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Meeting Abstracts  |   January 1997
Interaction of Halothane with α- and β-Adrenoceptor Stimulations in Rat Myocardium
Author Notes
  • (Hanouz) Research Fellow, Department of Anesthesiology, Centre Hospitalier Universitaire Caen.
  • (Riou) Director, Laboratory of Experimental Anesthesiology; Assistant Professor, Department of Anesthesiology, Centre Hospitalier Universitaire Pitie-Salpetriere.
  • (Massias) Assistant, Laboratory of Pharmacokinetics and Toxicology, Centre Hospitalier Universitaire Bichat, Paris.
  • (Lecarpentier) Professor of Physiology, Hopital de Bicetre.
  • (Coriat) Professor of Anesthesiology; Chair, Department of Anesthesiology, Centre Hospitalier Universitaire Pitie-Salpetriere.
  • Received from the Laboratoire d'Anesthesiologie, Departement d'Anesthesie-Reanimation, Centre Hospitalier Universitaire Pitie-Salpetriere, Universite Paris VI, Paris; Departement d'Anesthesie-Reanimation, Centre Hospitalier Universitaire Cote de Nacre, Caen; Laboratoire de Pharmacocinetique et de Toxicologie, Centre Hospitalier Universitaire Bichat, Paris; Institut National de la Sante et de la Recherche Medicale (INSERM) Unite 451, LOA-ENSTA-Ecole Polytechnique, Palaiseau; and Service de Physiologie, Hopital de Bicetre, Universite Paris Sud, Le Kremlin-Bicetre, France. Submitted for publication February 27, 1996. Accepted for publication August 29, 1996. Supported by INSERM (Contrat de Recherche Externe 92–0413). Dr. Hanouz was the recipient of a fellowship grant from the Fondation pour la Recherche Medicale.
  • Address reprint requests to Dr. Riou: Departement d'Anesthesie-Reanimation, Groupe Hospitalier Pitie-Salpetriere, 47 Boulevard de l'Hopital, 75651 Paris Cedex 13, France.
Article Information
Meeting Abstracts   |   January 1997
Interaction of Halothane with α- and β-Adrenoceptor Stimulations in Rat Myocardium
Anesthesiology 1 1997, Vol.86, 147-159. doi:
Anesthesiology 1 1997, Vol.86, 147-159. doi:
Halothane induces negative inotropic and lusitropic myocardial effects. [1–4] The depressant myocardial effects of halothane result from profound changes in intracellular calcium homeostasis, including a decrease in sarcolemmal calcium entry [5]; decreases in sarcoplasmic reticulum calcium content, uptake, and release [6–9]; a decrease in myofibrillar sensitivity and responsiveness to calcium [10]; and an inhibition in sodium-calcium exchange. [11] Halothane also interferes with the sympathetic nervous system at different levels. Indeed, halothane decreases ganglionic transmission, [12] central nervous system sympathetic activity, [13] and plasma catecholamine concentrations. [14] Although halothane has been shown to decrease beta-adrenergic receptor density in human lymphocyte membranes, [15] recently it was suggested that halothane may also alter the signal transduction pathway of muscarinic and adrenergic receptors because it inhibits muscarinic receptor regulation of adenylate cyclase activity in mouse heart [16], and stimulates G-protein-dependent adenylate cyclase activity in human myocardium. [17] This last effect could explain why halothane facilitates catecholamine-induced arrhythmias [18] and potentiates the positive inotropic effect of isoproterenol. [19] Nevertheless, the effects of halothane on the inotropic response to alpha-adrenoceptor stimulation remain unknown. Furthermore, although alpha- and beta-adrenoceptor stimulations induce important myocardial lusitropic effects, no data are available concerning the interaction of halothane with these lusitropic effects. This last point may be important because halothane impairs left ventricular diastolic function. [4] 
Therefore we conducted an in vitro study to determine the interaction of halothane with the inotropic and lusitropic responses of isolated rat myocardium to both alpha- and beta-adrenoceptor stimulations.
Materials and Methods
Care of the animals conformed to the recommendations of the Helsinski Declaration, and the study was performed in accordance with the regulations of the official edict of the French Ministry of Agriculture.
Experimental Protocol
After brief anesthesia with ether, the hearts were quickly removed from adult male Wistar rats (Iffa Credo, L'Arbresles, France) weighing 250–300 g. Left ventricular papillary muscles were carefully excised and suspended vertically in a 200-ml jacketed reservoir with Krebs-Henseleit bicarbonate buffer solution containing 118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 1.1 mM KH2PO4, 25 mM NaHCO3, 2.5 mM CaCl2, and 4.5 mM glucose. The Krebs-Henseleit solution was prepared daily with highly purified water (Ecopure, Barnstead/Thermolyne Corp., Dubuque, IA). The jacketed reservoir was maintained at 29 degrees Celsius with a thermostatic water circulator (Polystat 5HP; Bioblock, Illkirch, France) with continuous monitoring of the solution temperature using a temperature probe (Pt100, Bioblock). Preparations were field-stimulated at 12 pulses/min by two platinum electrodes with rectangular wave pulses lasting 5-ms just above threshold. The bathing solution was bubbled with 95% oxygen-5% carbon dioxide, resulting in a pH of 7.40. After a 60-min stabilization period at the initial muscle length at the apex of the length-active isometric tension curve (Lmax), papillary muscles recovered their optimal mechanical performance, which remained stable for several hours.
Suitable preparations were selected as previously described. [20] The control values of each mechanical parameter were recorded. Then the extracellular concentration of calcium ([Ca2+]o) was decreased from 2.5 to 0.5 mM. [Ca2+]o was decreased because rat myocardial contractility is nearly maximum at 2.5 mM and consequently it is difficult to quantify a positive inotropic response without first decreasing [Ca2+]o. [21] To ensure that the inotropic reserve [22] was comparable within groups, suitable preparations were also selected as follows: the decrease in active isometric force and maximum shortening velocity should be within 40–75% and 50–80% of control values at 2.5 mM [Ca2+]o, respectively. Thereafter the inotropic response to either alpha- or beta-adrenoceptor stimulations were studied in separate groups of papillary muscles in the absence or in the presence of halothane (0.5 or 1 minimum alveolar concentration [MAC]). Because inotropic responses were expressed as a percentage of control values (with or without halothane), the absolute values of the primary mechanical parameters are provided in Table 1.
Table 1. Comparison of Control Values of Inotropic and Lusitropic Parameters in the Different Groups of Papillary Muscles
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Table 1. Comparison of Control Values of Inotropic and Lusitropic Parameters in the Different Groups of Papillary Muscles
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In control groups, alpha-adrenoceptor stimulation was induced with cumulative concentrations of phenylephrine (10 sup -8 M, 10 sup -7 M, 10 sup -6 M, 10 sup -5 M, and 10 sup -4 M) with propranolol (10 sup -6 M). To study beta-adrenoceptor stimulation, cumulative concentrations of isoproterenol (10 sup -8 M, 10 sup -7 M, 10 sup -6 M, 10 sup -5 M, and 10 sup -4 M) with phentolamine (10 sup -6 M) were used. The volume of drugs did not exceed 2% of the bath volume. All drugs were purchased from Sigma-Aldrich Chimie (L'Isle d'Abeau Chesnes, France). Propranolol or phentolamine were added 15 min before phenylephrine or isoproterenol were introduced, respectively. The maximum inotropic responses at each concentration were recorded and expressed as a percentage of control values at 0.5 mM [Ca2+]o.
Halothane was added to the carbogen with a specific calibrated vaporizer (Fluotec 3; Cyprane Ltd., Keighley, UK). The gas mixture bubbled continuously in the bathing solution. To minimize evaporation of halothane vapors, the jacketed reservoir was almost completely sealed with a thin paraffin sheet (Parafilm M; American National Can, Greenwich, CT). The halothane concentration in the gas phase was monitored continuously with a calibrated infrared analyzer (Ohmeda 5330; Ohmeda, Louisville, CO). Halothane concentrations used were 0.3 and 0.6 %vol. These concentrations are equivalent to 0.5 and 1 MAC of halothane in the adult rat at 29 degrees Celsius, respectively. [23,24] After 30 min of equilibration with halothane, the inotropic response to either alpha- or beta-adrenoceptor stimulations were studied in the same cumulative manner as in the control groups.
Because halothane is a negative inotropic agent and thus could modify the inotropic reserve, we also studied the inotropic effect of alpha -(n = 8) and beta -(n = 8) adrenoceptor stimulation at a very low (0.25 mM)[Ca2+]o in separate groups of papillary muscles. At this [Ca2+]o, the maximum isometric active force normalized per cross-sectional area (AF) was comparable to that obtained at a [Ca2+]o of 0.5 mM in the presence of 1 MAC of halothane (Table 1). Moreover, we also tested the effects of increasing [Ca2+]o from 0.5 to 2.5 mM in the absence or in the presence of 1 MAC of halothane. Calcium was added to the bathing solution at the following concentrations: 0.75 mM, 1 mM, 1.5 mM, and 2.5 mM. The total volume of the solution added did not exceed 2% of the bath volume. The maximum inotropic response at each concentration was recorded 10 min after each step.
Halothane Concentration Measurements
Halothane concentrations in the Krebs-Henseleit bicarbonate buffer solution were measured by gas-liquid chromatography. The coefficient of variation of the measurement was 5.5% and the limit of quantitation was 0.02 mM. The halothane concentrations measured in the experimental solution (n = 6) after 15 min of continuous bubbling at 0.5 and 1 MAC were 0.28 +/- 0.01 mM and 0.48 +/- 0.02 mM, respectively.
Electromagnetic Lever System and Recording
The electromagnetic lever system has been described previously. [25] Briefly, the load applied to the muscle was determined using a servomechanism-controlled current through the coil of an electromagnet. Muscular shortening induced a displacement of the lever, which modulated the light intensity of a photoelectric transducer. All analyses were made from digital records of force and length obtained with a computer, as previously described. [20] 
Mechanical Parameters
Conventional mechanical parameters at Lmaxwere calculated from three twitches. The first twitch was isotonic and was loaded with the preload corresponding to Lmax. The second twitch was abruptly clamped to zero-load just after the electrical stimulus; the muscle was released from preload to zero-load with a critical damping to slow the first and rapid shortening overshoot resulting from the recoil of series-passive elastic components, as previously reported [26]; the maximum unloaded shortening velocity (Vmax) was determined from this twitch. The third twitch was fully isometric at Lmax. The mechanical parameters characterizing the contraction and relaxation phases, and the coupling between contraction and relaxation are defined as follows (Figure 1).
Figure 1. Mechanical parameters of contraction and relaxation. (Upper) Muscle shortening length (L/Lmax) plotted versus time. (Lower) Force (F) plotted versus time. Twitch 1 was loaded with preload only at Lmax. Twitch 2 was loaded with the same preload as twitch 1 but was abruptly clamped to zero-load with critical damping just after electrical stimulus; maximum unloaded shortening velocity (Vmax) was determined from this twitch. Twitch 3 was fully isometric. Coefficient R1, the ratio of maximum shortening velocity (sub max Vc) to maximum lengthening velocity (sub max Vr), tests lusitropy under low load; coefficient R2, the ratio of the peak of the positive force derivative (+dF [centered dot] dt sup -1) to the peak of the negative force derivative (-dF [centered dot] dt sup -1), tests lusitropy under high load.
Figure 1. Mechanical parameters of contraction and relaxation. (Upper) Muscle shortening length (L/Lmax) plotted versus time. (Lower) Force (F) plotted versus time. Twitch 1 was loaded with preload only at Lmax. Twitch 2 was loaded with the same preload as twitch 1 but was abruptly clamped to zero-load with critical damping just after electrical stimulus; maximum unloaded shortening velocity (Vmax) was determined from this twitch. Twitch 3 was fully isometric. Coefficient R1, the ratio of maximum shortening velocity (sub max Vc) to maximum lengthening velocity (sub max Vr), tests lusitropy under low load; coefficient R2, the ratio of the peak of the positive force derivative (+dF [centered dot] dt sup -1) to the peak of the negative force derivative (-dF [centered dot] dt sup -1), tests lusitropy under high load.
Figure 1. Mechanical parameters of contraction and relaxation. (Upper) Muscle shortening length (L/Lmax) plotted versus time. (Lower) Force (F) plotted versus time. Twitch 1 was loaded with preload only at Lmax. Twitch 2 was loaded with the same preload as twitch 1 but was abruptly clamped to zero-load with critical damping just after electrical stimulus; maximum unloaded shortening velocity (Vmax) was determined from this twitch. Twitch 3 was fully isometric. Coefficient R1, the ratio of maximum shortening velocity (sub max Vc) to maximum lengthening velocity (sub max Vr), tests lusitropy under low load; coefficient R2, the ratio of the peak of the positive force derivative (+dF [centered dot] dt sup -1) to the peak of the negative force derivative (-dF [centered dot] dt sup -1), tests lusitropy under high load.
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Contraction Phase.
We determined Vmaxusing the zero-load clamp technique, maximum shortening velocity (sub max Vc) of the twitch with preload only, maximum AF, and the peak of the positive force derivative normalized per cross-sectional area (+dF [centered dot] dt sup -1). Vmaxand AF tested the inotropic state under low (isotony) and high (isometry) loads, respectively.
Relaxation Phase.
We determined maximum lengthening velocity (sub max Vr) of the twitch with preload only and the peak of the negative force derivative at Lmaxnormalized per cross-sectional area (-dF [centered dot] dt sup -1). These two parameters allowed us to study relaxation under low- and high-loading conditions, respectively. Nevertheless, because changes in the contraction phase induce coordinated changes in the relaxation phase (Figure 2),maxVr and -dF [centered dot] dt sup -1 cannot assess lusitropy, and thus variations in contraction and relaxation must be considered simultaneously to quantify drug-induced changes in lusitropy. Indexes of contraction-relaxation coupling thus have been developed to study lusitropy. [27,28] 
Figure 2. Effects of calcium on indices of lusitropy under high or low load (n = 8). Under low load, in contrast to both maximum shortening velocity (sub max VC) and maximum lengthening velocity (sub max Vr), R1 is not significantly modified by major inotropic changes induced by decreasing [Ca2+]o. Under high load, R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than the peak of the positive force derivative (+dF [centered dot] df sup -1)* and the peak of the negative force derivative (-dF [centered dot] dt sup -1). Data are mean percentages of control values +/- SEM.
Figure 2. Effects of calcium on indices of lusitropy under high or low load (n = 8). Under low load, in contrast to both maximum shortening velocity (sub max VC) and maximum lengthening velocity (sub max Vr), R1 is not significantly modified by major inotropic changes induced by decreasing [Ca2+]o. Under high load, R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than the peak of the positive force derivative (+dF [centered dot] df sup -1)* and the peak of the negative force derivative (-dF [centered dot] dt sup -1). Data are mean percentages of control values +/- SEM.
Figure 2. Effects of calcium on indices of lusitropy under high or low load (n = 8). Under low load, in contrast to both maximum shortening velocity (sub max VC) and maximum lengthening velocity (sub max Vr), R1 is not significantly modified by major inotropic changes induced by decreasing [Ca2+]o. Under high load, R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than the peak of the positive force derivative (+dF [centered dot] df sup -1)* and the peak of the negative force derivative (-dF [centered dot] dt sup -1). Data are mean percentages of control values +/- SEM.
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Contraction-Relaxation Coupling.
The coefficient R1 =maxVc/sub max Vr evaluated the coupling between contraction and relaxation under low load, and thus the lusitropy in a manner that is independent of inotropic changes (Figure 2). Under isotonic conditions, the amplitude of sarcomere shortening is greater than that observed under isometric conditions. [29] Because of the lower sensitivity of myofilament for calcium when cardiac muscle is markedly shortened under low load, relaxation proceeds more rapidly than contraction, apparently as a result of the rapid uptake of calcium by the sarcoplasmic reticulum. Thus, in rat myocardium, R1 tests sarcoplasmic reticulum uptake function. In contrast to bothmaxVc andmaxVr, R1 is not significantly modified by major inotropic changes induced by decreasing [Ca2+]o (Figure 2). This is consistent with the fact that calcium uptake and release are precisely regulated by the sarcoplasmic reticulum. [30] 
Coefficient R2 =(+dF [centered dot]-dt sup -1/-dF [centered dot] dt sup -1) evaluated the coupling between contraction and relaxation under high load, and thus lusitropy under high load in a manner that is less dependent on inotropic changes (Figure 2). When the muscle contracts isometrically, sarcomeres shorten very little. [29] Because of the higher sensitivity of myofilament for calcium, [31] the time course of relaxation is determined by calcium unbinding from troponin C rather than by calcium sequestration by the sarcoplasmic reticulum. Thus R2 reflects myofilament calcium sensitivity. [22,27,28] R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than +dF [centered dot] dt sup -1 and -dF [centered dot] dt sup -1 (Figure 2). Because +dF [centered dot] dt sup -1 is depressed more than -dF [centered dot] dt sup -1, the resulting decrease in R2 reflects a positive lusitropic effect. The slight decrease in R2, as [Ca2+]o is decreased, is consistent with the fact that calcium per se modulates myofilament calcium sensitivity, according to the cooperativity concept. [32] The parameters R1 and R2, which evaluate lusitropy under low and high load, respectively, have been used empirically for many years but have been validated only recently. [33,34] 
At the end of the study, the muscle cross-sectional area was calculated from the length and weight of papillary muscle, assuming a density of 1.
Statistical Analysis
Data are expressed as mean +/- SEM. Control values among groups were compared by analysis of variance. Concentration-response curves were determined by fitting the data to the sigmoid pharmacologic model of Hill, [35] according to the following equation:Equation 1in which Effois the observed effect at the C concentration, Effmaxis the maximum effect, and C50is the concentration that results in 50% of Effmax. Iterative nonlinear least-squares regression curve fitting was used to obtain the best fit (Matlab 1.2c software; The MathWorks Inc., South Natick, MA). Comparison of several means was performed using analysis of variance and the Newman-Keuls test. The comparison of the relation between R1 or R2 (lusitropic effect) and AF (inotropic effect) among groups was performed using a multivariate analysis of variance. All probability values were two tailed, and a probability value less than 0.05 was required to reject the null hypothesis. Statistical analysis was performed on a computer using SOLO 6.4 software (BMDP Statistical Software, Inc., Los Angeles, CA).
Results
Ninety left ventricular papillary muscles were studied. The mean Lmaxwas 5.3 +/- 0.2 mm (range, 3–8); the mean cross-sectional area was 0.71 +/- 0.01 (range, 0.30–0.97) mm2; the ratio of resting force to total force was 0.12 +/- 0.01 (range, 0.07–0.20); R1 was 0.72 +/- 0.02 (range, 0.48–0.85), reflecting a faster relaxation (lengthening) rate than shortening rate, at a [Ca2+]o of 2.5 mM; and no significant differences were noted among groups. A decrease in contractility was observed as [Ca2+]o was decreased from 2.5 to 0.5 mM (n = 74); the decreases in Vmax(64 +/- 1% of the value at a [Ca2+]o of 2.5 mM) and AF (53 +/- 2% of the value at a [Ca2+]o of 2.5 mM) were consistent with previous reports. [27,36] In control conditions and at a [Ca2+]o of 0.5 mM, the mean Vmaxwas 1.99 +/- 0.04 Lmax[centered dot] s sup -1, the mean AF was 34 +/- 1 mN [centered dot] mm2, R1 was 0.66 +/- 0.01, R2 was 1.84 +/- 0.03, and no significant differences were noted among groups. An even greater decrease in contractility was observed as [Ca2+]o was decreased from 2.5 to 0.25 mM (n = 16); the decrease in AF was 36 +/- 3% of the value at a [Ca2+]o of 2.5 mM, the mean AF was 15 +/- 1 mN [centered dot] mm2, and no significant differences were noted among groups.
Effects of Halothane
Halothane induced a dose-dependent negative inotropic effect as shown by the decreases in Vmaxand AF (Table 2). One MAC halothane induced a significant increase in R1 and a significant decrease in R2. Halothane (0.5 MAC) induced a slight but not significant decrease in R1 and a significant decrease in R2 (Table 2). However, because R2 was slightly decreased as [Ca2+]o decreased (Figure 2), changes in AF should be considered to assess changes in R2. The negative inotropic effect of 1 MAC halothane on AF was equivalent to that obtained by decreasing [Ca2+]o from 0.50 to 0.25 mM (54 +/- 3 vs. 51 +/- 3% of control value). In these conditions, the effect of 1 MAC halothane on R2 also did not differ from that obtained by decreasing [Ca2+]o from 0.50 to 0.25 mM (89 +/- 2 vs. 92 +/- 2% of control value), suggesting that the effects of halothane on R2 were only due to its negative inotropic effect.
Table 2. Effects of Halothane (0.5 and 1 MAC) on Inotropic and Lusitropic Parameters
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Table 2. Effects of Halothane (0.5 and 1 MAC) on Inotropic and Lusitropic Parameters
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Effects of alpha- and beta-adrenergic Stimulation
In the control group, phenylephrine induced a positive inotropic effect, as shown by significant increases in Vmaxand AF (Figure 3;Table 3). This positive inotropic effect was associated with a significant decrease in R1 and no significant change in R2 (Table 3). These results were consistent with those previously reported in rat myocardium. [37] 
Figure 3. Effects of 1 MAC halothane on the inotropic response to alpha- and beta-adrenoceptor stimulation. Data are absolute mean values of isometric active force (AF)+/- SEM. C1 corresponds to the control value at a calcium concentration of 0.5 mM. C2 corresponds to the control value after halothane administration in the halothane group and after decreasing calcium concentration from 0.5 to 0.25 mM in the 0.25 mM calcium group. The potentiation of alpha- and beta-adrenoceptor stimulations by halothane could not overcome its negative inotropic effect.
Figure 3. Effects of 1 MAC halothane on the inotropic response to alpha- and beta-adrenoceptor stimulation. Data are absolute mean values of isometric active force (AF)+/- SEM. C1 corresponds to the control value at a calcium concentration of 0.5 mM. C2 corresponds to the control value after halothane administration in the halothane group and after decreasing calcium concentration from 0.5 to 0.25 mM in the 0.25 mM calcium group. The potentiation of alpha- and beta-adrenoceptor stimulations by halothane could not overcome its negative inotropic effect.
Figure 3. Effects of 1 MAC halothane on the inotropic response to alpha- and beta-adrenoceptor stimulation. Data are absolute mean values of isometric active force (AF)+/- SEM. C1 corresponds to the control value at a calcium concentration of 0.5 mM. C2 corresponds to the control value after halothane administration in the halothane group and after decreasing calcium concentration from 0.5 to 0.25 mM in the 0.25 mM calcium group. The potentiation of alpha- and beta-adrenoceptor stimulations by halothane could not overcome its negative inotropic effect.
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Table 3. Effects of Halothane (0.5 and 1 MAC) on the Inotropic and Lusitropic Responses to alpha Adrenoceptor Stimulation
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Table 3. Effects of Halothane (0.5 and 1 MAC) on the Inotropic and Lusitropic Responses to alpha Adrenoceptor Stimulation
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In the control group, isoproterenol induced a positive inotropic effect as reflected by significant increases in Vmaxand AF (Figure 3;Table 4). This positive inotropic effect was associated with significant decreases in R1 and R2 (Table 4). The positive inotropic effect of isoproterenol was more pronounced than that observed with phenylephrine (Figure 3). These results were consistent with those previously reported in rat myocardium. [22,37] 
Table 4. Effects of Halothane (0.5 and 1 MAC) on the lnotropic and Lusitropic Responses to beta Adrenoceptor Stimulation
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Table 4. Effects of Halothane (0.5 and 1 MAC) on the lnotropic and Lusitropic Responses to beta Adrenoceptor Stimulation
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Influence of Halothane on the Inotropic Effect of alpha- and beta-Adrenergic Stimulations
(Figure 3) shows the absolute values of AF recorded in response to increasing concentrations of phenylephrine and isoprotrenol, under control conditions, with 1 MAC halothane, and with calcium reduced to 0.25 mM. Although starting from a lower value in the presence of halothane (10 +/- 1 vs. 24 +/- 2 mN [centered dot] mm sup -2), phenylephrine induced a similar increase in AF (10 sup -4 M: 20 +/- 2 vs. 33 +/- 2 mN [centered dot] mm sup -2). Similarly, although starting from a lower value in the presence of halothane (12 +/- 2 vs. 23 +/- 3 mN [centered dot] mm sup -2), isoproterenol induced a similar increase in AF (10 sup -4 M: 25 +/- 3 vs. 37 +/- 4 mN [centered dot] mm sup -2). When measured as a percentage of baseline halothane response, the positive inotropic effect of phenylephrine was enhanced in the presence of 0.5 and 1 MAC halothane (Figure 4). The Eff sub max values for AF and Vmaxwere significantly greater with 1 MAC halothane compared with the control group (Table 3). C50(the concentration that results in 50% of the maximum effect) values for AF and Vmaxwere not significantly different among the three groups (Table 3), suggesting no significant shift in the concentration-response curve by halothane. Nevertheless, because of the negative inotropic effect of halothane, the control values of AF were significantly different in the two groups of papillary muscles (Table 1). Thus, to ensure that our results were valid, we compared the effect of phenylephrine at a very low (0.25 mM)[Ca2+]o with that at a [Ca2+]o of 0.5 mM and in the presence of 1 MAC halothane; indeed, with these conditions, the control values of AF were not significantly different (Table 1), and 1 MAC halothane still induced a significant potentiation of alpha-adrenoceptor stimulation (Effmax: 237 +/- 19 vs. 153 +/- 7% of control value, P <0.05).
Figure 4. Effect of 0.5 and 1 MAC halothane on the inotropic effect of phenylephrine or isoproterenol. AF = active isometric force. Data are mean +/- SEM.
Figure 4. Effect of 0.5 and 1 MAC halothane on the inotropic effect of phenylephrine or isoproterenol. AF = active isometric force. Data are mean +/- SEM.
Figure 4. Effect of 0.5 and 1 MAC halothane on the inotropic effect of phenylephrine or isoproterenol. AF = active isometric force. Data are mean +/- SEM.
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When measured as a percentage of the baseline halothane response, the positive inotropic effect of isoproterenol was significantly enhanced by 1 MAC halothane but not by 0.5 MAC (Figure 4). The Effmaxvalues for AF and Vmaxwere significantly greater with 1 MAC halothane compared with values for the control group (Table 4). C50values for AF and Vmaxwere not significantly different among the three groups (Table 4), suggesting no significant shift in the concentration-response curve by halothane. Nevertheless, because of the negative inotropic effect of halothane, the control values of AF were significantly different in the two groups of papillary muscles (Table 1). Thus, to ensure that our results were valid, we compared the effect of isoproterenol at a very low (0.25 mM)[Ca2+]o with that at a [Ca sup 2+]o of 0.5 mM and in the presence of 1 MAC halothane; indeed, with these conditions, the control values of AF were not significantly different (Table 1), and 1 MAC halothane still induced a significant potentiation of beta-adrenoceptor stimulation (Effmax: 205 +/- 11 vs. 160 +/- 6% of control value, P < 0.05).
Furthermore, in the presence of 1 MAC halothane, the inotropic effect of alpha-adrenoceptor stimulation was no longer significantly different from that of beta-adrenoceptor stimulation, in contrast to that observed with control conditions (Figure 5).
Figure 5. Comparison of the relative inotropic potency of alpha (10 sup -4 M phenylephrine) and beta (10 sup -4 M isoproterenol) adrenoceptor stimulations in control conditions and in the presence of 1 MAC halothane. AF = active isometric force. Data are mean +/- SEM. *P < 0.05; NS = not significant.
Figure 5. Comparison of the relative inotropic potency of alpha (10 sup -4 M phenylephrine) and beta (10 sup -4 M isoproterenol) adrenoceptor stimulations in control conditions and in the presence of 1 MAC halothane. AF = active isometric force. Data are mean +/- SEM. *P < 0.05; NS = not significant.
Figure 5. Comparison of the relative inotropic potency of alpha (10 sup -4 M phenylephrine) and beta (10 sup -4 M isoproterenol) adrenoceptor stimulations in control conditions and in the presence of 1 MAC halothane. AF = active isometric force. Data are mean +/- SEM. *P < 0.05; NS = not significant.
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Influence of Halothane on the Inotropic Effects of Calcium
The concentration-response curve of calcium was obtained with and without 1 MAC halothane. Under both conditions, [Ca2+]o induced a positive inotropic effect. However, there was no significant difference in the magnitude of the positive inotropic effects observed with (Vmax: 186 +/- 12% and AF: 204 +/- 16% of control values) and without halothane (Vmax: 202 +/- 15% and AF: 258 +/- 6% of control values). These results suggest that the inotropic reserve of rat papillary muscle was not significantly modified by 1 MAC halothane.
Influence of Halothane on the Lusitropic Effects of alpha- and beta-adrenergic Stimulations
In the control setting and also in the presence of 1 MAC halothane, phenylephrine significantly decreased R1, an apparent positive lusitropic effect under low load, but induced no significant change in R2 (Table 3). Because halothane potentiated the inotropic effect of phenylephrine and because the lusitropic effect of phenylephrine depends on its inotropic effect, [37] we studied the relation between R1 or R2 (lusitropic effect) and AF (inotropic effect). One MAC halothane did not modify these relations (Figure 6), implying that halothane did not modify the lusitropic effects of phenylephrine.
Figure 6. Effect of 1 MAC halothane on the phenylephrine-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of phenylephrine (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 6. Effect of 1 MAC halothane on the phenylephrine-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of phenylephrine (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 6. Effect of 1 MAC halothane on the phenylephrine-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of phenylephrine (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
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In the control setting and in the presence of 1 MAC halothane, isoproterenol induced a significant decrease in R1 and R2 (Table 4). Because halothane potentiated the inotropic effect of isoproterenol and because the lusitropic effects of isoproterenol depend on its inotropic effect, [22] we studied the relation between R1 or R2 (lusitropic effect) and AF (inotropic effect). One MAC halothane significantly modified the R1/AF relation (Figure 7), implying that it decreased the lusitropic effect of isoproterenol under low load. In contrast, 1 MAC halothane did not significantly modify the R2/AF relation (Figure 7).
Figure 7. Effect of 1 MAC halothane on the isoproterenol-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of isoproterenol (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 7. Effect of 1 MAC halothane on the isoproterenol-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of isoproterenol (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 7. Effect of 1 MAC halothane on the isoproterenol-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of isoproterenol (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
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Discussion
The main results of this study are that (1) halothane, at clinically relevant concentrations, enhanced the positive inotropic effects of both alpha- and beta-adrenoceptor stimulations in isolated rat myocardium;(2) halothane did not modify the lusitropic effects of alpha-adrenoceptor stimulation under either low or high load;(3) although halothane significantly altered the lusitropic effects of beta-adrenoceptor stimulation under low load, it did not modify its lusitropic effects under high load.
The negative inotropic and lusitropic effects of halothane have been studied extensively. [1–5] The main mechanisms by which volatile anesthetics induce myocardial depression are a concentration-dependent decrease in transarcolemmal calcium entry [5] and an alteration in sarcoplasmic reticulum function. [6,7,9] Indeed, at clinically relevant concentrations, the decrease in myofilament calcium sensitivity induced by volatile anesthetics remains modest. [10] A growing body of evidence suggests that halothane causes a depression of the central and peripheral sympathetic nervous system. [12–14] Because of this, and because the sympathetic nervous system is an important modulator of cardiovascular function, the precise effects of halothane on alpha- and beta-adrenoceptor stimulations of the myocardium are difficult to assess in vivo. Nevertheless, in vivo, halothane has been reported to facilitate the development of catecholamine-induced arrhythmias. [18] Research has shown that, in vitro, 1.25 and 2 MAC halothane enhance the positive inotropic effects of isoproterenol on human atrial and ventricular myocardium despite the fact that it inhibits high-affinity binding of isoproterenol to beta adrenoceptors. [15] Our study confirmed this result [19] and showed that halothane also potentiates the positive inotropic effects of alpha-adrenoceptor stimulations (Figure 4).
Nevertheless, because halothane induced a negative inotropic effect, it could have increased the inotropic reserve of the myocardium, leading to an increase in the magnitude of the inotropic effects of catecholamines without increasing their net maximal effects-that is, an artifactual potentiation. Two arguments support our demonstration that halothane actually potentiates both alpha- and beta-adrenoceptor stimulations. First, we compared the positive inotropic effects of calcium with and without 1 MAC halothane and we did not observe any significant potentiation of the inotropic effect of calcium by halothane. Second, we studied the effects of both phenylephrine and isoproterenol at a very low (0.25 mM)[Ca2+]o to obtain comparable control values of AF, and we still observed a significant potentiation of their positive inotropic effects by halothane. Furthermore, 1 MAC halothane changed the relative inotropic potency of alpha- and beta-adrenoceptor stimulations; indeed, in the presence of halothane, the inotropic effect of alpha-adrenoceptor stimulation was no longer significantly different from that of beta-adrenoceptor stimulation (Figure 5). These results enabled us to conclude that the enhanced inotropic effects of phenylephrine and isoproterenol observed with halothane were related to an effective potentiation of their positive inotropic effects. Nevertheless, although expression of data as a percentage of control values is appropriate for studying a pharmacologic phenomenon such as adrenoceptor stimulation (Figure 4), it tends to exaggerate this phenomenon because halothane-depressed muscles were starting from a lower baseline AF (Figure 3).
R1 quantitates lusitropic effect under low load, which primarily provides an estimate of calcium uptake by the sarcoplasmic reticulum. In control groups, both phenylephrine and isoproterenol decreased R1, indicating a positive lusitropic effect under low load (Table 3and Table 4). This effect was more pronounced with isoproterenol than with phenylephrine, as previously reported. [37] We observed that 1 MAC halothane significantly increases R1 (Table 3), suggesting an alteration in processes leading to the decrease in intracellular calcium concentration during the relaxation phase, mainly the sarcoplasmic reticulum calcium uptake in the rat myocardium. This result corresponds with that previously reported in isolated ferret myocardium. [4] In addition, research has shown that halothane impairs sarcoplasmic reticulum function. [6–9] Our study showed that halothane did not modify the relation between R1 and AF during alpha-adrenoceptor stimulation (Figure 6), but it did alter that obtained during beta-adrenoceptor stimulation; that is, relaxation as assessed by R1 was augmented less at any given AF in the presence of halothane (Figure 7). The effect of halothane on the lusitropic effect of beta-adrenoceptor stimulation under low load may be related to the known effect of halothane on calcium uptake by the sarcoplasmic reticulum. [6–9] Impairment of this positive lusitropic effect may be clinically important. Indeed, diastolic function significantly influences systolic cardiac function, left ventricular filling, and coronary blood flow. [38] 
The difference observed in the effects of halothane on the relation between R1 and AF during alpha- and beta-adrenoceptor stimulations remains unclear. Several hypothesis can be raised:(1) the weak lusitropic effect of alpha-adrenoceptor stimulation observed did not allow us to show a significant effect of halothane, and (2) halothane did not modify the lusitropic effects of alpha-adrenoceptor stimulation under low load because of the different transduction signaling pathways of cardiac alpha and beta adrenoceptors. Further studies are needed to elucidate this point.
R2 tested the lusitropic effect under high load and thus could indirectly reflect myofilament calcium sensitivity. The decrease in R2 induced by halothane could be explained only by its negative inotropic effect (Figure 2) and not by a direct effect on myofilament calcium sensitivity. Indeed, although halothane decreases myofilament calcium sensitivity of human skinned myocardial fibers, this effect remains modest at clinically relevant concentrations. [10] In the control groups, we observed that isoproterenol decreases R2 (Table 4) but that phenylephrine did not (Table 3), as previously reported. [22,37] Our study showed that halothane did not modify the lusitropic effects under high load of alpha- and beta-adrenoceptor stimulations (Figure 6and Figure 7). The fact that halothane did not modify the lusitropic effects of beta-adrenoceptor agonists under high load may be important because catecholamines play an important role in the modulation of cardiac relaxation under both physiologic and pathologic conditions in vivo. [22,39] 
The precise mechanism of action for the catecholamines myocardium sensitizing effect of halothane remains incompletely understood. An effect on the number or affinity of adrenoceptors can be easily dismissed because we did not observe any shift in the concentration-response curves in the presence of halothane (Table 3and Table 4) and because halothane has been shown to reduce the number of beta adrenoceptors. [15] In contrast, there is increasing evidence that halothane interferes with G-protein function: Halothane has been shown to stimulate G-protein-dependent adenylate cyclase activity in human myocardium probably by interfering with the alpha or beta gamma subunits of the inhibitory G protein. [17,40] The fact that we observed that halothane also potentiates the inotropic effects of phenylephrine is compatible with that hypothesis, because G proteins are involved in both alpha- and beta-adrenoceptor transduction pathways.
The following points must be considered when assessing the clinical relevance of our results. First, because this study was conducted in vitro, it considered only with intrinsic myocardial contractility. Observed changes in cardiac function after halothane and catecholamines interactions also depend on modifications in venous return, afterload, sympathetic nervous system activity, and compensatory mechanisms. Second, this study was performed with halothane and not with other volatile anesthetics. Indeed, isoflurane is reported to induce a weaker myocardial depressant effect, [2,3] mainly because it decreases sarcoplasmic reticulum function to a lesser degree, [3] and desflurane may increase sympathetic tone. [41] Third, this study was conducted at 29 degrees Celsius and at a low stimulation frequency. However, papillary muscles must be studied at this temperature because stability of mechanical parameters is not sufficient at 37 degrees Celsius, and at a low frequency because high-stimulation frequency induces core hypoxia. [42] Fourth, the study was performed on rat myocardium, which differs from human myocardium. In rat myocardium, contractility is high, the calcium-induced calcium release from the sarcoplasmic reticulum is more highly developed than in other species, and myosin isoforms are predominantly of the fast VI type. Nevertheless, the effects of volatile anesthetics on the myocardium appear to be similar among species, [2–8] and halothane-induced potentiation of beta-adrenoceptor stimulation effects also has been reported in human myocardium. [17] Furthermore, some results concerning lusitropy and obtained with this experimental model have been recently confirmed in humans in vivo. [43] Responses to alpha-adrenoceptor stimulation in the rat differ from those in other species. [44] In addition, alpha-adrenoceptor density and, consequently, the positive inotropic effect induced by their stimulation are greater in rats than in humans, [45] but the importance of alpha adrenoceptors in cardiac contractility can be increased in pathologic conditions. [46,47] 
In isolated rat myocardium, halothane enhanced the positive inotropic effects of both alpha- and beta-adrenoceptor stimulations. In addition, halothane changed the positive lusitropic effect of beta-adrenoceptor stimulation under low load, whereas halothane did not modify the positive lusitropic effect of beta-adrenoceptor stimulation under high load.
The authors thank Annie Auclair for technical assistance.
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Figure 1. Mechanical parameters of contraction and relaxation. (Upper) Muscle shortening length (L/Lmax) plotted versus time. (Lower) Force (F) plotted versus time. Twitch 1 was loaded with preload only at Lmax. Twitch 2 was loaded with the same preload as twitch 1 but was abruptly clamped to zero-load with critical damping just after electrical stimulus; maximum unloaded shortening velocity (Vmax) was determined from this twitch. Twitch 3 was fully isometric. Coefficient R1, the ratio of maximum shortening velocity (sub max Vc) to maximum lengthening velocity (sub max Vr), tests lusitropy under low load; coefficient R2, the ratio of the peak of the positive force derivative (+dF [centered dot] dt sup -1) to the peak of the negative force derivative (-dF [centered dot] dt sup -1), tests lusitropy under high load.
Figure 1. Mechanical parameters of contraction and relaxation. (Upper) Muscle shortening length (L/Lmax) plotted versus time. (Lower) Force (F) plotted versus time. Twitch 1 was loaded with preload only at Lmax. Twitch 2 was loaded with the same preload as twitch 1 but was abruptly clamped to zero-load with critical damping just after electrical stimulus; maximum unloaded shortening velocity (Vmax) was determined from this twitch. Twitch 3 was fully isometric. Coefficient R1, the ratio of maximum shortening velocity (sub max Vc) to maximum lengthening velocity (sub max Vr), tests lusitropy under low load; coefficient R2, the ratio of the peak of the positive force derivative (+dF [centered dot] dt sup -1) to the peak of the negative force derivative (-dF [centered dot] dt sup -1), tests lusitropy under high load.
Figure 1. Mechanical parameters of contraction and relaxation. (Upper) Muscle shortening length (L/Lmax) plotted versus time. (Lower) Force (F) plotted versus time. Twitch 1 was loaded with preload only at Lmax. Twitch 2 was loaded with the same preload as twitch 1 but was abruptly clamped to zero-load with critical damping just after electrical stimulus; maximum unloaded shortening velocity (Vmax) was determined from this twitch. Twitch 3 was fully isometric. Coefficient R1, the ratio of maximum shortening velocity (sub max Vc) to maximum lengthening velocity (sub max Vr), tests lusitropy under low load; coefficient R2, the ratio of the peak of the positive force derivative (+dF [centered dot] dt sup -1) to the peak of the negative force derivative (-dF [centered dot] dt sup -1), tests lusitropy under high load.
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Figure 2. Effects of calcium on indices of lusitropy under high or low load (n = 8). Under low load, in contrast to both maximum shortening velocity (sub max VC) and maximum lengthening velocity (sub max Vr), R1 is not significantly modified by major inotropic changes induced by decreasing [Ca2+]o. Under high load, R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than the peak of the positive force derivative (+dF [centered dot] df sup -1)* and the peak of the negative force derivative (-dF [centered dot] dt sup -1). Data are mean percentages of control values +/- SEM.
Figure 2. Effects of calcium on indices of lusitropy under high or low load (n = 8). Under low load, in contrast to both maximum shortening velocity (sub max VC) and maximum lengthening velocity (sub max Vr), R1 is not significantly modified by major inotropic changes induced by decreasing [Ca2+]o. Under high load, R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than the peak of the positive force derivative (+dF [centered dot] df sup -1)* and the peak of the negative force derivative (-dF [centered dot] dt sup -1). Data are mean percentages of control values +/- SEM.
Figure 2. Effects of calcium on indices of lusitropy under high or low load (n = 8). Under low load, in contrast to both maximum shortening velocity (sub max VC) and maximum lengthening velocity (sub max Vr), R1 is not significantly modified by major inotropic changes induced by decreasing [Ca2+]o. Under high load, R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than the peak of the positive force derivative (+dF [centered dot] df sup -1)* and the peak of the negative force derivative (-dF [centered dot] dt sup -1). Data are mean percentages of control values +/- SEM.
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Figure 3. Effects of 1 MAC halothane on the inotropic response to alpha- and beta-adrenoceptor stimulation. Data are absolute mean values of isometric active force (AF)+/- SEM. C1 corresponds to the control value at a calcium concentration of 0.5 mM. C2 corresponds to the control value after halothane administration in the halothane group and after decreasing calcium concentration from 0.5 to 0.25 mM in the 0.25 mM calcium group. The potentiation of alpha- and beta-adrenoceptor stimulations by halothane could not overcome its negative inotropic effect.
Figure 3. Effects of 1 MAC halothane on the inotropic response to alpha- and beta-adrenoceptor stimulation. Data are absolute mean values of isometric active force (AF)+/- SEM. C1 corresponds to the control value at a calcium concentration of 0.5 mM. C2 corresponds to the control value after halothane administration in the halothane group and after decreasing calcium concentration from 0.5 to 0.25 mM in the 0.25 mM calcium group. The potentiation of alpha- and beta-adrenoceptor stimulations by halothane could not overcome its negative inotropic effect.
Figure 3. Effects of 1 MAC halothane on the inotropic response to alpha- and beta-adrenoceptor stimulation. Data are absolute mean values of isometric active force (AF)+/- SEM. C1 corresponds to the control value at a calcium concentration of 0.5 mM. C2 corresponds to the control value after halothane administration in the halothane group and after decreasing calcium concentration from 0.5 to 0.25 mM in the 0.25 mM calcium group. The potentiation of alpha- and beta-adrenoceptor stimulations by halothane could not overcome its negative inotropic effect.
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Figure 4. Effect of 0.5 and 1 MAC halothane on the inotropic effect of phenylephrine or isoproterenol. AF = active isometric force. Data are mean +/- SEM.
Figure 4. Effect of 0.5 and 1 MAC halothane on the inotropic effect of phenylephrine or isoproterenol. AF = active isometric force. Data are mean +/- SEM.
Figure 4. Effect of 0.5 and 1 MAC halothane on the inotropic effect of phenylephrine or isoproterenol. AF = active isometric force. Data are mean +/- SEM.
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Figure 5. Comparison of the relative inotropic potency of alpha (10 sup -4 M phenylephrine) and beta (10 sup -4 M isoproterenol) adrenoceptor stimulations in control conditions and in the presence of 1 MAC halothane. AF = active isometric force. Data are mean +/- SEM. *P < 0.05; NS = not significant.
Figure 5. Comparison of the relative inotropic potency of alpha (10 sup -4 M phenylephrine) and beta (10 sup -4 M isoproterenol) adrenoceptor stimulations in control conditions and in the presence of 1 MAC halothane. AF = active isometric force. Data are mean +/- SEM. *P < 0.05; NS = not significant.
Figure 5. Comparison of the relative inotropic potency of alpha (10 sup -4 M phenylephrine) and beta (10 sup -4 M isoproterenol) adrenoceptor stimulations in control conditions and in the presence of 1 MAC halothane. AF = active isometric force. Data are mean +/- SEM. *P < 0.05; NS = not significant.
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Figure 6. Effect of 1 MAC halothane on the phenylephrine-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of phenylephrine (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 6. Effect of 1 MAC halothane on the phenylephrine-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of phenylephrine (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 6. Effect of 1 MAC halothane on the phenylephrine-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of phenylephrine (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
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Figure 7. Effect of 1 MAC halothane on the isoproterenol-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of isoproterenol (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 7. Effect of 1 MAC halothane on the isoproterenol-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of isoproterenol (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
Figure 7. Effect of 1 MAC halothane on the isoproterenol-induced changes in the relation between R1 (lusitropy under low load; upper) or R2 (lusitropy under high load; lower) and active isometric force (AF)(inotropy). Each point corresponds to a concentration of isoproterenol (from 10 sup -8 to 10 sup -4 M, producing a concentration-dependent increase in AF). Data are mean percentages of control values +/- SEM. The probability value refers to between-groups comparison using multivariate analysis of variance. NS = not significant.
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Table 1. Comparison of Control Values of Inotropic and Lusitropic Parameters in the Different Groups of Papillary Muscles
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Table 1. Comparison of Control Values of Inotropic and Lusitropic Parameters in the Different Groups of Papillary Muscles
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Table 2. Effects of Halothane (0.5 and 1 MAC) on Inotropic and Lusitropic Parameters
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Table 2. Effects of Halothane (0.5 and 1 MAC) on Inotropic and Lusitropic Parameters
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Table 3. Effects of Halothane (0.5 and 1 MAC) on the Inotropic and Lusitropic Responses to alpha Adrenoceptor Stimulation
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Table 3. Effects of Halothane (0.5 and 1 MAC) on the Inotropic and Lusitropic Responses to alpha Adrenoceptor Stimulation
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Table 4. Effects of Halothane (0.5 and 1 MAC) on the lnotropic and Lusitropic Responses to beta Adrenoceptor Stimulation
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Table 4. Effects of Halothane (0.5 and 1 MAC) on the lnotropic and Lusitropic Responses to beta Adrenoceptor Stimulation
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