omental arteries and veins. Br J Anaesth 1997; 78:296–300Wallerstedt, SM Bodelsson, M
Yamanoue T, Brum JM, Estafanous FG: Vasodilation and mechanism of action of propofol in porcine coronary artery. Anesthesiology 1994; 81:443–51Yamanoue, T Brum, JM Estafanous, FG
Chang KS, Davis RF: Propofol produces endothelium-independent vasodilation and may act as a Ca2+channel blocker. Anesth Analg 1993; 76:24–32Chang, KS Davis, RF
Nakamura K, Hatano Y, Hirakata H, Nishiwada M, Toda H, Mori K: Direct vasoconstrictor and vasodilator effects of propofol in isolated dog arteries. Br J Anaesth 1992; 68:193–7Nakamura, K Hatano, Y Hirakata, H Nishiwada, M Toda, H Mori, K
Bentley GN, Gent JP, Goodchild CS: Vascular effects of propofol: Smooth muscle relaxation in isolated veins and arteries. J Pharm Pharmacol 1989; 41:797–8Bentley, GN Gent, JP Goodchild, CS
Shapiro BM, Wendling WW, Ammaturo FJ, Chen D, Pham PS, Furukawa S, Carlsson C: Vascular effects of etomidate administered for electroencephalographic burst suppression in humans. J Neurosurg Anesthesiol 1998; 10:231–6Shapiro, BM Wendling, WW Ammaturo, FJ Chen, D Pham, PS Furukawa, S Carlsson, C
Ishii K, Kano T, Ando J: Pharmacological effects of flurazepam and diazepam on isolated canine arteries. Jpn J Pharmacol 1983; 33:65–71Ishii, K Kano, T Ando, J
Greenberg S, McGowan C, Xie J, Summer WR: Selective pulmonary and venous smooth muscle relaxation by furosemide: A comparison with morphine. J Pharmacol Exp Ther 1994; 270:1077–85Greenberg, S McGowan, C Xie, J Summer, WR
el-Sharkawy TY, al-Shireida MF, Pilcher CW: Vascular effects of some opioid receptor agonists. Can J Physiol Pharmacol 1991; 69:846–51el-Sharkawy, TY al-Shireida, MF Pilcher, CW
Spiss CK, Smith CM, Tsujimoto G, Hoffman BB, Maze M: Prolonged hyporesponsiveness of vascular smooth muscle contraction after halothane anesthesia in rabbits. Anesth Analg 1985; 64:1–6Spiss, CK Smith, CM Tsujimoto, G Hoffman, BB Maze, M
Muldoon SM, Hart JL, Bowen KA, Freas W: Attenuation of endothelium-mediated vasodilation by halothane. Anesthesiology 1988; 68:31–7Muldoon, SM Hart, JL Bowen, KA Freas, W
Stadnicka A, Flynn NM, Bosnjak ZJ, Kampine JP: Enflurane, halothane, and isoflurane attenuate contractile responses to exogenous and endogenous norepinephrine in isolated small mesenteric veins of the rabbit. Anesthesiology 1993; 78:326–34Stadnicka, A Flynn, NM Bosnjak, ZJ Kampine, JP
Kobayashi Y, Yoshida K, Noguchi M, Wakasugi Y, Ito H, Okabe E: Effect of enflurane on contractile reactivity in isolated canine mesenteric arteries and veins. Anesth Analg 1990; 70:530–6Kobayashi, Y Yoshida, K Noguchi, M Wakasugi, Y Ito, H Okabe, E
Su JY, Chang YI, Tang LJ: Mechanisms of action of enflurane on vascular smooth muscle: Comparison of rabbit aorta and femoral artery. Anesthesiology 1994; 81:700–9Su, JY Chang, YI Tang, LJ
Akata T, Nakashima M, Kodama K, Boyle WA III, Takahashi S: Effects of volatile anesthetics on acetylcholine-induced relaxation in the rabbit mesenteric resistance artery. Anesthesiology 1995; 82:188–204Akata, T Nakashima, M Kodama, K Boyle, WA Takahashi, S
Akata T, Kodama K, Takahashi S: Volatile anaesthetic actions on norepinephrine-induced contraction of small splanchnic resistance arteries. Can J Anaesth 1995; 42:1040–50Akata, T Kodama, K Takahashi, S
Su JY: Mechanisms of action of isoflurane on contraction of rabbit conduit artery. Anesth Analg 1996; 82:837–42Su, JY
Yamaguchi A, Okabe E: Effect of sevoflurane on the vascular reactivity of rabbit mesenteric artery. Br J Anaesth 1995; 74:576–82Yamaguchi, A Okabe, E
Xu J, Cheng Q, Niu X: Effects of sevoflurane on contractility of isolated thoracic aorta rings in rabbits. Bull Hunan Med Univ 1997; 22:294–6Xu, J Cheng, Q Niu, X
Kanmura Y, Yoshitake J, Casteels R: Ketamine-induced relaxation in intact and skinned smooth muscles of the rabbit ear artery. Br J Pharmacol 1989; 97:591–7Kanmura, Y Yoshitake, J Casteels, R
Boillot A, Laurant P, Berthelot A, Barale F: Effects of propofol on vascular reactivity in isolated aortae from normotensive and spontaneously hypertensive rats. Br J Anaesth 1999; 83:622–9Boillot, A Laurant, P Berthelot, A Barale, F
MacPherson RD, Rasiah RL, McLeod LJ: Propofol attenuates the myogenic response of vascular smooth muscle. Anesth Analg 1993; 76:822–9MacPherson, RD Rasiah, RL McLeod, LJ
Klockgether-Radke AP, Frerichs A, Kettler D, Hellige G: Propofol and thiopental attenuate the contractile response to vasoconstrictors in human and porcine coronary artery segments. Eur J Anaesthesiol 2000; 17:485–90Klockgether-Radke, AP Frerichs, A Kettler, D Hellige, G
Yamaguchi S, Kanmura Y, Yoshimura N: Effects of midazolam on contractions in smooth muscle of the rabbit mesenteric artery. Anesth Analg 1997; 84:199–205Yamaguchi, S Kanmura, Y Yoshimura, N
Shiraishi Y, Ohashi M, Kanmura Y, Yamaguchi S, Yoshimura N, Itoh T: Possible mechanisms underlying the midazolam-induced relaxation of the noradrenaline-contraction in rabbit mesenteric resistance artery. Br J Pharmacol 1997; 121:1155–63Shiraishi, Y Ohashi, M Kanmura, Y Yamaguchi, S Yoshimura, N Itoh, T
Toda N, Hatano Y: Alpha-adrenergic blocking action of fentanyl on the isolated aorta of the rabbit. Anesthesiology 1977; 46:411–6Toda, N Hatano, Y
Brendel JK, Johns RA: Isoflurane does not vasodilate rat thoracic aortic rings by endothelium-derived relaxing factor or other cyclic GMP–mediated mechanisms. Anesthesiology 1992; 77:126–31Brendel, JK Johns, RA
Flynn NM, Buljubasic N, Bosnjak ZJ, Kampine JP: Isoflurane produces endothelium-independent relaxation in canine middle cerebral arteries. Anesthesiology 1992; 76:461–7Flynn, NM Buljubasic, N Bosnjak, ZJ Kampine, JP
Stone DJ, Johns RA: Endothelium-dependent effects of halothane, enflurane, and isoflurane on isolated rat aortic vascular rings. Anesthesiology 1989; 71:126–32Stone, DJ Johns, RA
Witzeling TM, Sill JC, Hughes JM, Blaise GA, Nugent M, Rorie DK: Isoflurane and halothane attenuate coronary artery constriction evoked by serotonin in isolated porcine vessels and in intact pigs. Anesthesiology 1990; 73:100–8Witzeling, TM Sill, JC Hughes, JM Blaise, GA Nugent, M Rorie, DK
Yoshino J, Akata T, Izumi K, Takahashi S: Multiple actions of halothane on contractile response to noradrenaline in isolated mesenteric resistance arteries. Naunyn Schmiedebergs Arch Pharmacol 2005; 371:500–15Yoshino, J Akata, T Izumi, K Takahashi, S
Lischke V, Busse R, Hecker M: Inhalational anesthetics inhibit the release of endothelium-derived hyperpolarizing factor in the rabbit carotid artery. Anesthesiology 1995; 83:574–82Lischke, V Busse, R Hecker, M
Uggeri MJ, Proctor GJ, Johns RA: Halothane, enflurane, and isoflurane attenuate both receptor- and non–receptor-mediated EDRF production in rat thoracic aorta. Anesthesiology 1992; 76:1012–7Uggeri, MJ Proctor, GJ Johns, RA
Hart JL, Jing M, Bina S, Freas W, Van Dyke RA, Muldoon SM: Effects of halothane on EDRF/cGMP-mediated vascular smooth muscle relaxations. Anesthesiology 1993; 79:323–31Hart, JL Jing, M Bina, S Freas, W Van Dyke, RA Muldoon, SM
Nakamura K, Terasako K, Toda H, Miyawaki I, Kakuyama M, Nishiwada M, Hatano Y, Mori K: Mechanisms of inhibition of endothelium-dependent relaxation by halothane, isoflurane, and sevoflurane. Can J Anaesth 1994; 41:340–6Nakamura, K Terasako, K Toda, H Miyawaki, I Kakuyama, M Nishiwada, M Hatano, Y Mori, K
Iranami H, Hatano Y, Tsukiyama Y, Maeda H, Mizumoto K: A β-adrenoceptor agonist evokes a nitric oxide–cGMP relaxation mechanism modulated by adenylyl cyclase in rat aorta: Halothane does not inhibit this mechanism. Anesthesiology 1996; 85:1129–38Iranami, H Hatano, Y Tsukiyama, Y Maeda, H Mizumoto, K
Iranami H, Hatano Y, Tsukiyama Y, Yamamoto M, Maeda H, Mizumoto K: Halothane inhibition of acetylcholine-induced relaxation in rat mesenteric artery and aorta. Can J Anaesth 1997; 44:1196–203Iranami, H Hatano, Y Tsukiyama, Y Yamamoto, M Maeda, H Mizumoto, K
Higueras J, Sarria B, Ortiz JL, Cortijo J, Maruenda A, Barbera M, Morcillo EJ: Halothane inhibits endothelium-dependent relaxation elicited by acetylcholine in human isolated pulmonary arteries. Eur J Pharmacol 1997; 326:175–81Higueras, J Sarria, B Ortiz, JL Cortijo, J Maruenda, A Barbera, M Morcillo, EJ
Oshima Y, Ishibe Y, Okazaki N, Sato T: Isoflurane inhibits endothelium-mediated nitric oxide relaxing pathways in the isolated perfused rabbit lung. Can J Anaesth 1997; 44:1108–14Oshima, Y Ishibe, Y Okazaki, N Sato, T
Yoshida K, Okabe E: Selective impairment of endothelium-dependent relaxation by sevoflurane: Oxygen free radicals participation. Anesthesiology 1992; 76:440–7Yoshida, K Okabe, E
Arriero MM, Munoz Alameda L, Lopez-Farre A, Escribano Burgos M, Carrasco C, Millas I, Celdran A, de la Pinta JC: Sevoflurane reduces endothelium-dependent vasorelaxation: Role of superoxide anion and endothelin. Can J Anaesth 2002; 49:471–6Arriero, MM Munoz Alameda, L Lopez-Farre, A Escribano Burgos, M Carrasco, C Millas, I Celdran, A de la Pinta, JC
Castillo C, Asbun J, Escalante B, Villalon CM, Lopez P, Castillo EF: Thiopental inhibits nitric oxide production in rat aorta. Can J Physiol Pharmacol 1999; 77:958–66Castillo, C Asbun, J Escalante, B Villalon, CM Lopez, P Castillo, EF
Ogawa K, Tanaka S, Murray PA: Inhibitory effects of etomidate and ketamine on endothelium-dependent relaxation in canine pulmonary artery. Anesthesiology 2001; 94:668–77Ogawa, K Tanaka, S Murray, PA
Mimaroglu C, Utkan T, Kaya T, Kafali H, Sarioglu Y: Effects of propofol on vascular smooth muscle function in isolated rat aorta. Methods Find Exp Clin Pharmacol 1994; 16:257–61Mimaroglu, C Utkan, T Kaya, T Kafali, H Sarioglu, Y
Yamashita A, Kajikuri J, Ohashi M, Kanmura Y, Itoh T: Inhibitory effects of propofol on acetylcholine-induced, endothelium-dependent relaxation and prostacyclin synthesis in rabbit mesenteric resistance arteries. Anesthesiology 1999; 91:1080–9Yamashita, A Kajikuri, J Ohashi, M Kanmura, Y Itoh, T
Kondo U, Kim SO, Murray PA: Propofol selectively attenuates endothelium-dependent pulmonary vasodilation in chronically instrumented dogs. Anesthesiology 2000; 93:437–46Kondo, U Kim, SO Murray, PA
Lischke V, Busse R, Hecker M: Volatile and intravenous anesthetics selectively attenuate the release of endothelium-derived hyperpolarizing factor elicited by bradykinin in the coronary microcirculation. Naunyn Schmiedebergs Arch Pharmacol 1995; 352:346–9Lischke, V Busse, R Hecker, M
Kessler P, Lischke V, Hecker M: Etomidate and thiopental inhibit the release of endothelium-derived hyperpolarizing factor in the human renal artery. Anesthesiology 1996; 84:1485–8Kessler, P Lischke, V Hecker, M
Sohn JT, Kim HJ, Cho HC, Shin IW, Lee HK, Chung YK: Effect of etomidate on endothelium-dependent relaxation induced by acetylcholine in rat aorta. Anaesth Intensive Care 2004; 32:476–81Sohn, JT Kim, HJ Cho, HC Shin, IW Lee, HK Chung, YK
MacPherson RD, Rasiah RL, McLeod LJ: Intraarterial propofol is not directly toxic to vascular endothelium. Anesthesiology 1992; 76:967–71MacPherson, RD Rasiah, RL McLeod, LJ
Johns RA, Tichotsky A, Muro M, Spaeth JP, Le Cras TD, Rengasamy A: Halothane and isoflurane inhibit endothelium-derived relaxing factor–dependent cyclic guanosine monophosphate accumulation in endothelial cell–vascular smooth muscle co-cultures independent of an effect on guanylyl cyclase activation. Anesthesiology 1995; 83:823–34Johns, RA Tichotsky, A Muro, M Spaeth, JP Le Cras, TD Rengasamy, A
Az-ma T, Fujii K, Yuge O: Inhibitory effect of sevoflurane on nitric oxide release from cultured endothelial cells. Eur J Pharmacol 1995; 289:33–9Az-ma, T Fujii, K Yuge, O
Pajewski TN, Miao N, Lynch C III, Johns RA: Volatile anesthetics affect calcium mobilization in bovine endothelial cells. Anesthesiology 1996; 85:1147–56Pajewski, TN Miao, N Lynch, C Johns, RA
Simoneau C, Thuringer D, Cai S, Garneau L, Blaise G, Sauve R: Effects of halothane and isoflurane on bradykinin-evoked Ca2+influx in bovine aortic endothelial cells. Anesthesiology 1996; 85:366–79Simoneau, C Thuringer, D Cai, S Garneau, L Blaise, G Sauve, R
Tsuchida H, Seki S, Tanaka S, Okazaki K, Namiki A: Halothane attenuates the endothelial Ca2+increase and vasorelaxation of vascular smooth muscle in the rat aorta. Br J Anaesth 2000; 84:215–20Tsuchida, H Seki, S Tanaka, S Okazaki, K Namiki, A
Kanna T, Akata T, Izumi K, Nakashima M, Yonemitsu Y, Hashizume M, Takahashi S: Sevoflurane and bradykinin-induced calcium mobilization in pulmonary arterial valvular endothelial cells in situ  : Sevoflurane stimulates plasmalemmal calcium influx into endothelial cells. J Cardiovasc Pharmacol 2002; 40:714–24Kanna, T Akata, T Izumi, K Nakashima, M Yonemitsu, Y Hashizume, M Takahashi, S
Tas PW, Stobetael C, Roewer N: The volatile anesthetic isoflurane inhibits the histamine-induced Ca2+influx in primary human endothelial cells. Anesth Analg 2003; 97:430–5Tas, PW Stobetael, C Roewer, N
Jing M, Ling GS, Bina S, Hart JL, Muldoon SM: Halothane attenuates nitric oxide relaxation of rat aortas by competition for the nitric oxide receptor site on soluble guanylyl cyclase. Eur J Pharmacol 1998; 342:217–24Jing, M Ling, GS Bina, S Hart, JL Muldoon, SM
Toda H, Nakamura K, Hatano Y, Nishiwada M, Kakuyama M, Mori K: Halothane and isoflurane inhibit endothelium-dependent relaxation elicited by acetylcholine. Anesth Analg 1992; 75:198–203Toda, H Nakamura, K Hatano, Y Nishiwada, M Kakuyama, M Mori, K
Park KW, Dai HB, Lowenstein E, Darvish A, Sellke FW: Isoflurane attenuates cAMP-mediated vasodilation in rat microvessels. Circulation 1995; 92:II423–7Park, KW Dai, HB Lowenstein, E Darvish, A Sellke, FW
Tanaka S, Tsuchida H: Effects of halothane and isoflurane on β-adrenoceptor–mediated responses in the vascular smooth muscle of rat aorta. Anesthesiology 1998; 89:1209–17Tanaka, S Tsuchida, H
Larach DR, Schuler HG: Potassium channel blockade and halothane vasodilation in conducting and resistance coronary arteries. J Pharmacol Exp Ther 1993; 267:72–81Larach, DR Schuler, HG
Crystal GJ, Gurevicius J, Salem R, Zhou X: Role of adenosine triphosphate–sensitive potassium channels in coronary vasodilation by halothane, isoflurane, and enflurane. Anesthesiology 1997; 86:448–58Crystal, GJ Gurevicius, J Salem, R Zhou, X
Cason BA, Shubayev I, Hickey RF: Blockade of adenosine triphosphate–sensitive potassium channels eliminates isoflurane-induced coronary artery vasodilation. Anesthesiology 1994; 81:1245–55Cason, BA Shubayev, I Hickey, RF
Crystal GJ, Zhou X, Gurevicius J, Czinn EA, Salem MR, Alam S, Piotrowski A, Hu G: Direct coronary vasomotor effects of sevoflurane and desflurane in in situ  canine hearts. Anesthesiology 2000; 92:1103–13Crystal, GJ Zhou, X Gurevicius, J Czinn, EA Salem, MR Alam, S Piotrowski, A Hu, G
Kokita N, Stekiel TA, Yamazaki M, Bosnjak ZJ, Kampine JP, Stekiel WJ: Potassium channel–mediated hyperpolarization of mesenteric vascular smooth muscle by isoflurane. Anesthesiology 1999; 90:779–88Kokita, N Stekiel, TA Yamazaki, M Bosnjak, ZJ Kampine, JP Stekiel, WJ
Stekiel TA, Contney SJ, Kokita N, Bosnjak ZJ, Kampine JP, Stekiel WJ: Mechanisms of isoflurane-mediated hyperpolarization of vascular smooth muscle in chronically hypertensive and normotensive conditions. Anesthesiology 2001; 94:496–506Stekiel, TA Contney, SJ Kokita, N Bosnjak, ZJ Kampine, JP Stekiel, WJ
Seki S, Sato K, Nakayama M, Murray PA: Halothane and enflurane attenuate pulmonary vasodilation mediated by adenosine triphosphate–sensitive potassium channels compared to the conscious state. Anesthesiology 1997; 86:923–35Seki, S Sato, K Nakayama, M Murray, PA
Seki S, Horibe M, Murray PA: Halothane attenuates endothelium-dependent pulmonary vasorelaxant response to lemakalim, an adenosine triphosphate (ATP)–sensitive potassium channel agonist. Anesthesiology 1997; 87:625–34Seki, S Horibe, M Murray, PA
Fujiwara Y, Murray PA: Effects of isoflurane anesthesia on pulmonary vascular response to KATPchannel activation and circulatory hypotension in chronically instrumented dogs. Anesthesiology 1999; 90:799–811Fujiwara, Y Murray, PA
Nakayama M, Kondo U, Murray PA: Pulmonary vasodilator response to adenosine triphosphate–sensitive potassium channel activation is attenuated during desflurane but preserved during sevoflurane anesthesia compared with the conscious state. Anesthesiology 1998; 88:1023–35Nakayama, M Kondo, U Murray, PA
Sohn JT, Murray PA: Inhibitory effects of etomidate and ketamine on adenosine triphosphate–sensitive potassium channel relaxation in canine pulmonary artery. Anesthesiology 2003; 98:104–13Sohn, JT Murray, PA
Kakuyama M, Hatano Y, Nakamura K, Toda H, Terasako K, Nishiwada M, Mori K: Halothane and enflurane constrict canine mesenteric arteries by releasing Ca2+from intracellular Ca 2+stores. Anesthesiology 1994; 80:1120–7Kakuyama, M Hatano, Y Nakamura, K Toda, H Terasako, K Nishiwada, M Mori, K
Akata T, Boyle WA III: Dual actions of halothane on intracellular calcium stores of vascular smooth muscle. Anesthesiology 1996; 84:580–95Akata, T Boyle, WA
Akata T, Nakashima M, Izumi K: Comparison of volatile anesthetic actions on intracellular calcium stores of vascular smooth muscle: Investigation in isolated systemic resistance arteries. Anesthesiology 2001; 94:840–50Akata, T Nakashima, M Izumi, K
Mousa WF, Enoki T, Fukuda K: Thiopental induces contraction of rat aortic smooth muscle through Ca2+release from the sarcoplasmic reticulum. Anesth Analg 2000; 91:62–7Mousa, WF Enoki, T Fukuda, K
Henkel CC, Asbun J, Ceballos G, del Carmen Castillo M, Castillo EF: Relationship between extra and intracellular sources of calcium and the contractile effect of thiopental in rat aorta. Can J Physiol Pharmacol 2001; 79:407–14Henkel, CC Asbun, J Ceballos, G del Carmen Castillo, M Castillo, EF
Wallerstedt SM, Tornebrandt K, Bodelsson M: Relaxant effects of propofol on human omental arteries and veins. Br J Anaesth 1998; 80:655–9Wallerstedt, SM Tornebrandt, K Bodelsson, M
Introna RP, Pruett JK, Yodlowski EH, Grover E: Direct effects of propofol (2,6-diisopropylphenol) on canine coronary artery ring tension. Gen Pharmacol 1993; 24:497–502Introna, RP Pruett, JK Yodlowski, EH Grover, E
Waters A, Harder DR: Electromechanical coupling in rat basilar artery in response to morphine. Neurosurgery 1983; 13:676–80Waters, A Harder, DR
Sill JC, Uhl C, Eskuri S, Van Dyke R, Tarara J: Halothane inhibits agonist-induced inositol phosphate and Ca2+signaling in A7r5 cultured vascular smooth muscle cells. Mol Pharmacol 1991; 40:1006–13Sill, JC Uhl, C Eskuri, S Van Dyke, R Tarara, J
Sill JC, Eskuri S, Nelson R, Tarara J, Van Dyke RA: The volatile anesthetic isoflurane attenuates Ca++mobilization in cultured vascular smooth muscle cells. J Pharmacol Exp Ther 1993; 265:74–80Sill, JC Eskuri, S Nelson, R Tarara, J Van Dyke, RA
Ozhan M, Sill JC, Atagunduz P, Martin R, Katusic ZS: Volatile anesthetics and agonist-induced contractions in porcine coronary artery smooth muscle and Ca2+mobilization in cultured immortalized vascular smooth muscle cells. Anesthesiology 1994; 80:1102–13Ozhan, M Sill, JC Atagunduz, P Martin, R Katusic, ZS
Fujihara H, Fukuda S, Fujiwara N, Shimoji K: The effects of halothane on arginine-vasopressin-induced Ca2+mobilization from the intracellular stores and the receptor-mediated Ca2+entry from the extracellular space in single cultured smooth muscle cells of rat aorta. Anesth Analg 1996; 83:584–90Fujihara, H Fukuda, S Fujiwara, N Shimoji, K
Su JY, Tang L-J: Effects of halothane on the sarcoplasmic reticulum Ca2+stores and contractile proteins in rabbit pulmonary arteries. Anesthesiology 1998; 88:1096–106Su, JY Tang, L-J
Samain E, Bouillier H, Marty J, Safar M, Dagher G: The effect of propofol on angiotensin II-induced Ca2+mobilization in aortic smooth muscle cells from normotensive and hypertensive rats. Anesth Analg 2000; 90:546–52Samain, E Bouillier, H Marty, J Safar, M Dagher, G
Samain E, Bouillier H, Rucker-Martin C, Mazoit JX, Marty J, Renaud JF, Dagher G: Isoflurane alters angiotensin II–induced Ca2+mobilization in aortic smooth muscle cells from hypertensive rats: Implication of cytoskeleton. Anesthesiology 2002; 97:642–51Samain, E Bouillier, H Rucker-Martin, C Mazoit, JX Marty, J Renaud, JF Dagher, G
Su JY, Vo AC: Ca(2+)-calmodulin–dependent protein kinase II plays a major role in halothane-induced dose-dependent relaxation in the skinned pulmonary artery. Anesthesiology 2002; 97:207–14Su, JY Vo, AC
Su JY, Vo AC: Role of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and mitogen-activated protein kinases in volatile anesthetic–induced relaxation in newborn rabbit pulmonary artery. Anesthesiology 2003; 99:131–7Su, JY Vo, AC
Su JY, Vo AC: Role of PKC in isoflurane-induced biphasic contraction in skinned pulmonary arterial strips. Anesthesiology 2002; 96:155–61Su, JY Vo, AC
Iaizzo PA: The effects of halothane and isoflurane on intracellular Ca2+regulation in cultured cells with characteristics of vascular smooth muscle. Cell Calcium 1992; 13:513–20Iaizzo, PA
Kanmura Y, Missiaen L, Murray PA: The effects of ketamine on Ca2+movement in A7r5 vascular smooth muscle cells. Anesth Analg 1996; 83:1105–9Kanmura, Y Missiaen, L Murray, PA
Xuan YT, Glass PS: Propofol regulation of calcium entry pathways in cultured A10 and rat aortic smooth muscle cells. Br J Pharmacol 1996; 117:5–12Xuan, YT Glass, PS
Tanabe K, Kozawa O, Kaida T, Matsuno H, Niwa M, Ohta S, Dohi S, Uematsu T: Inhibitory effects of propofol on intracellular signaling by endothelin-1 in aortic smooth muscle cells. Anesthesiology 1998; 88:452–60Tanabe, K Kozawa, O Kaida, T Matsuno, H Niwa, M Ohta, S Dohi, S Uematsu, T
Tanabe K, Kozawa O, Matsuno H, Niwa M, Dohi S, Uematsu T: Effect of propofol on arachidonate cascade by vasopressin in aortic smooth muscle cells: Inhibition of PGI2 synthesis. Anesthesiology 1999; 90:215–24Tanabe, K Kozawa, O Matsuno, H Niwa, M Dohi, S Uematsu, T
Kobayashi S, Kitazawa T, Somlyo AV, Somlyo AP: Cytosolic heparin inhibits muscarinic and alpha-adrenergic Ca2+release in smooth muscle. J Biol Chem 1989; 264:17997–8004Kobayashi, S Kitazawa, T Somlyo, AV Somlyo, AP
Hatano Y, Nakamura K, Yakushiji T, Nishiwada M, Mori K, Anaes FC: Comparison of the direct effects of halothane and isoflurane on large and small coronary arteries isolated from dogs. Anesthesiology 1990; 73:513–7Hatano, Y Nakamura, K Yakushiji, T Nishiwada, M Mori, K Anaes, FC
Nakamura K, Toda H, Hatano Y, Mori K: Comparison of the direct effects of sevoflurane, isoflurane and halothane on isolated canine coronary arteries. Can J Anaesth 1993; 40:257–61Nakamura, K Toda, H Hatano, Y Mori, K
Buljubasic N, Flynn NM, Marijic J, Rusch NJ, Kampine JP, Bosnjak ZJ: Effects of isoflurane on K+and Ca2+conductance in isolated smooth muscle cells of canine cerebral arteries. Anesth Analg 1992; 75:590–6Buljubasic, N Flynn, NM Marijic, J Rusch, NJ Kampine, JP Bosnjak, ZJ
Buljubasic N, Rusch NJ, Marijic J, Kampine JP, Bosnjak ZJ: Effects of halothane and isoflurane on calcium and potassium channel currents in canine coronary arterial cells. Anesthesiology 1992; 76:990–8Buljubasic, N Rusch, NJ Marijic, J Kampine, JP Bosnjak, ZJ
Wilde DW: Isoflurane reduces Ca++channel current and accelerates current decay in guinea pig portal vein smooth muscle cells. J Pharmacol Exp Ther 1994; 271:1159–66Wilde, DW
Yamazaki M, Kamitani K, Ito Y, Momose Y: Effects of halothane and diltiazem on L-type calcium currents in single smooth muscle cells from rabbit portal veins. Br J Anaesth 1994; 73:209–13Yamazaki, M Kamitani, K Ito, Y Momose, Y
Sprague DH, Yang JC, Nfai SH: Effects of isoflurane and halothane on contractility and the cyclic 3′, 5′-adenosine monophosphate system in the rat aorta. Anesthesiology 1974; 40:162–7Sprague, DH Yang, JC Nfai, SH
Yamazaki M, Ito Y, Kuze S, Shibuya N, Momose Y: Effects of ketamine on voltage-dependent Ca2+currents in single smooth muscle cells from rabbit portal vein. Pharmacology 1992; 45:162–9Yamazaki, M Ito, Y Kuze, S Shibuya, N Momose, Y
Abdalla SS, Laravuso RB, Will JA: Mechanisms of the inhibitory effect of ketamine on guinea pig isolated main pulmonary artery. Anesth Analg 1994; 78:17–22Abdalla, SS Laravuso, RB Will, JA
Yamazaki M, Shibuya N, Kuze S, Ito Y, Momose Y: Effects of ketamine on voltage-dependent Ca2+current in single smooth muscle cells from rabbit portal vein. Jpn J Anesth 1990; 39:988–93Yamazaki, M Shibuya, N Kuze, S Ito, Y Momose, Y
Hirata S, Enoki T, Kitamura R, Vinh VH, Nakamura K, Mori K: Effects of isoflurane on receptor-operated Ca2+channels in rat aortic smooth muscle. Br J Anaesth 1998; 81:578–83Hirata, S Enoki, T Kitamura, R Vinh, VH Nakamura, K Mori, K
Vinh VH, Enoki T, Hirata S, Toda H, Kakuyama M, Nakamura K, Fukuda K: Comparative contractile effects of halothane and sevoflurane in rat aorta. Anesthesiology 2000; 92:219–27Vinh, VH Enoki, T Hirata, S Toda, H Kakuyama, M Nakamura, K Fukuda, K
Hughes AD, Schachter M: Multiple pathways for entry of calcium and other divalent cations in a vascular smooth muscle cell line (A7r5). Cell Calcium 1994; 15:317–30Hughes, AD Schachter, M
Clementi E, Meldolesi J: Pharmacological and functional properties of voltage-independent Ca2+channels. Cell Calcium 1996; 19:269–79Clementi, E Meldolesi, J
Yamamoto M, Hatano Y, Kakuyama M, Nakamura K, Tachibana T, Maeda H, Mori K: Different effects of halothane, isoflurane and sevoflurane on sarcoplasmic reticulum of vascular smooth muscle in dog mesenteric artery. Acta Anaesthesiol Scand 1997; 41:376–80Yamamoto, M Hatano, Y Kakuyama, M Nakamura, K Tachibana, T Maeda, H Mori, K
Kosk-Kosicka D, Roszczynska G: Inhibition of plasma membrane Ca2+-ATPase activity by volatile anesthetics. Anesthesiology 1993; 79:774–80Kosk-Kosicka, D Roszczynska, G
Franks JJ, Horn J-L, Janicki PK, Singh G: Halothane, isoflurane, xenon, and nitric oxide inhibit calcium ATPase activity in rat brain synaptic plasma membranes. Anesthesiology 1995; 82:108–17Franks, JJ Horn, J-L Janicki, PK Singh, G
Haworth RA, Goknur AB: Inhibition of sodium/calcium exchange and calcium channels of heart cells by volatile anesthetics. Anesthesiology 1995; 82:1255–65Haworth, RA Goknur, AB
Jin N, Siddiqui RA, English D, Rhoades RA: Communication between tyrosine kinase pathway and myosin light chain kinase pathway in smooth muscle. Am J Physiol 1996; 271:H1348–55Jin, N Siddiqui, RA English, D Rhoades, RA
Searle BM, Higashino H, Khalil F, Bogden JD, Tokushige A, Tamura H, Kino M, Aviv A: Vanadate effect on the Na,K-ATPase and the Na-K pump in in vitro  -grown rat vascular smooth muscle cells. Circ Res 1983; 53:186–91Searle, BM Higashino, H Khalil, F Bogden, JD Tokushige, A Tamura, H Kino, M Aviv, A
Yokoshiki H, Seki T, Sunagawa M, Sperelakis N: Inhibition of Ca2+-activated K+channels by tyrosine phosphatase inhibitors in rat mesenteric artery. Can J Physiol Pharmacol 2000; 78:745–50Yokoshiki, H Seki, T Sunagawa, M Sperelakis, N
Van Breemen C, Farinas BR, Gerba P, McNaughton ED: Excitation-contraction coupling in rabbit aorta studied by the lanthanum method for measuring cellular calcium influx. Circ Res 1972; 30:44–54Van Breemen, C Farinas, BR Gerba, P McNaughton, ED
Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, Imaizumi Y: TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res 2003; 93:829–38Muraki, K Iwata, Y Katanosaka, Y Ito, T Ohya, S Shigekawa, M Imaizumi, Y
Li PL, Tang WX, Valdivia HH, Zou AP, Campbell WB: cADP-ribose activates reconstituted ryanodine receptors from coronary arterial smooth muscle. Am J Physiol 2001; 280:H208–15Li, PL Tang, WX Valdivia, HH Zou, AP Campbell, WB
Katusic ZS, Shepherd JT, Vanhoutte PM: Potassium-induced endothelium-dependent rhythmic activity in canine basilar artery. J Cardiovasc Pharmacol 1988; 12:37–41Katusic, ZS Shepherd, JT Vanhoutte, PM
Omote M, Mizusawa H: Phenylephrine-induced rhythmic activity in the rabbit ear artery. Jpn J Physiol 1993; 43:511–20Omote, M Mizusawa, H
Wiedeman MP: Effect of venous flow on frequency of venous vasomotion in the bat wing. Circ Res 1957; 5:641–4Wiedeman, MP
Colantuoni A, Bertuglia S, Intaglietta M: Quantitation of rhythmic diameter changes in arterial microcirculation. Am J Physiol 1984; 246:H508–17Colantuoni, A Bertuglia, S Intaglietta, M
Gaylarde PM, Sarkany I: Periodic skin blood flow. N Engl J Med 1985; 312:1194–5Gaylarde, PM Sarkany, I
Meyer JU, Borgstrom P, Lindbom L, Intaglietta M: Vasomotion patterns in skeletal muscle arterioles during changes in arterial pressure. Microvasc Res 1988; 35:193–285Meyer, JU Borgstrom, P Lindbom, L Intaglietta, M
Strucl M, Peterec D, Finderle Z, Maver J: Pressure sensitivity of flow oscillations in postocclusive reactive skin hyperemia. Am J Physiol 1994; 266:H1762–8Strucl, M Peterec, D Finderle, Z Maver, J
Slaaf DW, Tangelder GJ, Teirlinck HC, Reneman RS: Arteriolar vasomotion and arterial pressure reduction in rabbit tenuissimus muscle. Microvasc Res 1987; 33:71–80Slaaf, DW Tangelder, GJ Teirlinck, HC Reneman, RS
Intaglietta M: Vasomotion as normal microvascular activity and a reaction to impaired homeostasis. Prog Appl Microcirc 1989; 15:1–9Intaglietta, M
Secomb TW, Intaglietta M, Gross JF: Effects of vasomotion on micro-circulatory mass transport. Prog Appl Microcirc 1989; 15:49–61Secomb, TW Intaglietta, M Gross, JF
Berridge MJ: Cytosolic calcium oscillations: A two pool model. Cell Calcium 1991; 12:63–72Berridge, MJ
Wier WG, Blatter LA: Ca2+-oscillations and Ca2+-waves in mammalian cardiac and vascular smooth muscle cells. Cell Calcium 1991; 12:241–54Wier, WG Blatter, LA
Hamada H, Damron DS, Murray PA: Intravenous anesthetics attenuate phenylephrine-induced calcium oscillations in individual pulmonary artery smooth muscle cells. Anesthesiology 1997; 87:900–7Hamada, H Damron, DS Murray, PA
Hong SJ, Damron DS, Murray PA: Benzodiazepines differentially inhibit phenylephrine-induced calcium oscillations in pulmonary artery smooth muscle cells. Anesthesiology 1998; 88:792–9Hong, SJ Damron, DS Murray, PA
Burt JM, Spray DC: Volatile anesthetics block intracellular communication between neonatal rat myocardial cells. Circ Res 1989; 65:829–37Burt, JM Spray, DC
He DS, Burt JM: Mechanism and selectivity of the effects of halothane on gap junction channel function. Circ Res 2000; 86:E104–9He, DS Burt, JM
Kakuyama M, Nakamura K, Mori K: Halothane decreases calcium sensitivity of rat aortic smooth muscle. Can J Anaesth 1999; 46:1164–71Kakuyama, M Nakamura, K Mori, K
Toda H, Su JY: Mechanisms of isoflurane-increased submaximum Ca2+-activated force in rabbit skinned femoral arterial strips. Anesthesiology 1998; 89:731–40Toda, H Su, JY
Alessi DR: The protein kinase C inhibitors Ro 318220 and GF 109203X are equally potent inhibitors of MAPKAP kinase-1beta (Rsk-2) and p70 S6 kinase. FEBS Lett 1997; 402:121–3Alessi, DR
Davies SP, Reddy H, Caivano M, Cohen P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000; 351:95–105Davies, SP Reddy, H Caivano, M Cohen, P
McGovern SL, Shoichet BK: Kinase inhibitors: Not just for kinases anymore. J Med Chem 2003; 46:1478–83McGovern, SL Shoichet, BK
Kim A, Bae YM, Kim J, Kim B, Ho WK, Earm YE, Cho SI: Direct block by bisindolylmaleimide of the voltage-dependent K+currents of rat mesenteric arterial smooth muscle. Eur J Pharmacol 2004; 483:117–26Kim, A Bae, YM Kim, J Kim, B Ho, WK Earm, YE Cho, SI
Ito S, Kajikuri J, Itoh T, Kuriyama H: Effect of lemakalim on changes in Ca2+concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery. Br J Pharmacol 1991; 104:227–33Ito, S Kajikuri, J Itoh, T Kuriyama, H
Quast U, Baumlin Y: Cromakalim inhibits contractions of rat isolated mesenteric bed induced by noradrenaline but not caffeine in Ca2+-free medium: Evidence for interference with receptor-mediated Ca2+mobilization. Eur J Pharmacol 1991; 200:239–49Quast, U Baumlin, Y
Yamagishi T, Yanagisawa T, Taira N: Activation of phospholipase C by the agonist U-46619 is inhibited by cromakalim-induced hyperpolarization in porcine coronary artery. Biochem Biophys Res Commun 1992; 187:1517–22Yamagishi, T Yanagisawa, T Taira, N
Challiss RAJ, Patel N, Arch JRS: Comparative effects of BRL 38227, nitrendipine and isoprenalin on carbachol- and histamine-stimulated phospholipase metabolism in airway smooth muscle. Br J Pharmacol 1992; 105:997–1003Challiss, RAJ Patel, N Arch, JRS
Schultz JE, Klumpp S, Benz R, Schurhoff-Goeters WJC, Schmid A: Regulation of adenylate cyclase from Paracium  by an intrinsic potassium conductance. Science 1992; 255:600–3Schultz, JE Klumpp, S Benz, R Schurhoff-Goeters, WJC Schmid, A
Maelicke A: An ion channel-gated adenylate cyclase. Trends Biochem Sci 1992; 17:51Maelicke, A
Ding X, Damron DS, Murray PA: Ketamine attenuates acetylcholine-induced contraction by decreasing myofilament Ca2+sensitivity in pulmonary veins. Anesthesiology 2005; 102:588–96Ding, X Damron, DS Murray, PA
Sill JC, Ozhan M, Nelson R, Uhl C: Isoflurane-, halothane- and agonist-evoked responses in pig coronary arteries and vascular smooth muscle cells. Adv Exp Med Biol 1991; 301:257–69Sill, JC Ozhan, M Nelson, R Uhl, C
Yu J, Tokinaga Y, Ogawa K, Iwahashi S, Hatano Y: Sevoflurane inhibits angiotensin II–induced, protein kinase C–mediated but not Ca2+-elicited contraction of rat aortic smooth muscle. Anesthesiology 2004; 100:879–84Yu, J Tokinaga, Y Ogawa, K Iwahashi, S Hatano, Y
Park KW, Dai HB, Lowenstein E, Sellke FW: Protein kinase C-induced contraction is inhibited by halothane but enhanced by isoflurane in rat coronary arteries. Anesth Analg 1996; 83:286–90Park, KW Dai, HB Lowenstein, E Sellke, FW
Yu J, Ogawa K, Tokinaga Y, Hatano Y: Sevoflurane inhibits guanosine 5′-[gamma-thio]triphosphate–stimulated, Rho/Rho-kinase–mediated contraction of isolated rat aortic smooth muscle. Anesthesiology 2003; 99:646–51Yu, J Ogawa, K Tokinaga, Y Hatano, Y
Mori T, Yanagisawa T, Taira N: Phorbol 12,13-dibutyrate increases vascular tone but has a dual action on intracellular calcium levels in porcine coronary arteries. Naunyn Schmiedebergs Arch Pharmacol 1990; 341:251–5Mori, T Yanagisawa, T Taira, N
Eskinder H, Gebremedhin D, Lee JG, Rusch NJ, Supan FD, Kampine JP, Bosnjak ZJ: Halothane and isoflurane decrease the open state probability of K+channels in dog cerebral arterial muscle cells. Anesthesiology 1995; 82:479–90Eskinder, H Gebremedhin, D Lee, JG Rusch, NJ Supan, FD Kampine, JP Bosnjak, ZJ
Wilde DW: Isoflurane reduces K+current in single smooth muscle cells of guinea pig portal vein. Anesth Analg 1996; 83:1307–13Wilde, DW
Villeneuve E, Blaise G, Sill JC, Guerard MJ, Buluran J, Girard D: Halothane 1.5 MAC, isoflurane 1.5 MAC, and the contractile responses of coronary arteries obtained from human hearts. Anesth Analg 1991; 72:454–61Villeneuve, E Blaise, G Sill, JC Guerard, MJ Buluran, J Girard, D
Duman A, Saide Sahin A, Esra Atalik K, oZtin ogun C, Basri Ulusoy H, Durgut K, oKesli S: The in vitro  effects of remifentanil and fentanyl on isolated human right atria and saphenous veins. J Cardiothorac Vasc Anesth 2003; 17:465–9Duman, A Saide Sahin, A Esra Atalik, K oZtin ogun, C Basri Ulusoy, H Durgut, K oKesli, S
Masuda T, Tomiyama Y, Kitahata H, Kuroda Y, Oshita S: Propofol inhibits volume-sensitive chloride channels in human coronary artery smooth muscle cells. Anesth Analg 2003; 97:657–62Masuda, T Tomiyama, Y Kitahata, H Kuroda, Y Oshita, S
Thorlacius K, Zhoujun C, Bodelsson M: Effects of sevoflurane on sympathetic neurotransmission in human omental arteries and veins. Br J Anaesth 2003; 90:766–73Thorlacius, K Zhoujun, C Bodelsson, M
Masuda T, Tomiyama Y, Kitahata H, Kuroda Y, Oshita S: Effect of propofol on hypotonic swelling-induced membrane depolarization in human coronary artery smooth muscle cells. Anesthesiology 2004; 100:648–56Masuda, T Tomiyama, Y Kitahata, H Kuroda, Y Oshita, S
Thorlacius K, Bodelsson M: Sevoflurane promotes endothelium-dependent smooth muscle relaxation in isolated human omental arteries and veins. Anesth Analg 2004; 99:423–8Thorlacius, K Bodelsson, M
Sahin AS, Duman A, Atalik EK, Ogun CO, Sahin TK, Erol A, Ozergin U: The mechanisms of the direct vascular effects of fentanyl on isolated human saphenous veins in vitro  J Cardiothorac Vasc Anesth 2005; 19:197–200Sahin, AS Duman, A Atalik, EK Ogun, CO Sahin, TK Erol, A Ozergin, U
Busija DW, Miller AW, Katakam P, Simandle S, Erdos B: Mechanisms of vascular dysfunction in insulin resistance. Curr Opin Investig Drugs 2004; 5:929–35Busija, DW Miller, AW Katakam, P Simandle, S Erdos, B
Dandona P, Chaudhuri A, Aljada A: Endothelial dysfunction and hypertension in diabetes mellitus. Med Clin North Am 2004; 88:911–31Dandona, P Chaudhuri, A Aljada, A
Christ G, Wingard C: Calcium sensitization as a pharmacological target in vascular smooth-muscle regulation. Curr Opin Investig Drugs 2005; 6:920–33Christ, G Wingard, C
Salamanca DA, Khalil RA: Protein kinase C isoforms as specific targets for modulation of vascular smooth muscle function in hypertension. Biochem Pharmacol 2005; 70:1537–47Salamanca, DA Khalil, RA
Schiffrin EL: Vascular endothelin in hypertension. Vascul Pharmacol 2005; 43:19–29Schiffrin, EL
Jarajapu YP, Knot HJ: Relative contribution of Rho kinase and protein kinase C to myogenic tone in rat cerebral arteries in hypertension. Am J Physiol 2005; 289:H1917–22Jarajapu, YP Knot, HJ
Stekiel TA, Kokita N, Yamazaki M, Bosnjak ZJ, Kampine JP, Stekiel WJ: Effect of isoflurane on in situ  vascular smooth muscle transmembrane potential in spontaneous hypertension. Anesthesiology 1999; 91:207–14Stekiel, TA Kokita, N Yamazaki, M Bosnjak, ZJ Kampine, JP Stekiel, WJ
Yu J, Ogawa K, Tokinaga Y, Iwahashi S, Hatano Y: The vascular relaxing effects of sevoflurane and isoflurane are more important in hypertensive than in normotensive rats. Can J Anaesth 2004; 51:979–85Yu, J Ogawa, K Tokinaga, Y Iwahashi, S Hatano, Y
Marijic J, Madden JA, Kampine JP, Bosnjak ZJ: The effects of halothane on norepinephrine responsiveness in rabbit small mesenteric veins. Anesthesiology 1990; 73:479–84Marijic, J Madden, JA Kampine, JP Bosnjak, ZJ
Yamazaki M, Nagakawa T, Hatakeyama N, Shibuya N, Stekiel TA: The effects of propofol on neural and endothelial control of in situ  rat mesenteric vascular smooth muscle transmembrane potentials. Anesth Analg 2002; 94:892–7Yamazaki, M Nagakawa, T Hatakeyama, N Shibuya, N Stekiel, TA
Nagakawa T, Yamazaki M, Hatakeyama N, Stekiel TA: The mechanisms of propofol-mediated hyperpolarization of in situ  rat mesenteric vascular smooth muscle. Anesth Analg 2003; 97:1639–45Nagakawa, T Yamazaki, M Hatakeyama, N Stekiel, TA
de Wit C, Bolz SS, Pohl U: Interaction of endothelial autacoids in microvascular control. Zeitschrift fur Kardiologie 2000; 89:113–6de Wit, C Bolz, SS Pohl, U
Feigl EO: Neural control of coronary blood flow. J Vasc Res 1998; 35:85–92Feigl, EO
Sekiguchi N, Kanatsuka H, Komaru T, Akai K, Sato K, Wang Y, Sugi M, Ashikawa K, Takishima T: Effects of alpha and beta adrenergic blockade on coronary arterial microvessels in the beating canine heart. Cardiovasc Res 1992; 26:415–21Sekiguchi, N Kanatsuka, H Komaru, T Akai, K Sato, K Wang, Y Sugi, M Ashikawa, K Takishima, T
Park KW, Dai HB, Lowenstein E, Sellke FW: Flow-induced dilation of rat coronary microvessels is attenuated by isoflurane but enhanced by halothane. Anesthesiology 1998; 89:132–42Park, KW Dai, HB Lowenstein, E Sellke, FW
Park KW, Dai HB, Lowenstein E, Sellke FW: Steady-state myogenic response of rat coronary microvessels is preserved by isoflurane but not by halothane. Anesth Analg 1996; 82:969–74Park, KW Dai, HB Lowenstein, E Sellke, FW
Park KW, Dai HB, Lowenstein E, Sellke FW: Effect of sevoflurane and desflurane on the myogenic constriction and flow-induced dilation in rat coronary arterioles. Anesthesiology 1999; 90:1422–7Park, KW Dai, HB Lowenstein, E Sellke, FW
Schubert R, Mulvany MJ: The myogenic response: Established facts and attractive hypotheses. Clin Sci 1999; 96:313–26Schubert, R Mulvany, MJ
Gustafsson F, Holstein-Rathlou N: Conducted vasomotor responses in arterioles: Characteristics, mechanisms and physiological significance. Acta Physiol Scand 1999; 167:11–21Gustafsson, F Holstein-Rathlou, N
Rivers RJ, Frame MD: Network vascular communication initiated by increases in tissue adenosine. J Vasc Res 1999; 36:193–200Rivers, RJ Frame, MD
Rivers RJ, Hein TW, Zhang C, Kuo L: Activation of barium-sensitive inward rectifier potassium channels mediates remote dilation of coronary arterioles. Circulation 2001; 104:1749–53Rivers, RJ Hein, TW Zhang, C Kuo, L
Satitpunwaycha P, Rivers RJ: Volatile anesthetic agents and vascular communication in the microcirculation of the hamster cheek pouch. Anesthesiology 1998; 88:1062–70Satitpunwaycha, P Rivers, RJ
Zhou X, Abboud W, Manabat NC, Salem R, Crystal GJ: Isoflurane-induced dilation of porcine coronary arterioles is mediated by ATP-sensitive potassium channels. Anesthesiology 1998; 89:182–9Zhou, X Abboud, W Manabat, NC Salem, R Crystal, GJ
Klockgether-Radke AP, Gravemann J, Kettler D, Hellige G: Influence of opioids on the vascular tone of isolated porcine coronary artery segments. Acta Anaesthesiol Scand 2000; 44:1134–7Klockgether-Radke, AP Gravemann, J Kettler, D Hellige, G
Yu J, Mizumoto K, Tokinaga Y, Ogawa K, Hatano Y: The inhibitory effects of sevoflurane on angiotensin II- induced, p44/42 mitogen-activated protein kinase-mediated contraction of rat aortic smooth muscle. Anesth Analg 2005; 101:315–21Yu, J Mizumoto, K Tokinaga, Y Ogawa, K Hatano, Y
Qi YM, Yang DJ, Duan X, Yang F, Li SR, Shen JM, Wang R: Endomorphins inhibit contractile responses of rat thoracic aorta rings induced by phenylephrine and angiotensin II in vitro  . Acta Pharmacologica Sinica 2002; 23:40–4Qi, YM Yang, DJ Duan, X Yang, F Li, SR Shen, JM Wang, R
Larach DR, Schuler HG, Derr JA, Larach MG, Hensley FA Jr, Zelis R: Halothane selectively attenuates α2-adrenoceptor mediated vasoconstriction, in vivo  and in vitro  . Anesthesiology 1987; 66:781–91Larach, DR Schuler, HG Derr, JA Larach, MG Hensley, FA Zelis, R
Boillot A, Vallet B, Marty J, Auclerc A, Barale F: Effects of halothane, enflurane and isoflurane on contraction of rat aorta induced by endothelin-1. Br J Anaesth 1995; 75:761–7Boillot, A Vallet, B Marty, J Auclerc, A Barale, F
Coughlan MG, Flynn NM, Kenny D, Warltier DC, Kampine JP: Differential relaxant effect of high concentrations of intravenous anesthetics on endothelin-constricted proximal and distal canine coronary arteries. Anesth Analg 1992; 74:378–83Coughlan, MG Flynn, NM Kenny, D Warltier, DC Kampine, JP
Lundy PM, Frew R: Ketamine potentiates catecholamine responses of vascular smooth muscle by inhibition of extraneuronal uptake. Can J Physiol Pharmacol 1981; 59:520–7Lundy, PM Frew, R
Harder DR, Gradall K, Madden JA, Kampine JP: Cellular actions of halothane on cat cerebral arterial muscle. Stroke 1985; 16:680–3Harder, DR Gradall, K Madden, JA Kampine, JP
Klockgether-Radke AP, Thudium A, Frerichs A, Kettler D, Hellige G: High-dose midazolam and the attenuation of the contractile response to vasoconstrictors in coronary artery segments. Eur J Anaesthesiol 2003; 20:289–93Klockgether-Radke, AP Thudium, A Frerichs, A Kettler, D Hellige, G
Parra L, Perez-Vizcaino F, Alsasua A, Martin MI, Tamargo J: Mu- and delta-opioid receptor-mediated contractile effects on rat aortic vascular smooth muscle. Eur J Pharmacol 1995; 277:99–105Parra, L Perez-Vizcaino, F Alsasua, A Martin, MI Tamargo, J
Griffin MJ, Breen PM, O’Connor JJ, Hannon V: Desflurane, compared to halothane, augments phenylephrine-induced contraction in isolated rat aorta smooth muscle. Can J Anaesth 2001; 48:361–8Griffin, MJ Breen, PM O’Connor, JJ Hannon, V
Ogawa K, Tanaka S, Murray PA: Propofol potentiates phenylephrine-induced contraction via  cyclooxygenase inhibition in pulmonary artery smooth muscle. Anesthesiology 2001; 94:833–9Ogawa, K Tanaka, S Murray, PA
Park WK, Lynch C III, Johns RA: Effects of propofol and thiopental in isolated rat aorta and pulmonary artery. Anesthesiology 1992; 77:956–63Park, WK Lynch, C Johns, RA
Blaise GA, Witzeling TM, Sill JC, Vinay P, Vanhoutte PM: Fentanyl is devoid of major effects on coronary vasoreactivity and myocardial metabolism in experimental animals. Anesthesiology 1990; 72:535–41Blaise, GA Witzeling, TM Sill, JC Vinay, P Vanhoutte, PM
Karasawa F, Iwanov V, Moulds RF: Effects of fentanyl on the rat aorta are mediated by alpha-adrenoceptors rather than by the endothelium. Br J Anaesth 1993; 71:877–80Karasawa, F Iwanov, V Moulds, RF
Harkin CP, Hudetz AG, Schmeling WT, Kampine JP, Farber NE: Halothane-induced dilatation of intraparenchymal arterioles in rat brain slices: A comparison to sodium nitroprusside. Anesthesiology 1997; 86:885–94Harkin, CP Hudetz, AG Schmeling, WT Kampine, JP Farber, NE
Farber NE, Harkin CP, Niedfeldt J, Hudetz AG, Kampine JP, Schmeling WT: Region-specific and agent-specific dilation of intracerebral microvessels by volatile anesthetics in rat brain slices. Anesthesiology 1997; 87:1191–8Farber, NE Harkin, CP Niedfeldt, J Hudetz, AG Kampine, JP Schmeling, WT
Flynn NM, Kenny D, Pelc LR, Warltier DC, Bosnjak ZJ, Kampine JP: Endothelium-dependent vasodilation of canine coronary collateral vessels. Am J Physiol 1991; 261:H1797–801Flynn, NM Kenny, D Pelc, LR Warltier, DC Bosnjak, ZJ Kampine, JP
Gacar N, Gok S, Kalyoncu NI, Ozen I, Soykan N, Akturk G: The effect of endothelium on the response to propofol on bovine coronary artery rings. Acta Anaesthesiol Scand 1995; 39:1080–3Gacar, N Gok, S Kalyoncu, NI Ozen, I Soykan, N Akturk, G
Chung HC, Ho ST, Ho W, Yen MH, Lin CY: Partially endothelium-dependent relaxing effect of ketamine on the canine basilar artery in vitro  . Ma Tsui Hsueh Tsa Chi Anaesthesiologica Sinica 1992; 30:1–6Chung, HC Ho, ST Ho, W Yen, MH Lin, CY
Liu R, Lang MG, Luscher TF, Kaufmann M: Propofol-induced relaxation of rat mesenteric arteries: Evidence for a cyclic GMP-mediated mechanism. J Cardiovasc Pharmacol 1998; 32:709–13Liu, R Lang, MG Luscher, TF Kaufmann, M
Von Kugelgen I, Illes P, Wolf D, Starke K: Presynaptic inhibitory opioid delta- and kappa-receptors in a branch of the rabbit ileocolic artery. Eur J Pharmacol 1985; 118:97–105Von Kugelgen, I Illes, P Wolf, D Starke, K
Illes P, Pfeiffer N, von Kugelgen I, Starke K: Presynaptic opioid receptor subtypes in the rabbit ear artery. J Pharmacol Exp Ther 1985; 232:526–33Illes, P Pfeiffer, N von Kugelgen, I Starke, K
MacPherson RD, Quail AW: Halothane attenuates myogenicity in the rabbit ear artery. Anesth Analg 1999; 89:1400–5MacPherson, RD Quail, AW
French JF, Rapoport RM, Matlib MA: Possible mechanism of benzodiazepine-induced relaxation of vascular smooth muscle. J Cardiovasc Pharmacol 1989; 14:405–11French, JF Rapoport, RM Matlib, MA
Yu J, Ogawa K, Tokinaga Y, Mizumoto K, Kakutani T, Hatano Y: The inhibitory effects of isoflurane on protein tyrosine phosphorylation-modulated contraction of rat aortic smooth muscle. Anesthesiology 2004; 101:1325–31Yu, J Ogawa, K Tokinaga, Y Mizumoto, K Kakutani, T Hatano, Y
Persico P, Calignano A, Mancuso F, Sorrentino L: Involvement of NK receptors and beta-adrenoceptors in nitric oxide-dependent relaxation of rabbit aorta rings following electrical-field stimulation. Eur J Pharmacol 1993; 238:105–9Persico, P Calignano, A Mancuso, F Sorrentino, L
Jing M, Bina S, Verma A, Hart JL, Muldoon SM: Effects of halothane and isoflurane on carbon monoxide–induced relaxations in the rat aorta. Anesthesiology 1996; 85:347–54Jing, M Bina, S Verma, A Hart, JL Muldoon, SM
Kinoshita H, Ishida K, Ishikawa T: Thiopental and propofol impair relaxation produced by ATP-sensitive potassium channel openers in the rat aorta. Br J Anaesth 1998; 81:766–70Kinoshita, H Ishida, K Ishikawa, T
Germann P, Laher I, Poseno T, Bevan JA: Barbiturate attenuation of agonist affinity in cerebral arteries correlates with anesthetic potency and lipid solubility. Can J Physiol Pharmacol 1994; 72:963–9Germann, P Laher, I Poseno, T Bevan, JA
Fehr DM, Larach DR, Zangari KA, Schuler HG: Halothane constricts bovine pulmonary arteries by release of intracellular calcium. J Pharmacol Exp Ther 1996; 277:706–13Fehr, DM Larach, DR Zangari, KA Schuler, HG
Zhong L, Su JY: Isoflurane activates, PKC, and Ca2+-calmodulin–dependent protein kinase II via  MAP kinase signaling in cultured vascular smooth muscle cells. Anesthesiology 2002; 96:148–54Zhong, L Su, JY
Eskinder H, Hillard CJ, Flynn N, Bosnjak ZJ, Kampine JP: Role of guanylate cyclase–cGMP systems in halothane-induced vasodilation in canine cerebral arteries. Anesthesiology 1993; 77:482–7Eskinder, H Hillard, CJ Flynn, N Bosnjak, ZJ Kampine, JP
Petros AJ, Bogle RG, Pearson JD: Propofol stimulates nitric oxide release from cultured porcine aortic endothelial cells. Br J Pharmacol 1993; 109:6–7Petros, AJ Bogle, RG Pearson, JD
Harder DR, Madden JA: Cellular mechanisms of opiate receptor stimulation in cat middle cerebral artery. Eur J Pharmacol 1984; 102:411–6Harder, DR Madden, JA
Hong Y, Puil E, Mathers DA: Effect of halothane on large-conductance calcium-dependent potassium channels in cerebrovascular smooth muscle cells of the rat. Anesthesiology 1994; 81:649–56Hong, Y Puil, E Mathers, DA
Han J, Kim N, Joo H, Kim E: Ketamine blocks Ca2+-activated K+channels in rabbit cerebral arterial smooth muscle cells. Am J Physiol 2003; 285:H1347–55Han, J Kim, N Joo, H Kim, E
Yamazaki M, Ito Y, Hatakeyama N, Masuda A, Shibuya N, Momose Y: Electrophysiological effects of ketamine on Ca2+-activated K+channel in single rabbit portal vein cell. Jpn J Anesth 1993; 42:840–7Yamazaki, M Ito, Y Hatakeyama, N Masuda, A Shibuya, N Momose, Y
Hayashi Y, Minamino N, Isumi Y, Kangawa K, Kuro M, Matsuo H: Effects of thiopental, ketamine, etomidate, propofol and midazolam on the production of adrenomedullin and endothelin-1 in vascular smooth muscle cells. Res Commun Mol Pathol Pharmacol 1999; 103:325–31Hayashi, Y Minamino, N Isumi, Y Kangawa, K Kuro, M Matsuo, H
Blaise G, To Q, Parent M, Lagarde B, Asenjo F, Sauve R: Does halothane interfere with the release, action, or stability of endothelium-derived relaxing factor/nitric oxide? Anesthesiology 1994; 80:417–26Blaise, G To, Q Parent, M Lagarde, B Asenjo, F Sauve, R
Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, Casares F, Goligorsky MS: Presence of the mu3 opiate receptor in endothelial cells: Coupling to nitric oxide production and vasodilation. J Biol Chem 1995; 270:30290–3Stefano, GB Hartman, A Bilfinger, TV Magazine, HI Liu, Y Casares, F Goligorsky, MS
Morikawa N, Higuchi K, Tsukamoto T, Takeyama M, Nakano M, Tosaki Y, Uefuji T, Ogli K, Terada H: Pharmacokinetics of thiamylal following bolus injection and continuous administration. Yakuzaigaku 1990; 50:246–55Morikawa, N Higuchi, K Tsukamoto, T Takeyama, M Nakano, M Tosaki, Y Uefuji, T Ogli, K Terada, H
Endler GC, Stout M, Magyar DM, Hayes MF, Moghissi KS, Sacco AG: Follicular fluid concentrations of thiopental and thiamylal during laparoscopy for oocyte retrieval. Fert Ster 1987; 48:828–33Endler, GC Stout, M Magyar, DM Hayes, MF Moghissi, KS Sacco, AG
Sueyasu M, Fujito K, Shuto H, Mizokoshi T, Kataoka Y, Oishi R: Protein binding and the metabolism of thiamylal enantiomers in vitro  . Anesth Analg 2000; 91:736–40Sueyasu, M Fujito, K Shuto, H Mizokoshi, T Kataoka, Y Oishi, R
Becker KE Jr, Tonnesen AS: Cardiovascular effects of plasma levels of thiopental necessary for anesthesia. Anesthesiology 1978; 49:197–200Becker, KE Tonnesen, AS
Burch PG, Stanski DR: The role of metabolism and protein binding in thiopental anesthesia. Anesthesiology 1983; 58:146–52Burch, PG Stanski, DR
Setnikar I, Temelcou O: Effect of temperature on toxicity and distribution of pentobarbital and barbital in rats and dogs. J Pharmacol Exp Ther 1962; 135:213–22Setnikar, I Temelcou, O
Smith RB, Dittert LW, Griffen WO Jr, Doluisio JT: Pharmacokinetics of pentobarbital after intravenous and oral administration. J Pharmacokinet Biopharm 1973; 1:5–16Smith, RB Dittert, LW Griffen, WO Doluisio, JT
Ehrnebo M: Pharmacokinetics and distribution properties of pentobarbital in humans following oral and intravenous administration. J Pharm Sci 1974; 63:1114–8Ehrnebo, M
Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE: Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay. Anesth Analg 1982; 61:87–92Domino, EF Zsigmond, EK Domino, LE Domino, KE Kothary, SP Domino, SE
Dayton PG, Stiller RL, Cook DR, Perel JM: The binding of ketamine to plasma proteins: Emphasis on human plasma. Eur J Clin Pharmacol 1983; 24:825–31Dayton, PG Stiller, RL Cook, DR Perel, JM
Wieber J, Gugler R, Hengstmann JH, Dengler HJ: Pharmacokinetics of ketamine in man. Anaesthesist 1975; 24:260–3Wieber, J Gugler, R Hengstmann, JH Dengler, HJ
Servin F, Desmonts JM, Haberer JP, Cockshott ID, Plummer GF, Farinotti R: Pharmacokinetics and protein binding of propofol in patients with cirrhosis. Anesthesiology 1988; 69:887–91Servin, F Desmonts, JM Haberer, JP Cockshott, ID Plummer, GF Farinotti, R
Costela JL, Jimenez R, Calvo R, Suarez E, Carlos R: Serum protein binding of propofol in patients with renal failure or hepatic cirrhosis. Acta Anaesthesiol Scand 1996; 40:741–5Costela, JL Jimenez, R Calvo, R Suarez, E Carlos, R
Mazoit JX, Samii K: Binding of propofol to blood components: Implications for pharmacokinetics and for pharmacodynamics. Br J Clin Pharmacol 1999; 47:35–42Mazoit, JX Samii, K
Meuldermans WE, Heykants JJ: The plasma protein binding and distribution of etomidate in dog, rat and human blood. Arch Int Pharmacodyn Ther 1976; 221:150–62Meuldermans, WE Heykants, JJ
Doenicke A, Loffler B, Kugler J, Suttmann H, Grote B: Plasma concentration and E.E.G. after various regimens of etomidate. Br J Anaesth 1982; 54:393–400Doenicke, A Loffler, B Kugler, J Suttmann, H Grote, B
Macklon AF, Barton M, James O, Rawlins MD: The effect of age on the pharmacokinetics of diazepam. Clin Sci 1980; 59:479–83Macklon, AF Barton, M James, O Rawlins, MD
Samuelson PN, Reves JG, Kouchoukos NT, Smith LR, Dole KM: Hemodynamic responses to anesthetic induction with midazolam or diazepam in patients with ischemic heart disease. Anesth Analg 1981; 60:802–9Samuelson, PN Reves, JG Kouchoukos, NT Smith, LR Dole, KM
Gardner MJ, Baris BA, Wilner KD, Preskorn SH: Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers. Clin Pharmacokinet 1997; 1:43–9Gardner, MJ Baris, BA Wilner, KD Preskorn, SH
Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI: Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984; 61:27–35Greenblatt, DJ Abernethy, DR Locniskar, A Harmatz, JS Limjuco, RA Shader, RI
Aitkenhead AR, Vater M, Achola K, Cooper CM, Smith G: Pharmacokinetics of single-dose i.v. morphine in normal volunteers and patients with end-stage renal failure. Br J Anaesth 1984; 56:813–9Aitkenhead, AR Vater, M Achola, K Cooper, CM Smith, G
Wood M: Plasma drug binding: Implications for anesthesiologists. Anesth Analg 1986; 65:786–804Wood, M
Chauvin M, Sandouk P, Scherrmann JM, Farinotti R, Strumza P, Duvaldestin P: Morphine pharmacokinetics in renal failure. Anesthesiology 1987; 66:327–31Chauvin, M Sandouk, P Scherrmann, JM Farinotti, R Strumza, P Duvaldestin, P
Wynands JE, Townsend GE, Wong P, Whalley DG, Srikant CB, Patel YC: Blood pressure response and plasma fentanyl concentrations during high- and very high-dose fentanyl anesthesia for coronary artery surgery. Anesth Analg 1983; 62:661–5Wynands, JE Townsend, GE Wong, P Whalley, DG Srikant, CB Patel, YC
Fig. 1. Proposed mechanisms of vascular smooth muscle contraction (see text for details). The location of cytosolic molecules or their translocation to the cell membrane or other subcellular sites  (e.g.  , translocation of protein kinase C [PKC], Rho A, Rho kinase, or mitogen-activated protein kinases [MAPKs] to the cell membrane) is not considered in this figure. It is controversial whether Rho kinase functions upstream on, downstream on, or independently of PKC. += Stimulation; −= inhibition; AA = arachidonic acid; APL = arachidonyl phospholipids; CIF = Ca2+-influx factor; CaM = calmodulin; CaMKII = Ca2+/CaM-dependent protein kinase II; CICR = Ca2+-induced Ca2+release; ClCa= Ca2+-activated Clchannel; CPI-17 = PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kd; DAG = 1,2-diacyl-glycerol; G = guanosine-5′-triphosphate–binding protein; IP3= inositol 1, 4, 5-triphosphate; IICR = IP3-induced Ca2+release; KCa= Ca2+-activated K+channel; LG-NSCC = ligand-gated nonselective cation channel; MLC20= regulatory light chain of myosin (20 kd); MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; PC = phosphatidylcholine; PIP2= phosphatidyl-inositol 4,5-bisphosphate; PLA2= phospholipase A2; PLC = phospholipase C; PLD = phospholipase D; RhoA-GDP = GDP-bound RhoA; RhoA-GTP = GTP-bound RhoA; ROCC = receptor-operated Ca2+channel; SMOCC = second messenger–operated Ca2+channel; SOCC = store-operated Ca2+channel (Ca2+release–activated Ca2+channel); SR = sarcoplasmic reticulum; TK = tyrosine kinase; VOCC = voltage-operated Ca2+channel. 
Fig. 1. Proposed mechanisms of vascular smooth muscle contraction (see text for details). The location of cytosolic molecules or their translocation to the cell membrane or other subcellular sites 
	(e.g.  , translocation of protein kinase C [PKC], Rho A, Rho kinase, or mitogen-activated protein kinases [MAPKs] to the cell membrane) is not considered in this figure. It is controversial whether Rho kinase functions upstream on, downstream on, or independently of PKC. += Stimulation; −= inhibition; AA = arachidonic acid; APL = arachidonyl phospholipids; CIF = Ca2+-influx factor; CaM = calmodulin; CaMKII = Ca2+/CaM-dependent protein kinase II; CICR = Ca2+-induced Ca2+release; ClCa= Ca2+-activated Cl−channel; CPI-17 = PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kd; DAG = 1,2-diacyl-glycerol; G = guanosine-5′-triphosphate–binding protein; IP3= inositol 1, 4, 5-triphosphate; IICR = IP3-induced Ca2+release; KCa= Ca2+-activated K+channel; LG-NSCC = ligand-gated nonselective cation channel; MLC20= regulatory light chain of myosin (20 kd); MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; PC = phosphatidylcholine; PIP2= phosphatidyl-inositol 4,5-bisphosphate; PLA2= phospholipase A2; PLC = phospholipase C; PLD = phospholipase D; RhoA-GDP = GDP-bound RhoA; RhoA-GTP = GTP-bound RhoA; ROCC = receptor-operated Ca2+channel; SMOCC = second messenger–operated Ca2+channel; SOCC = store-operated Ca2+channel (Ca2+release–activated Ca2+channel); SR = sarcoplasmic reticulum; TK = tyrosine kinase; VOCC = voltage-operated Ca2+channel. 
Fig. 1. Proposed mechanisms of vascular smooth muscle contraction (see text for details). The location of cytosolic molecules or their translocation to the cell membrane or other subcellular sites  (e.g.  , translocation of protein kinase C [PKC], Rho A, Rho kinase, or mitogen-activated protein kinases [MAPKs] to the cell membrane) is not considered in this figure. It is controversial whether Rho kinase functions upstream on, downstream on, or independently of PKC. += Stimulation; −= inhibition; AA = arachidonic acid; APL = arachidonyl phospholipids; CIF = Ca2+-influx factor; CaM = calmodulin; CaMKII = Ca2+/CaM-dependent protein kinase II; CICR = Ca2+-induced Ca2+release; ClCa= Ca2+-activated Clchannel; CPI-17 = PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kd; DAG = 1,2-diacyl-glycerol; G = guanosine-5′-triphosphate–binding protein; IP3= inositol 1, 4, 5-triphosphate; IICR = IP3-induced Ca2+release; KCa= Ca2+-activated K+channel; LG-NSCC = ligand-gated nonselective cation channel; MLC20= regulatory light chain of myosin (20 kd); MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; PC = phosphatidylcholine; PIP2= phosphatidyl-inositol 4,5-bisphosphate; PLA2= phospholipase A2; PLC = phospholipase C; PLD = phospholipase D; RhoA-GDP = GDP-bound RhoA; RhoA-GTP = GTP-bound RhoA; ROCC = receptor-operated Ca2+channel; SMOCC = second messenger–operated Ca2+channel; SOCC = store-operated Ca2+channel (Ca2+release–activated Ca2+channel); SR = sarcoplasmic reticulum; TK = tyrosine kinase; VOCC = voltage-operated Ca2+channel. 
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Table 1. Previously Observed Effects of General Anesthetic Agents on Basal Vascular Tone or Vasoconstrictor Response 
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Table 1. Previously Observed Effects of General Anesthetic Agents on Basal Vascular Tone or Vasoconstrictor Response 
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Table 2. Previously Observed Effects of General Anesthetic Agents on Vasodilator Response 
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Table 2. Previously Observed Effects of General Anesthetic Agents on Vasodilator Response 
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Table 3. Proposed Effects of Anesthetic Agents on Cellular Mechanisms Involved in Vasoconstrictor Response 
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Table 3. Proposed Effects of Anesthetic Agents on Cellular Mechanisms Involved in Vasoconstrictor Response 
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Table 4. Proposed Effects of Anesthetic Agents on Regulatory Mechanisms in Vascular Smooth Muscle Cells 
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Table 4. Proposed Effects of Anesthetic Agents on Regulatory Mechanisms in Vascular Smooth Muscle Cells 
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Table 5. Proposed Effects of General Anesthetic Agents on Regulatory Mechanisms in Vascular Endothelial Cells 
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Table 5. Proposed Effects of General Anesthetic Agents on Regulatory Mechanisms in Vascular Endothelial Cells 
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Table 6. Plasma Concentrations of Intravenous Anesthetics after Bolus Intravenous Injection 
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Table 6. Plasma Concentrations of Intravenous Anesthetics after Bolus Intravenous Injection 
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