Editorial Views  |   September 1999
Anesthetic Preconditioning  : Not Just for the Heart?
Author Notes
  • Robert M. Epstein Professor and Chair
  • Department of Anesthesiology
  • University of Virginia Health System
  • Charlottesville, Virginia 22906–0010
Article Information
Editorial Views
Editorial Views   |   September 1999
Anesthetic Preconditioning  : Not Just for the Heart?
Anesthesiology 9 1999, Vol.91, 606. doi:
Anesthesiology 9 1999, Vol.91, 606. doi:
THE observation that brief episodes of ischemia in the heart, occurring before a subsequent longer interruption of blood flow, provides protection against dysfunction and necrosis has been termed ischemic preconditioning  . 1 The protection is well described in a variety of animal models as well as in clinical settings, and it is not a trivial effect. In models of stunned myocardium in which dysfunction persists for hours or days after ischemia/reperfusion, preconditioning can virtually prevent contractile dysfunction. In models of infarction, the necrotic area within a region at risk can be reduced by 60–75%. Clinically, this can mean the difference between sustained inotropic support in the postoperative period or considerably greater functional capacity in patients after discharge. The study by Novalija et al.  2 in this issue of ANESTHESIOLOGY continues the series of rather remarkable studies demonstrating that brief exposure to a volatile anesthetic, in this case sevoflurane, can mimic a brief ischemic insult and thereby precondition the myocardium, decreasing reperfusion damage and dysfunction.
The preconditioning protection observed with brief ischemia seems to be mediated by release of adenosine—it can be duplicated by adenosine administration, 3 prevented by blockade of adenosine receptors 4 and by inhibition of 5′-nucleotidase, 5 which is responsible for generation of adenosine. Adenosine binds to its receptor (A1 and possibly A3), and via  a G-protein–linked process, increases protein kinase C (PKC) activity. The resulting phosphorylation of the adenosine triphosphate (ATP)-sensitive K channel (KATP) results in the channel being less sensitive to inhibition by ATP. 6 Physiologically, the KATPchannel opens when intracellular ATP stores are depleted, permitting K+to flow out of the cell, thus restoring the resting membrane potential and decreasing activity. This channel plays an important role in regulating the tone of vascular smooth muscle by causing hyperpolarization and relaxation when oxygen delivery results in decreased ATP production. In the heart, the KATPchannel is not normally active, but its sensitivity to inhibition by ATP is decreased with PKC activation. When KATPchannel activity is increased, the cardiac action potential shortens, accompanied by a mild negative inotropic action and remarkable protection against a subsequent sustained ischemic or hypoxic insult. Preconditioning can also be elicited by activation of a variety of ligand receptors (endothelin, δ-opiate, α-adrenergic) that increase PKC activity, as well as by drugs such as KATPchannel openers (e.g.  , nicorandil or cromakalim). Of special relevance to anesthesiology, brief exposure to a volatile anesthetic can activate cardioprotection against a subsequent prolonged ischemia that is identical to ischemic preconditioning in that it can be inhibited by blocking KATPchannels or adenosine receptors. 7–12 Similar effects of ischemia and isoflurane and sevoflurane in preconditioning have also been demonstrated in isolated human atrium. 13,14 
Although initially attributed to KATPchannel effects on the sarcolemma, the remarkably profound protective effect exceeds the modest electrophysiologic changes. Furthermore, preconditioning actions are observed in the absence of alterations in electrophysiologic behavior. 15–17 However, in addition to their location on the myocyte membrane, KATPchannels are located in the mitochondrial inner membrane, where they seem to regulate mitochondrial volume as well as the massive electrical and proton gradient that powers ATP synthesis. Preconditioning can be initiated by the opening of mitochondrial KATPchannels and prevented by their blockade. 18,19 The model that emerges is one in which surface receptor activation turns on PKC activity, resulting in activation of mitochondrial KATPchannels to provide protection to myocytes. 17,20 PKC activity is actually mediated by a large class of ubiquitous phosphorylating enzymes that have varying requirements for activity (Gproteins, phospholipids, diacylglycerol, and increased intracellular Ca2+). A recent study suggests that a particular isoform (PKC-δ) is the type that is translocated to the mitochondria to activate KATPchannels located there. 21 Evidence is accumulating to document the functional role of KATPchannels in mitochondria, suggesting that channel activation leads to a decrease in the voltage gradient and a decrease in Ca2+accumulation. 20,22,23 However, the exact pathway by which mitochondria and cells are protected remains to be defined.
Although demonstrating the cardioprotective effect of sevoflurane, the more newsworthy result in the article by Novalija et al.  may be that this protection occurs not only in cardiac myocytes, but also extends to the endothelium of the coronary vasculature. A study dating back to the early 1990s demonstrated that a brief episode of ischemia also protects the functional integrity of the endothelium, demonstrating that the vasodilating capacity of the coronary vasculature was retained in hearts that were ischemically preconditioned. 24 The ischemic preconditioning of the endothelium also seems to be mediated, at least in part, by adenosine receptors and KATPchannels. 25 In addition, further studies have demonstrated that structural integrity of endothelial cells is better maintained after preconditioning. 26 It is interesting that these structural studies of endothelial cells subjected to ischemia/reperfusion show marked mitochondrial swelling, an effect not observed in preconditioned endothelium. 26 In addition, the structural evidence of protection seemed to last for up to 1 month. Further studies are required to demonstrate more precisely how volatile anesthetic preconditioning compares with ischemic preconditioning of both myocytes as well as the endothelium.
One of the major features of endothelial protection by brief ischemia or anesthetics is the ability to generate nitric oxide and mediate vasodilation. 2,25 The presence of nitric oxide is not only important for regulating vascular tone, but also for its ability to prevent leukocyte adhesion and migration into reperfused tissues. Endothelial nitric oxide production can prevent recruitment of polymorphonuclear leukocytes (neutrophil) into ischemic regions. 27–29 Because neutrophil accumulation and infiltration clearly contributes to the postischemic “no reflow” phenomenon, contractile dysfunction, and myocardial necrosis, prevention of their accumulation by maintained endothelial integrity is critically important. In addition, ischemia can induce expression of a variety of cell surface markers (P-selectin, intercellular adhesion molecule-1) and inflammatory mediators (tumor necrosis factor-α) that also contribute to neutrophil accumulation. 30 If endothelial protection by anesthesia includes the prevention of the expression of the cell adhesion molecules such as P-selectin, the endothelial protection provided by the anesthetics during ischemia may have profound implications with regard to maintaining vascular integrity during the stressful period of reperfusion. Although there are conflicting data concerning the role of free radicals as well as the exact cellular biochemical pathways involved, the studies with regard to anesthetics suggest that there may be remarkable protection provided by these agents.
The good news for anesthesiologists is that volatile agents that we routinely use seem to provide a significant protective effect, not only on the myocardium, but on the vascular endothelium. If endothelium in other vascular beds shows similar degrees of protection, then the use of volatile anesthetics may provide important protection for a far wider variety of tissues. Over the next few years we can look forward to more detailed explanations of the pathways of anesthetic preconditioning, as well as the extent to which other tissues share the beneficial effects observed in the myocardium. Considerable effort will no doubt be expended to develop pharmacologic means to maximize protection, perhaps seeking other drugs that can provide the similar kind of protection provided by volatile anesthetics. In the mean time, we can be assured that at least certain anesthetic agents seem to precondition and protect, but much work remains to be performed to define fully the extent of protection.
Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124–36
Novalija E, Fujita S, Kampine JP, Stowe DF: Sevoflurane mimics ischemic preconditioning effects on coronary flow and nitric oxide release in isolated hearts. A NESTHESIOLOGY 1999; 91: 701–12
Yao Z, Gross GJ: A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs: Efficacy, time course, and role of KATPchannels. Circulation 1994; 89: 1229–36
Van Winkle DM, Chien GL, Wolff RA, Soifer BE, Kuzume K, David RF: Cardioprotection provided by adenosine receptor activation is abolished by blockade of the KATPchannel. Am J Physiol 1994; 266: H829–39
Kitakaze M, Hori M, Morioka T, Minamino T, Takashima S, Sato H, Shinozaki Y, Chujo M, Mori H, Inoue M, Kamada T: Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5′-nucleotidase activity and attenuation of adenosine release. Circulation 1994; 89: 1237–46
Light PE, Sabir AA, Allen BG, Walsh MP, French RJ: Protein kinase C-induced changes in the stoichiometry of ATP binding activate cardiac ATP-sensitive K+channels. Circ Res 1996; 79: 399–406
Cason BA, Shubayev I, Hickey RF: Blockade of adenosine triphosphate-sensitive potassium channels eliminates isoflurane-induced coronary artery vasodilation. A NESTHESIOLOGY 1994; 81: 1245–55
Kersten JR, Lowe D, Hettrick DA, Pagel PS, Gross GJ, Warltier DC: Glyburide, a KATPchannel antagonist, attenuates the cardioprotective effects of isoflurane in stunned myocardium. Anesth Analg 1996; 83: 27–33
Kersten JR, Schmeling TJ, Hettrick DA, Pagel PS, Gross GJ, Warltier DC: Mechanism of myocardial protection by isoflurane: Role of adenosine triphosphate-regulated potassium (KATP) channels. A NESTHESIOLOGY 1996; 85: 794–807
Kersten JR, Orth KG, Pagel PS, Mei DA, Gross GJ, Warltier DC: Role of adenosine in isoflurane-induced cardioprotection. A NESTHESIOLOGY 1997; 86: 1128–39
Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC: Isoflurane mimics ischemic preconditioning via  activation of KATPchannels: Reduction of myocardial infarct size with an acute memory phase. A NESTHESIOLOGY 1997; 87: 361–70
Cope DK, Impastato WK, Cohen MV, Downey JM: Volatile anesthetics protect the ischemic rabbit myocardium from infarction. A NESTHESIOLOGY 1997; 109: 699–709
Roscoe AK, Lynch C III: Isoflurane activates preconditioning and ischemic protection in human atrial myocardium, halothane does not (abstract). Anesth Analg 1998; 86: SCA37
Roscoe AK, Lynch C III, Baum VC: Sevoflurane protects human myocardium from ischemia via activation of ATP-sensitive potassium channels (abstract). Anesth Analg 1999; 88: SCA57
Yao Z, Gross GJ: Effects of the KATPchannel opener bimakalim on coronary blood flow, monophasic action potential duration, and infarct size in dogs. Circulation 1994; 89: 1769–75
Grover GJ, D'Alonzo AJ, Parham CS, Darbenzio RB: Cardioprotection with the KATPchannel opener cromakalim is not correlated with ischemic myocardial action potential duration. J Cardiovasc Pharmacol 1995; 25: 145–52
Gross GJ, Fryer RM: Sarcolemmal versus mitochondrial ATP-sensitive K+channels and myocardial preconditioning. Circ Res 1999; 84: 973–9
Garlid KD, Paucek P, Yarov-Yarovoy V, Sun X, Schindler PA: The mitochondrial K channel as a receptor for potassium channel openers. J Biol Chem 1996; 271: 8796–9
Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ: Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+channels: Possible mechanism of cardioprotection. Circ Res 1997; 81: 1072–82
Sato T, O'Rourke B, Marban E: Modulation of mitochondrial ATP-dependent K+channels by protein kinase C. Circ Res 1998; 83: 110–4
Wang Y, Ashraf M: Role for protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+overload injury in rat myocardium. Circ Res 1999; 84: 1156–65
Liu Y, Sato T, O'Rourke B, Marban E: Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection? Circulation 1998; 97: 2463–9
Holmuhamedov EL, Jovanovic S, Dzeja PP, Jovanovic A, Terzic A: Mitochondrial ATP-sensitive K+channels modulate cardiac mitochondrial function. Am J Physiol 1998; 275: H1567–76
Richard V, Kaeffer N, Tron C, Thuillez C: Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion. Circulation 1994; 89: 1254–61
Bouchard J-F, Lamontagne D: Mechanisms of protection afforded by preconditioning to endothelial function against ischemic injury. Am J Physiol 1996; 271: H1801–6
Kaeffer N, Richard V, Francois A, Lallemand F, Henry JP, Thuillez C: Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats. Am J Physiol 1996; 271: H842–9
Pabla R, Buda AJ, Flynn DM, Blesse SA, Shin AM, Curtis MJ, Lefer DJ: Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction after ischemia and reperfusion. Circ Res 1996; 78: 65–72
Jones SP, Girod WG, Palazzo AJ, Granger DN, Grisham MB, Jourd'heuil D, Huang PL, Lefer DJ: Myocardial ischemia-reperfusion injury is exacerbated in the absence of endothelial cell nitric oxide synthase. Am J Physiol 1999; 276: H1567–73
Thourani VH, Nakamura M, Duarte IG, Bufkin BL, Zhao ZQ, Jordan JE, Shearer ST, Guyton RA, Vinten-Johansen J: Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass grafting. J Thorac Cardiovasc Surg 1999; 117: 383–9
Kupatt C, Habazettl H, Goedecke A, Wolf DA, Zahler S, Boekstegers P, Kelly RA, Becker BF: Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts. Circ Res 1999; 84: 392–400