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Review Article

Mechanisms of Cardioprotection by Volatile Anesthetics

Tanaka, Katsuya M.D.*; Ludwig, Lynda M. B.S.†; Kersten, Judy R. M.D.‡; Pagel, Paul S. M.D., Ph.D.§; Warltier, David C. M.D., Ph.D.∥

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A RAPIDLY growing body of evidence indicates that volatile anesthetics protect myocardium against reversible and irreversible ischemic injury. Identifying the mechanisms by which volatile agents mediate these antiischemic actions is the subject of intense research. This objective has been difficult to accomplish because volatile anesthetics also profoundly affect cardiovascular function. Volatile agents reduce arterial and coronary perfusion pressure, cause dose-related depression of myocardial contractility, produce coronary vasodilation, affect electrophysiologic function, and modify autonomic nervous system activity to varying degrees. Therefore, the antiischemic effects of volatile anesthetics may be mediated, at least in part, by favorable alterations in myocardial oxygen supply-demand relations, preservation of energy-dependent cellular functions, and increased coronary blood flow. However, it seems unlikely that changes in myocardial metabolism and coronary perfusion caused by volatile anesthetics are solely responsible for protection against ischemic damage. Instead, several endogenous signal transduction pathways, acting through the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel and involving the generation of reactive oxygen species (ROS), have been implicated in mediating the antiischemic actions of volatile anesthetics. The experimental and clinical findings documenting the phenomenon of volatile anesthetic preconditioning against ischemic injury of myocardium are evaluated. Recent findings in vitro and in vivo that seek to define the intracellular mechanisms responsible for these beneficial actions are also summarized.
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Historical Perspective

The antiischemic effects of volatile anesthetics were initially proposed more than 20 yr ago. Lowenstein et al.1 demonstrated that halothane reduced ST segment elevation in a canine model of brief coronary artery occlusion. These data were consistent with the hypothesis that exposure to halothane reduced acute ischemic injury. A subsequent study by this research group also demonstrated that halothane reduced myocardial infarct size when administered before prolonged coronary artery occlusion in dogs. 2 Lactate production was decreased in the presence as compared with the absence of enflurane during demand-induced ischemia produced by a critical coronary artery stenosis and ventricular pacing when coronary perfusion pressure was maintained. 3 These results suggested that myocardial metabolism may be improved by administration of a volatile agent during an ischemic episode independent of alterations in hemodynamics. The relative importance of these early findings was initially overshadowed 4 by a series of reports published in the mid-1980s 5–8 suggesting that isoflurane may be capable of producing an abnormal redistribution of coronary blood flow away from ischemic toward normal myocardium. 9–11 This “coronary steal” phenomenon was attributed to the coronary vasodilating properties of isoflurane that are known to occur primarily in arterioles of less than 100 μm in diameter. 12 Isoflurane was thought to be capable of directly producing myocardial ischemia in susceptible patients with “steal-prone” coronary artery anatomy under certain hemodynamic conditions 13 in a fashion similar to that of potent coronary vasodilators (e.g., adenosine, chromonar, dipyridamole).
The implication that isoflurane might produce myocardial ischemia through such a steal mechanism was subsequently dispelled by several investigations conducted in animal models 14–17 and humans with coronary artery disease. 18–20 For example, isoflurane did not selectively redistribute blood flow away from the collateral-dependent region in a chronically instrumented canine model of multivessel coronary artery disease. 15 In contrast, adenosine produced marked coronary steal by preferentially shunting blood flow away from collateral-dependent myocardium in this model. 15 Other studies 14,16–20 also suggested that isoflurane-induced hypotension may reduce myocardial perfusion, but true coronary steal did not occur when coronary perfusion pressure was maintained. Subsequent investigations with the newer volatile anesthetics sevoflurane 21,22 and desflurane 23 showed that these drugs also did not reduce or abnormally redistribute coronary collateral blood flow. Therefore, despite initial concerns, volatile anesthetics were subsequently shown to be relatively weak coronary vasodilators that are incapable of causing coronary steal under the vast majority of clinical conditions. 24
Contrary to the hypothesis that the use of volatile anesthetics may be potentially deleterious in some patients with coronary artery disease, many laboratory and clinical investigations conducted since the resolution of the coronary steal controversy have convincingly shown that volatile anesthetics protect the heart against ischemia and reperfusion injury. In addition to previously cited studies suggesting that halothane 1,2 and enflurane 3 exerted antiischemic effects, halothane was also shown to preserve contractile function and ultrastructural integrity during cardioplegic arrest. 25 This latter study was of considerable interest because these data indicated that halothane was capable of exerting a cardioprotective effect completely independent of improvements in myocardial oxygen supply-demand balance. In addition, halothane, 26 enflurane, 26 desflurane, 26–28 and sevoflurane 26–31 have been shown to reduce myocardial damage when administered during reperfusion after prolonged coronary occlusion or cardioplegic arrest. Another study showed that preservation of high-energy phosphate concentrations was coupled to the protective effects of enflurane. 32 Isoflurane and desflurane did not depress but modestly enhanced left ventricular diastolic function during acute coronary occlusion in dogs. 33 Halothane, 34–36 enflurane, 34,37,38 isoflurane, 34,35,37 and sevoflurane 39 were shown to improve the functional recovery of isolated hearts subjected to global ischemia and reperfusion. Halothane and isoflurane markedly augmented the recovery of regional contractile function of stunned myocardium in vivo. 40,41 Halothane 2 and isoflurane 42 reduced myocardial infarct size in dogs, and this beneficial action was found to persist despite discontinuation of the volatile anesthetic before coronary artery occlusion. 42 The myocardium acted as if it had “remembered” the previous exposure to the volatile agent. This phenomenon was termed anesthetic-induced preconditioning (APC) 43 and was characterized by a short-term memory phase similar to that observed during ischemic preconditioning (IPC).
Anesthetic-induced preconditioning has also been described in other animal species, including rats 44 and rabbits. 43 The efficacy of APC conferred by isoflurane to reduce infarct size has been shown to be dose dependent in rats, 44 an animal model with minimal coronary collateral flow. 45 High concentrations of isoflurane may also have greater efficacy to protect myocardium during conditions of low coronary collateral blood flow in dog myocardium. 46 Similarly, isoflurane and sevoflurane dose-dependently preserved the viability of isolated cardiac myocytes during ischemia. 47 Isoflurane has been shown to elicit cardioprotective effects after discontinuation for 15 min or 30 min before coronary artery occlusion in rats and rabbits 43,44 or dogs, 42 respectively. In contrast, sevoflurane did not exert antiischemic actions after a 30-min washout period. 48 Taken together, these data suggest that the memory period associated with APC may differ between volatile anesthetics and among species. Interestingly, recent findings showed that isoflurane reduced myocardial damage when administered 24 h before coronary artery occlusion and reperfusion in rabbit hearts in vivo. 49 Pretreatment with isoflurane also preserved endothelial and vascular smooth muscle cell viability 12–48 h after cytokine-induced injury. 50 Therefore, volatile anesthetics also produce a late phase (i.e., a second window) of myocardial protection similar to IPC. In addition, sevoflurane reduced the duration of a brief ischemic episode required to protect against infarction during IPC. 48 Sevoflurane also enhanced cardioprotection when administered 24 h after an initial IPC stimulus. 51 These important findings showed that administration of a volatile anesthetic combined with a brief ischemic event synergistically protects myocardium against subsequent damage as well.
Additional data about the effects of volatile agents on the coronary circulation also stand in contrast with the conclusions implicated by the coronary steal hypothesis. These results indicated that volatile agents are certainly not deleterious to but may instead exert beneficial actions on coronary collateral perfusion to ischemic myocardium. Volatile anesthetics have been shown to produce coronary vasodilation by activating KATP channels 39,52–55 or by favorably affecting intracellular Ca2+ homeostasis in vascular smooth muscle. 56 Halothane attenuated reductions in coronary collateral perfusion associated with acute coronary occlusion and also improved the myocardial oxygen supply-demand relation in collateral-dependent myocardium. 57 In addition, halothane reduced cyclical changes in coronary blood flow and prevented the development of platelet thrombi in the presence of a critical coronary artery stenosis. 58 Sevoflurane increased collateral blood flow to ischemic myocardium when perfusion pressure was maintained. 21,59 Sevoflurane also improved the functional recovery of coronary vascular reactivity and nitric oxide release in isolated hearts after global ischemia. 39 Lastly, volatile anesthetics attenuated neutrophil and platelet aggregation 60 and also inhibited cytokine-induced cell death 50,61 after ischemia-reperfusion injury in vitro. The results of these studies collectively show the protection against ischemia and reperfusion injury may be at least partially based on favorable effects of volatile agents on coronary perfusion.
The precise mechanisms responsible for volatile anesthetic-induced protection against ischemic injury remain unclear despite extensive study. Although it is clear that volatile anesthetics may indirectly improve myocardial oxygen supply-demand relations or enhance coronary collateral perfusion, it is equally clear that these actions are not entirely responsible for the antiischemic effects of these agents. This contention is emphasized by findings showing that volatile anesthetics conferred protection during cardioplegic arrest 25 and during reperfusion, 26–30 conditions in which myocardial oxygen supply-demand relations play little if any role. Similarly, isoflurane and sevoflurane increased the viability of isolated cardiac myocytes, 47 and sevoflurane 62 and desflurane 63 improved contractility of isolated cardiac muscle exposed to simulated ischemia. These results were initially attributed to reductions in excessive intracellular Ca2+ concentrations during ischemia and reperfusion 64 produced by partial inhibition of Ca2+ channel activity. 65–68 However, this relatively generic Ca2+ hypothesis did not address the precise mechanisms or provide deeper insight into the intracellular processes by which volatile anesthetics exert protective effects in the intact heart.
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KATP Channels
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The signal transduction pathways involved in APC bear striking similarity to those responsible for IPC. It is hypothesized that volatile anesthetics stimulate a trigger that initiates a cascade of events leading to activation of an end-effector that is responsible for resistance to injury. To date, adenosine type 1 (A1) receptors, 34,69,70 protein kinase C (PKC), 34,71,72 inhibitory guanine nucleotide binding (Gi) proteins, 73 ROS, 74–76 and mitochondrial and sarcolemmal KATP (mito KATP and sarc KATP, respectively) channels 42,77–79 have been shown to mediate APC (fig. 1). KATP channels are heteromultimeric complexes containing an inward-rectifying potassium (Kir) channel and a sulfonylurea receptor (SUR). 80 Pharmacologic and recombinant techniques indicate that sarc KATP and mito KATP channels 81,82 are composed of the Kir6.2/SUR2A and Kir6.1/SUR1 isoforms, 83 respectively. KATP channel opening was initially implicated as the central end-effector during APC, 84 similar to the findings during studies of the mechanisms responsible for IPC. 85,86 Isoflurane and sevoflurane preserved myocardial viability in a cellular model of ischemia, and this protective effect was abolished by the selective mito KATP channel antagonist 5-hydroxydecanoate (5-HD) but not the selective sarc KATP channel antagonist HMR-1098. 47 Isoflurane, 69 sevoflurane, 62 and desflurane 63 but not halothane 69 enhanced the recovery of contractile force of isolated human right atrial trabeculae after hypoxia and reoxygenation. The nonselective KATP channel blocker glyburide (glibenclamide) or 5-HD inhibited this protective effect. HMR-1098 also attenuated the beneficial actions produced by sevoflurane in isolated human atria. 62 Glyburide blocked the enhanced recovery of contractile function produced by isoflurane in stunned myocardium in vivo. 41,87 Reductions in canine myocardial infarct size produced by isoflurane 42 and the ATP-sparing effects of this agent 88 have been shown to be blocked by glyburide as well. 5-HD also inhibited preconditioning by isoflurane in rats 44 and rabbits. 77 Both 5-HD and HMR-1098 abolished the protective effects of desflurane against ischemia and reperfusion injury in dogs, 78 supporting a role for both mito KATP and sarc KATP channels in APC. In contrast, another study showed that HMR-1098 did not modify desflurane-induced preconditioning in isolated human right atria in vitro. 63 Therefore, some controversy continues to exist about the relative contribution of sarc KATP and mito KATP channels in APC.
Carefully conducted in vitro experiments suggest that volatile anesthetics are capable of modifying KATP channel activity. Isoflurane stimulated outward K+ current through sarc KATP channels in isolated ventricular myocytes during patch clamping. 89,90 Volatile anesthetics also reduced sarc KATP channel sensitivity to inhibition by ATP, thereby increasing open state probability. 91 In contrast, other patch clamp results suggested that volatile agents alone did not open KATP channels. Isoflurane did not affect sarc KATP channel current in human atrial cells 69 and also inhibited sarc KATP channel activity in rabbit ventricular myocytes. 91 However, some volatile anesthetics were able to enhance sarc KATP channel current by facilitating channel opening after initial activation. 89,90 Isoflurane enhanced sarc KATP channel opening in the presence of the mitochondrial uncoupler 2,4-dinitrophenol, the KATP channel opener pinacidil, and the protein tyrosine kinase (PTK) inhibitor genistein in a whole cell patch clamp model. 89,92 Activation of PKC, 90 adenosine receptors, 93 and phosphatidylinositol kinase 93 seemed to be necessary for this process to occur. Isoflurane also directly opened sarc KATP channels during intracellular acidosis, a condition that is known to occur during ischemia. 94 These data suggest that volatile anesthetics may not directly interact with sarc KATP channels but instead may affect other signaling elements that modulate sarc KATP channel activity. In contrast with the findings with isoflurane, halothane had no effect on pinacidil-induced increases in sarc KATP channel current and even inhibited KATP channel current that had been maximally activated by 2,4-dinitrophenol. 89 The anesthetic specificity for APC remains to be well characterized, although studies such as these do suggest important differences in efficacy may exist among individual agents.
The ability of volatile anesthetics to directly open mito KATP channels has also been examined. Isoflurane and sevoflurane increased mitochondrial flavoprotein oxidation, an index of mito KATP channel activity, in guinea pig cardiac myocytes. 95 This process was inhibited by 5-HD. 95 Flavoprotein fluorescence may not be entirely specific for mito KATP channel opening, 96 but isoflurane has also been shown to directly activate mito KATP channels reconstituted in lipid bilayers. 97 In contrast with these intriguing findings, 97 Zaugg et al.47 recently demonstrated that although isoflurane or sevoflurane did not directly enhance flavoprotein oxidation in rat ventricular myocytes, these volatile agents did potentiate increases in fluorescence produced by the selective mito KATP channel agonist diazoxide. These results suggested that volatile anesthetics may not directly open but instead act to prime mito KATP channels, thus enhancing their ability to open in response to an agonist. Sarc KATP channels may also be linked to the function of the mitochondrial inner membrane. For example, ROS generated by mitochondria may act to open sarc KATP channels. 98 2,4-Dinitrophenol-induced activation of sarc KATP channel current was reversible and accompanied by nicotinamide adenine dinucleotide oxidation, suggesting the existence of cross-talk between mito KATP and sarc KATP channels. 99 Taken as a whole, the preponderance of evidence collected to date implies that volatile anesthetics do not necessarily directly open KATP channels but instead prime the activation of these channels in both sarcolemmal and mitochondrial membranes.
Adenosine triphosphate-sensitive potassium channels in vascular smooth muscle cells have been shown to be essential regulators of coronary vascular tone when ATP production is reduced. 100 Volatile anesthetic-induced coronary vasodilation 39,52–55 was attenuated by glyburide, indicating an important role for KATP channels in this process. These data suggest that the beneficial actions of volatile agents during myocardial ischemia may be partially attributed to increased oxygen supply mediated via KATP channel-dependent coronary vasodilation. However, sevoflurane increased coronary collateral blood flow in the presence of glyburide in vivo, indicating that volatile anesthetics enhance collateral perfusion independent of KATP channel activation. 59 In fact, sevoflurane-induced increases in collateral perfusion were recently shown to occur as a result of Ca2+-regulated potassium and not KATP channel activation. 101 Based on these findings and results obtained in isolated cardiac myocytes where blood flow is not a factor, 47 it seems highly unlikely that myocardial protection produced by volatile anesthetics is solely related to favorable alterations in coronary vascular tone mediated by KATP channels.
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G Protein-coupled Receptors
Volatile anesthetics may activate parallel or redundant signaling pathways that involve KATP channel opening to generate a physiologically meaningful cellular response. The sequential activation of several intracellular elements within a given transduction pathway may facilitate signal amplification and interaction between other redundant signaling systems. For example, administration of isoflurane in the presence of the KATP channel openers nicorandil 102 or diazoxide 103 markedly enhances protection against ischemic injury beyond that observed with either drug alone. Several receptor-mediated events and intracellular signaling elements that converge on the KATP channel have been implicated in APC. Pretreatment with pertussis toxin abolished any reduction in infarct size produced by isoflurane, indicating that Gi proteins are linked to the signal transduction pathways that mediate APC. 73 In contrast, pertussis toxin did not alter the beneficial effects of direct KATP channel opening produced by nicorandil. These data strongly support the contention that volatile anesthetics modulate KATP channel activity through second messenger signaling.
Halothane-induced protection against infarction was completely abolished by blockade of the adenosine A1 receptor. 34 The nonselective adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline abolished isoflurane-induced preconditioning in rabbits. 79 The selective A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine partially attenuated the beneficial effects of isoflurane in canine stunned myocardium. 70 A role for adenosine receptors in APC was also identified in isolated human right atrial myocardium in vitro. 69 Isoflurane eliminated increases in interstitial adenosine during repetitive periods of coronary artery occlusion and reperfusion using a microdialysis technique. 70 These findings suggest that ATP preservation and a subsequent reduction of adenosine released into the interstitium occur during isoflurane anesthesia. 70 In addition, the data imply that volatile agents may either directly activate A1 receptors or indirectly enhance A1 receptor sensitivity to diminished endogenous adenosine concentrations. 70 These results were also similar to those observed during IPC 104 or bimakalim-induced pharmacologic preconditioning. 105 The preservation of cardiac myocyte viability during ischemia produced by volatile anesthetics was also sensitive to adenosine receptor and Gi protein inhibition in rats. 47
Stimulation of the δ1-opioid receptor has been shown to produce a cardioprotective effect that is abolished by selective opioid antagonists 106–110 or KATP channel blockers. 107,108,110–113 The acute and delayed phases of IPC are also mediated by activation of the δ1-opioid receptor. 114 Recent results indicated that the combined administration of isoflurane and selective δ1-opioid receptor agonists TAN-67 or BW373U86 potentiated KATP channel opening and enhanced protection against myocardial ischemia and reperfusion injury. 103 Combined administration of isoflurane and morphine, a μ receptor agonist with δ1 receptor agonist properties, also reduced the extent of myocardial infarction to a greater degree than either drug alone. 44 This beneficial effect was shown to be mediated by mito KATP channels and opioid receptors. Interestingly, the nonselective opioid antagonist naloxone abolished isoflurane-induced preconditioning. 44 These intriguing data suggest an important link between volatile anesthetics and the opioid family of G protein-coupled receptors. Another recent study also indicated that halothane competitively inhibited the ligand-binding site of G protein-coupled receptors. 115 Adrenergic receptor blockade was shown to abolish desflurane-induced preconditioning in isolated human right atria 63 but had no effect on the antiischemic actions of sevoflurane in isolated rat cardiac myocytes. 47 Overall, APC seems to be associated with the activation of separate receptor-mediated pathways that are linked to Gi proteins.
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Protein Kinases
Translocation and phosphorylation of multiple protein kinases are known to be involved in signal transduction pathways involved in protecting myocardium against cell death after ischemia and reperfusion. 116–118 In particular, PKC is an essential component of the signaling pathways associated with preserving cellular viability. 119 The diverse PKC isoform family is a large group of serine/threonine protein kinases that are distinguished by variable regulatory domains and cofactors and also display diverse tissue and species distributions. 120 Activation of G protein-coupled receptors (e.g., A1, 121,122 bradykinin, 123,124 δ1 opioid 125,126) stimulate PKC during IPC. Volatile anesthetics have also been shown to stimulate PKC translocation and activity, 127 possibly by interacting with the regulatory domain of the enzyme. 128 Inhibition of PKC attenuated isoflurane-enhanced recovery of contractile function in canine stunned myocardium. 71 The antiischemic actions of halothane were abolished by selective PKC antagonism in rabbits. 34 The δ and ε isoforms of PKC translocated to mitochondria and sarcolemma, respectively, 10 min after discontinuation of isoflurane in isolated rat hearts. 129 In contrast, isoflurane stimulated translocation of PKC-δ and -ε to sarcolemmal and mitochondrial membranes, respectively, in the in vivo rat heart. 72 These discrepancies may be attributed to differences in experimental model or time of tissue sampling. The microtubule depolymerizing drug, colchicine, prevented isoflurane-induced reductions in myocardial infarct size in rabbits, 130 suggesting that an intact cytoskeleton is essential for translocation of these protein kinases. 72,129
Recent findings strongly suggest that volatile anesthetic-induced PKC activation is required to open KATP channels and produce myocardial protection. For example, the nonselective PKC antagonist chelerythrine abolished sevoflurane-induced increases in mito KATP channel activity in rat ventricular myocytes and prevented protection against simulated ischemia. 47 Patch clamp experiments showed that isoflurane did not facilitate KATP channel opening in excised membrane patches but enhanced KATP channel current in a whole cell configuration concomitant with PKC stimulation. 90 These observations were supported by other studies showing that adenosine and PKC increased KATP channel activity. 103,131–134 Specific PKC consensus sites have been identified on KATP channels, indicating a molecular basis for phosphorylation and activation of the channel by the enzyme. 135 Mito KATP channel opening also occurred after PKC activation during IPC in isolated rabbit hearts. 136 In contrast, recent evidence indicates that 5-HD inhibited PKC translocation, 72 suggesting that mito KATP channel opening may be upstream of PKC activation. Therefore, a possible feed-forward system between PKC and KATP channel activation may occur during APC.
Protein kinase C has been shown to stimulate PTK 137,138 and mitogen-activated protein kinases (MAPKs), 139 and volatile anesthetics may modulate several of these critical intracellular signaling proteins independent of direct receptor activation as well. Ischemic and pharmacologic preconditioning have been shown to be mediated by activation of PKC, 34,71,106,124,140 PTK, 116,137,138,141,142 and MAPK. 117,118,143–145 A recent investigation showed that the PTK inhibitor lavendustin A and the Src-selective inhibitor PP1 abolished isoflurane-induced preconditioning in rats. 72 The MAPK family plays an important role in signal transduction from the cell surface and the nucleus and has been strongly implicated in the initiation and progression of cell death (i.e., apoptosis). 146–148 The p38 MAPK subfamily mediated IPC of myocardium in dogs, and activation of p38 MAPK was also associated with phosphorylation and translocation of heat shock protein 27 in vivo. 144 In contrast with the findings during IPC, recent data suggest that p38 MAPK may not play a role in APC in isolated rat hearts. 149 Nonetheless, volatile anesthetics modulate activity of one or more intracellular kinases to produce APC, and it seems that activation of PKC is critical to cardioprotection.
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Reactive Oxygen Species
Large quantities of ROS are released during reperfusion of ischemic myocardium that damage proteins responsible for intracellular homeostasis, depress contractile function, and produce membrane damage. 150–152 Halothane, isoflurane, and enflurane have been shown to attenuate the toxic effects of ROS on left ventricular pressure development in isolated hearts. 153 Isoflurane decreased hydroxyl radical generation in the ischemic rat heart, 154 and halothane had a similar effect in dogs. 155 The protective effects of sevoflurane were associated with reduced dityrosine formation, an indirect marker of ROS and reactive nitrogen species. 76 These results support the hypothesis that volatile anesthetics reduce the release of deleterious quantities of ROS associated with coronary artery occlusion and reperfusion. Isoflurane also inhibited superoxide anion production by activated neutrophils, an action that occurred independent of KATP channel opening. 156 In addition, isoflurane and sevoflurane have been shown to abolish activated neutrophil-induced myocardial dysfunction. 157 These effects were associated with reductions in superoxide anion production and neutrophil adherence to coronary vascular endothelium. Therefore, volatile anesthetics also seem to exert beneficial actions by inhibiting neutrophil-induced injury during reperfusion.
In contrast with data implicating a pathologic role of large amounts of ROS, other findings strongly suggest that a variety of preconditioning stimuli, including brief ischemia, direct mito KATP channel openers, opioids, and volatile anesthetics, stimulate a small burst of ROS that initiate downstream signaling events and produce protection from subsequent ischemic injury. 158 For example, pretreatment with low concentrations of ROS have been shown to mimic the beneficial actions of IPC. 159,160 Free radical scavengers administered before or during brief ischemia markedly attenuated the protective effect of the preconditioning stimulus on infarct size. 161,162 These findings indicate that IPC is mediated by small quantities of ROS released during the preconditioning stimulus. The beneficial actions of sevoflurane against ischemic damage were abolished by scavengers of superoxide anion and inhibition of nitric oxide synthase. 76 These results suggest that superoxide anion may act to trigger APC and further indicated that nitric oxide may scavenge superoxide anion on reperfusion to reduce injury. ROS scavengers attenuated isoflurane-induced reductions in myocardial infarct size in rabbits 74,75 and also inhibited the beneficial effects of direct mito KATP channel activation. 163 Isoflurane has been shown to directly increase superoxide anion formation in vivo independent of an ischemic episode by use of the fluorescent probe dihydroethidium and laser confocal microscopy. 75 These data 75 indicated for the first time that volatile anesthetics were capable of producing small amounts of ROS that were correlated with a reduction in myocardial infarct size after prolonged ischemia. Taken as a whole, these reports provide compelling evidence that small quantities of ROS also play a critical role in APC.
Reactive oxygen species have been shown to act as regulatory mediators in many signaling processes that protect the cells against oxidative stress. 164 ROS-induced activation of PKC 159 and MAPK 165–167 have been implicated in both ischemic and pharmacologic preconditioning. Hydrogen peroxide activated all three MAPK subtypes in neonatal rat ventricular myocytes, but stimulation of the p38 MAPK family and the consequent phosphorylation of heat shock protein 25/27 seemed to be of critical importance during cardioprotection. 165 ROS have also been shown to activate Gαi and Gαo proteins. 168,169 Recent findings showed that sevoflurane-induced ROS generation was unaffected by PKC inhibition, 170 but ROS scavengers inhibited isoflurane-induced PKC translocation. 72 These findings provide indirect evidence linking ROS production by volatile anesthetics to subsequent activation of protein kinases implicated in the signal transduction responsible for APC.
A controversy continues to exist regarding the temporal relation between mito KATP channel opening and ROS production during ischemic or pharmacologic preconditioning. 171 Although sarc KATP channel opening was initially assumed to be the end-effector of IPC, 81,85 mito KATP channel activation may instead trigger preconditioning by generating ROS. 163,172 Mito KATP channel opening produced by selective agonists generates ROS 163,172 that seem to be essential for activation of MAPK 166 and are also required for beneficial effects on myocardium. 173 The mito KATP channel agonist diazoxide caused oxidation of the ROS probe MitoTracker® orange (Molecular Probes, Eugene, OR) and enhanced cell viability after hypoxia and reoxygenation in vitro. 172 These actions were attenuated by pretreatment with 5-HD or ROS scavengers. Therefore, the protective effects of mito KATP channel agonists may occur as a consequence of triggering by ROS that subsequently reduces myocyte injury, including the release of large quantities of these reactive intermediates during reperfusion injury. Morphine increased cardiomyocyte viability and the fluorescence intensity of the hydrogen peroxide-sensitive probe, 2′7′-dichlorofluorescin. 111 These actions were abolished by 5-HD pretreatment, suggesting that activation of mito KATP channels by opioids results in ROS production. Conversely, other studies 174,175 have indicated that ROS modulate mito KATP channel activity 174 to provide a beneficial effect, indirectly suggesting that mito KATP channels may also function as an end-effector of preconditioning. For example, superoxide anion generated by xanthine oxidase activated mito KATP channels from bovine ventricular myocardium reconstituted from lipid bilayers. 174 Lebuffe et al.175 demonstrated that ROS may serve as a trigger by opening mito KATP channels, which subsequently generates additional ROS and nitric oxide that are both required for preconditioning in isolated chick neonatal myocytes. Therefore, whether mito KATP channel opening serves as a trigger or end-effector of ischemic or pharmacologic preconditioning remains unclear. 176 Nevertheless, the apparently complimentary interaction between ROS and mito KATP channels suggest the intriguing possibility that positive feedback loops may exist between these elements that contribute to myocardial protection.
It also remains unclear whether volatile anesthetic-induced mito KATP channel opening precedes or follows ROS generation. Pretreatment with 5-HD or the ROS scavengers N-acetylcysteine or N-2-mercaptopropionyl glycine before administration of isoflurane abolished ROS generation in vivo. 177 In contrast, administration of 5-HD after discontinuation of isoflurane but before prolonged ischemia only partially attenuated this effect. These data suggest that mito KATP channel opening acted as a trigger of APC by generating ROS. Conversely, another recent investigation conducted in isolated guinea pig hearts showed that sevoflurane-induced generation of ROS was not inhibited by 5-HD before ischemia. 178 Therefore, experimental findings remain equivocal in support of the hypothesis that mito KATP channel opening is the major trigger of APC.
Reactive oxygen species derived from the mitochondrial respiratory chain have been shown to play important roles during IPC or pharmacologic preconditioning. 111,160,179,180 The complex III inhibitor myxothiazol blocked hypoxia- 160 or acetylcholine-induced 179 ROS generation and abolished preconditioning in isolated chick cardiac myocytes. The precise source of volatile anesthetic-induced production of ROS has yet to be finally established, but volatile agents have been previously shown to inhibit electron transport chain complexes I and II of cardiac mitochondria. 181,182 Interestingly, sevoflurane-induced complex I inhibition was attenuated by the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride. 182 These results suggested that ROS may inhibit mitochondrial respiration through a positive feedback mechanism to amplify the ROS signal for triggering APC. In contrast, a recent investigation showed that the complex III inhibitor myxothiazol, but not the complex I inhibitor diphenyleneiodonium, abolished isoflurane-induced reductions in myocardial infarct size and generation of ROS. 183 These preliminary data indicated that mitochondrial electron transport chain complex III may be the source of ROS production induced by isoflurane during APC. Taken together, it is possible that volatile anesthetics may modulate multiple sites of the electron transport chain either directly or indirectly via a ROS-mediated feedback mechanism. Despite these compelling results, other potential enzymatic sources of ROS (i.e., nicotinamide adenine dinucleotide oxidase, cyclooxygenase, lipoxygenase, xanthine oxidase, nitric oxide synthase, cytochrome P450 184–188) may play a role in APC and have yet to be excluded from this process.
The precise identities of the specific ROS involved in APC have yet to be defined, and the signaling pathways that may be modulated by these ROS are also largely unknown. ROS activated PKC, restored contractility, and reduced infarct size in rabbit hearts. 159 Superoxide anion also opened mito KATP channels. 174 Hydrogen peroxide stimulated PTK-dependent activation of phospholipase C in mouse embryonic fibroblasts, rendering these cells resistant to stress. 189 Hydrogen peroxide has also been shown to directly activate Gi and Go proteins 168,169 and other protein kinases involved in reducing cellular injury. 166,190–192 Hydrogen peroxide may also be converted to other more reactive species that modify cysteine residues of specific G proteins, resulting in their selective activation. 169 Recent results showed that isoflurane administration produced ethidium fluorescence in rabbit myocardium. 75,177 Dihydroethidium is oxidized by intracellular superoxide anion to produce ethidium that subsequently binds to DNA, further amplifying its fluorescence. 193 These results strongly suggest that superoxide anion is the particular ROS involved in isoflurane-induced preconditioning. Sevoflurane also generated superoxide anion before ischemia and reperfusion in isolated hearts. 178 Alternatively, different ROS may exert opposing actions on mito KATP channel activity. Dismutation of superoxide anion leads to production of secondary ROS, including hydrogen peroxide, hydroxyl radical, and peroxynitrite, 194 and these radicals may differentially alter channel activity. For example, superoxide anion and hydrogen peroxide enhanced but peroxynitrite decreased Ca2+-regulated potassium channel activity. 195 Therefore, it remains possible that volatile anesthetics may also generate ROS other than superoxide that activate mito KATP channels, or these agents may inhibit the formation of intermediates such as peroxynitrite that adversely affect mito KATP channel function. Further research is needed to clarify this issue.
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Mechanisms of Protection
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Opening of sarc KATP channels was originally implicated in IPC and pharmacologic preconditioning by shortening the action potential duration, 81,196 thereby reducing intracellular Ca2+ overload during ischemia. 81 However, subsequent studies conducted after the discovery of mito KATP channels 82 indicated that the antiischemic actions of KATP channel activation occurred independent of action potential duration. 197–199 Nevertheless, IPC did not occur in Kir6.2-deficient mice, suggesting that the presence of the sarc KATP channel was still required for myocardial protection to occur. 200 Despite these latter data, the majority of findings accumulated indicate that preservation of mitochondrial bioenergetic function that occurs as a consequence of mito KATP channel opening seems to be of critical importance for protection against ischemia. 201–204 Selective pharmacologic openers of mito KATP channels (e.g., diazoxide) maintain mitochondrial Ca2+ homeostasis and inhibit Ca2+ overload within the organelle. 203,204 Alteration of the mitochondrial oxidation-reduction balance by mito KATP channel opening may also act to promote cellular protection. 204,205 Membrane depolarization, matrix swelling, and uncoupling of ATP synthesis occur as a result of mito KATP channel opening that may mediate cellular viability during IPC. 205 Mito KATP channel opening depolarizes the inner mitochondrial membrane and causes a transient swelling of the mitochondrial matrix, 206 resulting from a shift in the ionic balance. 207 These actions initially reduce ATP production 204 but subsequently stimulate a compensatory increase in respiration that optimizes the efficacy of oxidative phosphorylation in part through energy-dependent matrix volume regulation. 208 Therefore, the moderate disturbance of mitochondrial homeostasis caused by mito KATP channel opening (fig. 2) may promote tolerance to subsequent ischemic damage by reducing Ca2+ overload, 203,204 preventing activation of necrotic or apoptotic pathways, 209,210 or attenuating oxidative stress. 211
Mitochondrial ATP synthesis has also been shown to be preserved after prolonged as compared with brief ischemia and reperfusion. 212 This beneficial effect was abolished by 5-HD, suggesting that activation of mito KATP channels improves mitochondrial energy production. 213 Opening of mito KATP channels has been hypothesized to preserve outer mitochondrial membrane permeability to ATP precursors (e.g., adenosine, adenosine diphosphate) and cytochrome c. The structure of the intermembrane space may also be maintained as a consequence of mito KATP channel activation despite generalized swelling of the mitochondrial matrix. 201 Preservation of ATP substrates and mitochondrial structure may facilitate more efficient energy transfer between the mitochondria and the cytosol immediately after ischemia. Sevoflurane was recently shown to preserve ATP synthesis in isolated cardiac mitochondria obtained during early reperfusion after ischemia in vivo, and this beneficial effect was abolished by pretreatment with a ROS scavenger. 214 Sevoflurane-induced preconditioning improved mitochondrial bioenergetics through mito KATP channel activation in isolated guinea pig hearts as assessed using flavoprotein fluorescence. 215 Therefore, it seems likely that mito KATP channel opening by volatile anesthetics may be associated with preservation of mitochondrial function during reperfusion and, further, that this maintenance of mitochondrial performance contributes to cardioprotection.
Experiments conducted in isolated mitochondria have shown that a triggering quantity of ROS exceeding a critical threshold results in a transition in mitochondrial inner membrane permeability and the subsequent release of a burst of ROS in a process that has been termed ROS-induced ROS release. 216 This mitochondrial permeability transition (MPT) has been shown to precede necrotic or apoptotic cell death, 217 and glutathione is a primary defense against this event. 216,218 These data suggest that volatile anesthetics or other mito KATP channel agonists may prevent MPT in an oxidant-sensitive fashion, but this intriguing hypothesis has yet to be tested. Opening of an MPT pore using the agonist atractyloside during reperfusion was recently shown to abolish IPC and diazoxide-induced preconditioning in isolated rat hearts. 219 These findings suggested that inhibition of MPT pore opening may represent a distal effector responsible for preconditioning, whereas mito KATP activation functions as a trigger or a mediator. Most recently, rabbit hearts pretreated with desflurane before ischemia and reperfusion exhibited resistance to MPT pore opening. 220 Future investigations are necessary to delineate the role of MPT during APC.
Cytosolic and mitochondrial Ca2+ overload during prolonged ischemia and reperfusion have been shown to be associated with mitochondrial damage and myocardial cell death. 221–223 Ischemic and sevoflurane-induced preconditioning were shown to reduce cytosolic Ca2+ overload and improve the recovery of contractile function during reperfusion. 64 Administration of sevoflurane after ischemia also reduced cytosolic Ca2+ and myocardial damage. 31 IPC and APC attenuated mitochondrial Ca2+ overload during ischemia in rat and guinea pig hearts, 224,225 actions that were abolished by 5-HD. These data suggested that volatile anesthetics protect against ischemia-reperfusion injury, at least in part, by attenuating cytosolic and mitochondrial Ca2+ overload through a mito KATP channel-dependent mechanism. Volatile anesthetics have also been shown to suppress sarcoplasmic reticulum Ca2+ release 226,227 and depress myofilament Ca2+ sensitivity. 227 Therefore, modulation of the sarcoplasmic reticulum to reduce cellular Ca2+ overload and alterations of myofilament Ca2+ sensitivity under conditions of excess Ca2+ have been implicated in cardioprotection. 228,229 The inhibitory actions of the volatile anesthetics on the voltage-dependent Ca2+ channel are also well known, 65–68 and reductions in cytosolic and mitochondrial Ca2+ overload during ischemia and reperfusion injury may also occur through this mechanism.
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Myocardial Protection in Clinical Conditions
Compelling experimental data in multiple animal models regarding the protective effects of volatile anesthetics remain to be translated into therapeutic approaches to reduce morbidity and mortality in patients with ischemic heart disease. However, evidence accumulated to date strongly suggests that APC occurs in human myocardium. Repetitive, brief (60- to 90-s) balloon inflations and deflations performed during percutaneous transluminal coronary angioplasty were associated with progressive reductions in the severity of chest pain and in the extent of ST segment elevation, decreases in myocardial lactate production, and declines in cardiac enzyme and troponin release. 230–233 Adenosine 234 or the mito KATP channel opener nicorandil 235 administered before the first balloon inflation during percutaneous transluminal coronary angioplasty was also shown to reduce the severity of ST changes during subsequent occlusions. Pretreatment with nicorandil before percutaneous transluminal coronary angioplasty also attenuated the release of troponin T, an indicator of myocyte necrosis. 236 These findings suggest that both ischemic and pharmacologic preconditioning can be elicited during percutaneous transluminal coronary angioplasty. Consecutive exercise stress tests (separated by 15 min) performed in patients with critical left anterior descending coronary artery stenoses showed that anginal symptoms, ST segment depression, and myocardial oxygen consumption were reduced during the second as compared with the first exercise period for an equivalent amount of work. 237 This “warm-up” phenomenon occurred independent of coronary vasodilation 237 and also provides evidence of IPC in humans. 238,239
Ischemic preconditioning has also been shown during cardiac surgery in patients with coronary artery disease. Yellon et al.239 used intermittent aortic cross clamping to produce IPC during coronary artery bypass graft surgery (CABG) and found enhanced preservation of ATP content in preconditioned hearts as compared with those that did not receive preconditioning stimuli. These investigators also showed that less troponin T was released in the presence as compared with the absence of IPC in this model. 240 The incidence of ventricular tachyarrhythmias was reduced after cardiopulmonary bypass in patients undergoing CABG when cold blood cardioplegia was used for myocardial preservation. 241–243 Regional IPC produced by brief coronary occlusion has also been shown to result in improved hemodynamic recovery and reduced release of cardiac troponin I during off-pump CABG. 244 In contrast with the findings of these investigations, other studies have failed to show that IPC exerts beneficial effects during CABG in the presence of cardioplegia and cardiopulmonary bypass. 245–247 Therefore, although the myocardial protective effects of IPC have been clearly identified in the experimental laboratory, further large scale clinical trials are needed to definitively demonstrate the beneficial actions of IPC in humans.
Documentation of APC in patients has been complicated by alterations in systemic and coronary hemodynamics; the use of other anesthetics, analgesics, or vasoactive drugs; preexisting disease states; and the acute influence of surgery on cardiovascular homeostasis. Nevertheless, isoflurane, 69 desflurane, 63 and sevoflurane 62 enhanced the recovery of contractile function of human atrial trabeculae in vitro by stimulation of adenosine receptors and opening of KATP channels. Other studies have previously shown a role for adenosine receptors, MAPK, 248 and ROS 172 in other forms of preconditioning concomitant with opening of mito KATP channels in human atrial myocytes. Isoflurane increased the tolerance to pacing-induced ischemia in patients with coronary artery disease. 249 Isoflurane also decreased postoperative release of troponin I and creatine kinase-MB in patients undergoing CABG. 250 Although the aforementioned results 250 were not statistically significant, these data suggest that reduction in the extent of myocardial necrosis had occurred. Administration of isoflurane immediately before aortic cross clamping in patients undergoing CABG was shown to decrease the severity of subsequent ST segment changes and preserve cardiac index to a greater extent than that observed in patients who did not receive pretreatment with the volatile anesthetic. 251 Administration of enflurane before cardioplegic arrest enhanced recovery of postischemic contractile function assessed using pressure-area relations in CABG patients. 252 Sevoflurane 253–255 and desflurane 253,255 but not the intravenous anesthetic propofol was shown to preserve myocardial function in patients undergoing CABG as well as a reduction in troponin I release. Most recently, preconditioning with sevoflurane reduced a biochemical marker of myocardial dysfunction (i.e., N-terminal pro-brain natriuretic peptide) in patients undergoing CABG concomitant with translocation of PKC-δ and -ε. 256 This compelling evidence strongly suggests that volatile anesthetics exert beneficial effects against ischemic injury in humans.
In contrast with the aforementioned results, no differences in PKC and p38 MAPK activity or peak troponin I release were observed between patients undergoing cardioplegic arrest in the presence or absence of sevoflurane pretreatment. 257 The activities of PKC, PTK, and p38 MAPK were increased equally in both groups, suggesting that cardiopulmonary bypass and cardioplegic arrest may produce a preconditioning-like effect that obscured the antiischemic actions of sevoflurane in this setting. However, sevoflurane was recently shown to reduce myocardial injury to a greater degree than propofol in patients undergoing off-pump CABG, 254 a clinical setting that does not require cardiopulmonary bypass. Most investigations conducted in humans seem to indicate that volatile anesthetics represent an important therapeutic modality to reduce the sequelae of perioperative myocardial ischemia and infarction. 258,259 A large-scale, randomized clinical trial is clearly needed to firmly establish this conclusion. Given the recent data suggesting that cardiopulmonary bypass and cardioplegia may exert a protective effect, 257 such a clinical trial may best be conducted in patients undergoing off-pump CABG 254 or those with documented coronary artery disease undergoing noncardiac surgery. 4 Furthermore, no clinical study has shown that the use of volatile anesthetics in patients with coronary artery disease contributes to reduced cardiac morbidity or perioperative mortality. Additional multicenter trials also need to be conducted to identify the relative impact of APC on clinical outcome.
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Future Perspectives

Experimental evidence collected indicates that volatile anesthetics exert important cardioprotective effects that reduce the consequences of reversible and irreversible ischemia and reperfusion injury. Differences in the efficacy of APC and timing of administration among volatile anesthetics alone and in combination with other cardioprotective drugs remain to be fully distinguished. Another important aspect is to determine the effect of aging on APC. 255,260 Characterization of a late phase or second window of APC may be of special clinical significance to protect against ischemic events that frequently occur in the postoperative period. Several endogenous signaling elements seem to mediate APC, and mito KATP channels, PKC, and ROS have emerged as central features in this process. Future investigations are needed to further delineate and identify essential components in these complex signal transduction cascades that mediate the early and late phases of APC. In this regard, microarray technology may prove useful in ascertaining candidate genes that are responsible for APC. 261 Use of other fundamental molecular and biochemical tools is needed to determine whether preservation of mitochondrial integrity and metabolic homeostasis ultimately enhances tolerance to myocardial ischemia. Volatile anesthetics also act to elicit signaling that is probably present in many types of cells. Therefore, it is not surprising that these agents may reduce injury to other tissues. 256,262 This may also be based on preventing cytokine-induced injury in endothelial and vascular smooth muscle cells. 50,61 Finally, recent investigations have also strongly implied that APC occurs in humans and may represent an important therapeutic approach to reduce morbidity and mortality in patients with coronary artery disease. Nevertheless, further investigation is needed to firmly link this emerging body of clinical evidence to the already strongly established experimental data about the protective effects of volatile anesthetics in myocardium.
The authors thank David Schwabe, B.S.E.E., for technical assistance and Mary Lorence-Hanke, A.A. (Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin), for assistance in preparation of the manuscript.
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