Postconditioning by Volatile Anesthetics: Salvaging Ischemic Myocardium at Reperfusion by Activation of Prosurvival Signaling

REVIEW ARTICLE William C. Oliver, Jr, MD Gregory A. Nuttall, MD Section Editors

Postconditioning by Volatile Anesthetics: Salvaging Ischemic Myocardium at Reperfusion by Activation of Prosurvival Signaling Paul S. Pagel, MD, PhD

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EPERFUSION AFTER PROLONGED coronary artery occlusion is a prerequisite for salvaging ischemic myocardium. Unfortunately, reperfusion also paradoxically exacerbates the initial damage caused by the ischemia itself.1-3 Experiments conducted in the 1980s by Buckberg and associates4-7 provided the first evidence that modification of reperfusion conditions may reduce the extent of injury resulting from restoration of coronary blood flow. Studies of controlled coronary hemodynamics after myocardial ischemia indicated that gradual reperfusion at low intracoronary pressures reduces the size of the resulting myocardial infarction.4 For example, selective low-pressure (40-50 mmHg) coronary artery reperfusion before total reversal of coronary occlusion not only reduced infarct size but also enhanced postischemic systolic function in the absence or presence of inotropic drugs and attenuated myocardial tissue edema compared with abrupt reperfusion.5 Similarly, elimination of reactive hyperemia during early reperfusion by maintenance of coronary blood flow at levels present before the onset of coronary occlusion preserved myocardial metabolism, reduced intracellular calcium (Ca2⫹) accumulation, and improved regional wall motion compared with uncontrolled reperfusion.8 Gradual reperfusion of the ischemic territory during the first 30 minutes after prolonged coronary occlusion also reduced myocardial necrosis in vivo and preserved endothelial function in postischemic coronary arterial rings in vitro.9 These and other studies6,7,10,11 suggested that “gentle” or “staged” control of coronary hemodynamics during early reperfusion was a critical determinant of myocardial integrity and contractile function after a brief or prolonged ischemic episode.8 Despite the compelling nature of these observations, the vast majority of the experimental and clinical research investigations examining the adverse consequences of ischemia-reperfusion injury and how they may be mitigated have instead focused on interventions performed before the onset of ischemia (ie, preconditioning). However, coronary artery occlusion cannot be temporally predicted in most patients with acute myocardial infarction with any degree of certainty, and, as a result, the application of ischemic or pharmacologic preconditioning strategies has been limited to conditions in which the precise onset of ischemia is well defined (eg, inflation of an angioplasty balloon during cardiac catheterization, application of the aortic cross-clamp during cardiopulmonary bypass, and coronary occlusion to facilitate vascular anastomosis during off-pump coronary artery bypass graft surgery).

In 2003, Zhao et al12 re-examined the circumstances by which reperfusion conditions may be altered to favorably reduce myocardial damage from a new perspective. Instead of attempting to produce gradual reperfusion by controlling coronary hemodynamics, the authors used a series of brief (30 seconds) episodes of coronary artery occlusion interspersed with 30-second periods of complete reperfusion conducted immediately before final restoration of coronary blood flow in acutely instrumented, open-chest dogs. They reported that this brief, repetitive coronary occlusion-reperfusion technique reduced myocardial infarct size, attenuated neutrophil accumulation, partially blocked cytotoxic reactive oxygen species (ROS) production, decreased endothelial cell dysfunction, and inhibited apoptosis (programmed cell death).12,13 The reductions in myocardial injury caused by this “ischemic postconditioning” were remarkably similar to those produced by ischemic preconditioning.12 Activation of mitogen-activated protein kinases p42 and p44 (also known as extracellular signal-regulated kinases 1 and 2 [Erk1/2]) and formation of nitric oxide (NO) were initially shown to mediate this form of cardioprotection.12,14 Subsequently, the prosurvival phosphatidylinositol-3kinase (PI3K)-Akt (also known as protein kinase B) signaling cascade, including the downstream enzymes endothelial NO synthase (eNOS) and mammalian target of rapamycin 70kilodalton ribosomal protein s6 kinase (mTOR/p70s6K), was shown to play a key role in ischemic postconditioning (Fig 1).15,16 These signaling elements are critical mediators of cellular necrosis and apoptosis via their actions on the relative balance of pro- compared with antiapoptotic proteins, the activity of the central regulatory enzyme glycogen synthase kinase-3␤ (GSK-3␤), and the transition state of the mitochondrial permeability transition pore (mPTP).17-20 Administration of a diverse variety of drugs (eg, G protein-coupled receptor ligands

From the Anesthesia Service, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI. Address reprint requests to Paul S. Pagel, MD, PhD, Clement J. Zablocki Veterans Affairs Medical Center, Anesthesia Service, 5000 W National Avenue, Milwaukee, WI 53295. E-mail: [email protected] © 2008 Elsevier Inc. All rights reserved. 1053-0770/08/2205-0022$34.00/0 doi:10.1053/j.jvca.2008.03.005 Key words: myocardial ischemia, reperfusion injury, volatile anesthetics, postconditioning, cardioprotection

Journal of Cardiothoracic and Vascular Anesthesia, Vol 22, No 5 (October), 2008: pp 753-765

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Fig 1. A schematic illustration of interactions between volatile anesthetics and prosurvival signaling pathways implicated in postconditioning. G protein– coupled or growth factor receptors activate phosphotidylinositol-3-kinase (PI3K), leading to the sequential phosphorylation and activation of phosphoinositide-dependent kinase-1 (PDK-1) and Akt (protein kinase B [PKB]). Wortmannin and LY294002 are selective inhibitors of PI3K. PI3K and PDK-1 also activate PKC and PTK. Akt stimulates the activity of antiapoptotic proteins (eg, B cell lymphoma 2 [Bcl-2]) and simultaneously inhibits activity of proapoptotic proteins (eg, Bad, Bax, Bim, and caspases). Akt also directly inhibits GSK-3␤ and activates eNOS, mammalian target of rapamycin (mTOR) and its immediate downstream target 70-kilodalton ribosomal protein s6 kinase (p70s6K), and murine double minute-2 (Mdm2) protein. Akt also indirectly inhibits GSK-3␤ through its actions on p70s6K. Bcl-2 and NO produced by eNOS inhibit the mPTP. Mdm2-induced phosphorylation of the proapoptotic protein p53 inactivates this mPTP opener. HA14-1, L-NAME, and pifithrin-␣ are inhibitors of Bcl-2, eNOS, and p53, respectively. The regulatory enzyme GSK-3␤ facilitates mPTP opening, and the selective inhibitor SB216763 blocks this action. Cyclosporin A, NIM811, Mg2ⴙ, adenine nucleotides (ATP and ADP), acidosis, and activation of mitochondrial KATP channels inhibit whereas atractyloside, increases in intramitochondrial matrix Ca2ⴙ and inorganic phosphate (Pi) concentrations, and ROS facilitate opening of mPTP. G protein– coupled or tyrosine kinase receptors activate mitogen-activated protein kinase-extracellular signal-regulated kinase 1 (MEK-1, blocked by PD 098059), the upstream enzyme responsible for the phosphorylation, and the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2 activates PKC and p70s6K, stimulates the formation of hypoxia-inducible factor-1␣ (HIF-1␣), and VEGF and inhibits GSK-3␤ activity. G protein– coupled receptors also activate phospholipases (PLC/D), resulting in the production of the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG), activation of PKC, ERK1/2, and PI3K, and inhibition of GSK-3␤. Volatile anesthetics have been proposed to enhance the activity of PI3K, p70s6k, ERK1/2, eNOS, PKC, and PTK. Volatile anesthetics have also been suggested to directly inhibit GSK-␤ and mPTP concomitant with enhanced expression and activity of Bcl-2 and inhibition of p53. These actions of volatile agents may contribute to cardioprotection during early reperfusion. The arrows indicate activation, whereas line stops designate inhibition. Arrows associated with plus (ⴙ) signs indicate pathways that open mPTP.

[adenosine,21,22 bradykinin,14 and opioids23,24], insulin,25 statins,26,27 and growth factors28,29) immediately before or during early reperfusion mimicked the beneficial actions of ischemic postconditioning, and many elements of prosurvival signaling

were shown to mediate this “pharmacologic postconditioning.”30,31 Ischemic postconditioning-induced activation of the PI3K-Akt reperfusion injury signaling kinase (“RISK”) pathway31 was also subsequently shown in a model of postin-

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farction ventricular hypertrophy.32 Furthermore, clinical evidence of ischemic postconditioning has been reported because brief repetitive balloon inflation and deflation conducted during coronary angioplasty exerted cardioprotective effects in patients with acute myocardial infarction.33 Peak creatine kinase release was lower in patients who received 4 or more balloon inflations during angioplasty as compared with those treated with 1 to 3 inflations, suggesting that relief of sustained ischemia by stuttering reperfusion produces cardioprotection.34 Similarly, postconditioning compared with conventional reperfusion improved coronary artery blood flow velocity after final reperfusion, attenuated acute increases in biochemical markers of cellular necrosis, improved regional left ventricular wall motion 8 weeks after intervention, and facilitated recovery of endothelial-dependent vasoreactivity.35,36 Since its initial description, postconditioning has attracted intense interest precisely because reperfusion may be a controllable event in many patients with acute coronary syndrome, and several excellent comprehensive reviews about this phenomenon have already appeared in the literature.19,30,37-39 Similar to ischemic and other forms of pharmacologic preconditioning, anesthetic preconditioning has been extensively studied and many of the responsible mechanisms characterized in detail.40-43 However, little attention has been directed toward exploration of the potential beneficial effects of volatile anesthetics when administered immediately before or during reperfusion (termed “anesthetic postconditioning”). Nevertheless, some experimental evidence indicated that volatile anesthetics are capable of exerting cardioprotective effects under these conditions. For example, halothane prevented reoxygenationinduced hypercontracture of cardiac myocytes in vitro, a potential cause of myocyte necrosis during early reperfusion.44 Halothane also reduced reperfusion injury after regional myocardial ischemia in rabbit hearts.45 Desflurane and sevoflurane reduced infarct size when administered during the first 15 minutes of reperfusion in rabbits.46 Isoflurane enhanced the functional recovery of isolated rat hearts when administered solely during reperfusion.47 The salutary actions of sevoflurane during reperfusion were shown to be dose dependent in rats.48 The administration of sevoflurane after ischemia also improved contractile and metabolic function concomitant with reduced myoplasmic Ca2⫹ loading in isolated guinea pig hearts.49 These data suggested that volatile anesthetics may reduce myocardial necrosis and enhance function when administered exclusively during reperfusion, but how these agents produce such cardioprotective effects has yet to be firmly established. Halothane abolished reoxygenation-induced attenuation of sarcoplasmic reticulum-dependent oscillations of intramyoplasmic Ca2⫹ concentration in isolated cardiac myocytes.44 These44 and other findings49 indicated that volatile anesthetics may prevent intracellular Ca2⫹ overload during early reperfusion, presumably by virtue of their actions as voltage-dependent Ca2⫹ channel antagonists. Isoflurane and sevoflurane also reduced postischemic adhesion of neutrophils,50 an important source of oxygenderived free radicals during reperfusion that are known to be critical mediators of reperfusion injury.1 However, the precise mechanisms by which volatile anesthetics act to reduce intracellular Ca2⫹ overload or attenuate the adverse consequences of large quantities of reactive oxygen intermediates during early

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reperfusion were not specifically elucidated by these previous studies44,49,50 nor were endogenous signal transduction pathways previously identified in anesthetic preconditioning42 initially implicated in postconditioning by volatile agents. It is tempting to postulate that very similar signaling pathways mediate both anesthetic pre- and postconditioning, and some of the experimental evidence collected to date suggests that these processes may share a number of common features. For example, the activation of mitochondrial adenosine triphosphatesensitive potassium (KATP) channels plays a central role in anesthetic preconditioning,42 and these channels were subsequently implicated in postconditioning by volatile agents.51,52 Nevertheless, important differences between the genomic responses associated with these phenomena were shown that question the validity of such a unifying hypothesis of volatile anesthetic-induced cardioprotection.53 Chiari et al54 showed that 1.0 minimum alveolar concentration (MAC) isoflurane administered during the final 3 minutes of coronary artery occlusion and the first 2 minutes of reperfusion reduces myocardial infarct size in rabbits.54 In contrast to previous studies in which volatile agents were initiated upon reperfusion,46-48 the experimental approach used by these investigators54 was specifically designed to establish a plasma concentration of isoflurane and thereby produce a pharmacologic effect immediately at the onset of reperfusion. The reductions in infarct size observed with this isoflurane postconditioning strategy were similar in magnitude to those obtained using postconditioning ischemia (3 cycles of 20 seconds of coronary artery occlusion interspersed with 20 seconds of reperfusion during early reperfusion)54 and were also indistinguishable from the cardioprotection produced by isoflurane preconditioning.55 Interestingly, postconditioning with 0.5 MAC isoflurane (an anesthetic concentration that did not decrease myocardial necrosis alone) also reduced the time threshold required for ischemic postconditioning (reduction in each brief ischemia and reperfusion episode from 20 to 10 seconds).54 The beneficial actions of isoflurane before and during early reperfusion were abolished by pretreatment with the selective PI3K antagonist wortmannin (Fig 2).56 Isoflurane also increased the phosphorylation of the PI3K downstream enzyme Akt, and this effect was inhibited by wortmannin pretreatment. These data showed for the first time that activation of the PI3K-signaling pathway directly mediates the protective effects of isoflurane postconditioning in vivo. PI3K is responsible for the phosphorylation of many subcellular targets implicated in protein synthesis, metabolism, and cell survival.57,58 Activation of PI3K during early reperfusion by growth factors or G protein– coupled receptor ligands has been shown to reduce cell necrosis and inhibit apoptosis,59 thereby decreasing the extent of myocardial infarction after prolonged coronary occlusion and reperfusion.2,60 PI3K converts phosphatidylinositol-4,5-bisphosphate to phosphatidylinositol-3,4,5-trisphosphate,57 and phosphatidylinositol-3,4,5trisphosphate–stimulated phosphorylation of the Akt by phosphoinositide-dependent kinase 1 (PDK1) subsequently blocks the formation of several proapoptotic proteins (eg, p53, Bad, Bax, and caspases). Mitochondria are the putative target of apoptotic proteins that either directly damage mitochondrial membranes or indirectly open the mPTP. Phosphorylation of

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Fig 2. A schematic illustration of rabbit myocardium subjected to a 60-minute coronary artery occlusion and reperfusion and then stained to identify the region of myocardial infarction (black area) within the area of the left ventricular myocardium at risk for infarction (light gray area). The brief administration of 1.0 MAC isoflurane before and during early reperfusion significantly (p < 0.05) reduced myocardial infarct size. The cardioprotective effect of isoflurane was abolished by pretreatment with the selective PI3K antagonist wortmannin. Data are infarct size as a percentage of area at risk expressed as mean ⴞ standard deviation.

Bad by PI3K results in its sequestration from mitochondria and inhibits apoptosis.61 Similarly, the activation of the PI3K-Akt cascade prevents Bax-induced apoptosis by inhibiting the critical conformational change required for its translocation to mitochondrial membranes.62,63 Activation of PI3K has also been shown to phosphorylate and inactivate procaspase-9, thereby blocking formation of caspase-9 (one of a number of enzymes responsible for execution of the apoptotic signal).64 PI3K and PDK1 are also potent activators of other protein kinases,57 including a number of protein kinase C (PKC) isoforms65,66 and protein tyrosine kinase (PTK), that have been strongly implicated in cardioprotection during anesthetic preconditioning.42 Thus, isoflurane postconditioning appears to reduce reperfusion injury by recruiting endogenous cardioprotective pathways mediated by the PI3K signaling cascade.54 A central role for PI3K-Akt signaling in isoflurane postconditioning was subsequently shown in infarct-remodeled myocardium as well, suggesting that postconditioning by volatile anesthetics is also maintained in the presence of compensatory ventricular hypertrophy associated with remote myocardial infarction.67 In contrast to the well-known generalized cellular destruction and profound inflammatory response that typifies necrosis, the highly regulated, ATP-dependent phenomenon of apoptosis is characterized by the absence of inflammation, preservation of cell membrane architecture, selective DNA lysis, formation of apoptotic bodies, and the appearance of condensed chromatin.68

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Reperfusion after a prolonged ischemia initiates or accelerates apoptosis,2,69,70 and recent data suggest that selective inhibition of many components of the cell suicide program by volatile anesthetics appears to play a central role in minimizing myocardial damage after prolonged ischemia. For example, brief administration of isoflurane immediately before and during early reperfusion reduced cytochrome c translocation from mitochondria (an important early marker of apoptosis mediated by PI3KAkt71) and decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL; another index of apoptosis)-positive ventricular myocytes in situ.72 These data provided the first direct evidence indicating that isoflurane postconditioning preserves myocardial integrity in part by attenuating apoptosis. The activation of Akt by isoflurane also protected rat atrial and ventricular myocytes against apoptosis produced by 2 in vitro models of reperfusion-induced oxidative stress (exposure to hydrogen peroxide or activated neutrophils) concomitant with increased expression of the antiapoptotic B cell lymphoma-2 (Bcl-2) protein.73 Volatile anesthetics were previously shown to abolish norepinephrineinduced apoptosis in rat ventricular myocytes as indicated by reductions in TUNEL-positive cell staining, attenuation of increases in annexinV staining (an index of DNA laddering characteristic of cell suicide), and inhibition of elevated caspase-9 activity.74 Thus, volatile agents have been shown to attenuate programmed cell death associated with myocardial stress produced by reperfusion injury or excessive catecholamine exposure. A role for PI3K signaling in isoflurane preconditioning was also recently shown. Wortmannin abolished reductions in infarct size and blocked Akt phosphorylation caused by the administration of isoflurane before prolonged coronary artery occlusion in rabbits.75 Isoflurane preconditioning also enhanced Akt phosphorylation and Bcl-2 expression and reduced expression of the apoptotic protein Bax in rabbits concomitant with decreases in infarct size and the total number of apoptotic myocytes.76 Wortmannin and another selective PI3K antagonist (LY294002) abolished these actions, indicating that PI3K-induced modulation of pro- and antiapoptotic protein balance plays a role in isoflurane cardioprotection when this volatile agent is administered and then discontinued before coronary artery occlusion.76 Isoflurane also attenuated hypoxia-reoxygenation injury in vitro by activating Akt and upregulating Bcl-2.73 Collectively, these data suggested that PI3K mediates both anesthetic pre- and postconditioning. Similar to the observations during anesthetic postconditioning, these results also suggest that at least part of the cardioprotection associated with anesthetic preconditioning is mediated by attenuation of apoptosis upon reperfusion. This contention appears likely because an analogous link in PI3K-mediated reductions in apoptosis has been suggested during ischemic pre- and postconditioning.39,77 The importance of G protein– coupled receptor-mediated activation of PI3K signal transduction during anesthetic postconditioning was recently emphasized.72 Gross et al23,24 and Fryer et al78 showed that opioid-induced pre- and postconditioning was mediated by activation of G protein– coupled ␦1-opioid receptors, PI3K-mediated signaling, and mitochondrial KATP channels. Similar to adenosine A1 receptors,79 opioid receptors have also been implicated in the anesthetic preconditioning.

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Two selective ␦1-opioid receptor agonists (TAN-67 and BW373U86) and morphine (a ␮1-opioid receptor agonist with ␦1 agonist properties) were initially shown to augment isoflurane preconditioning in rats,80,81 and the nonselective opioid antagonist naloxone inhibited these salutary actions. Interestingly, naloxone pretreatment also abolished reductions in infarct size produced by administration of isoflurane alone before ischemia and reperfusion, showing for the first time that opioid receptors mediate anesthetic preconditioning.80,81 Morphine (administered in a dose that does not affect infarct size alone) was subsequently shown to lower the threshold of isoflurane postconditioning against infarction in rabbits.72 The protective effects of morphine, isoflurane, and the combination of subthreshold doses of these drugs during early reperfusion were abolished by pretreatment with wortmannin, showing the PI3K dependence of this cardioprotection. Furthermore, naloxone also inhibited the protective effects of morphine, isoflurane, and their subthreshold combination during early reperfusion. These results indicated that activation of G protein– coupled opioid receptors is required for isoflurane postconditioning and its augmentation by morphine through PI3K signaling. Because cardioprotection by opioids during reperfusion occurs as a result of ␦1-opioid receptor activation,23 it appears highly likely postconditioning against infarction by isoflurane and its potentiation by morphine may also be mediated by this opioid receptor subtype, but this hypothesis remains to be formally tested. The mitogen-activated protein kinase family of serine-threonine kinase proteins plays an important role in signal transduction from the cell surface to the nucleus and in the initiation and progression of apoptosis. Erk1/2 mediates cell division, proliferation, and survival31 and is activated by phosphorylation via the upstream enzyme mitogen-activated protein kinase– extracellular signal-regulated kinase 1 (MEK-1) through occupation of tyrosine kinase or G protein– coupled receptors.82 Similar to and often in parallel with PI3K, Erk1/2 has been shown to stimulate prosurvival signaling to favorably influence reperfusion injury.31 Previous studies indicated that Erk1/2 mediates ischemic83 and pharmacologic postconditioning in vivo.14 For example, Darling et al84 showed ischemic postconditioning produced by “stuttering” reperfusion limited infarct size by activation of Erk1/2 in rabbit hearts. The administration of G protein– coupled receptor ligands (eg, adenosine A1/A2 agonist 5=-(N-ethylcarboxamido) adenosine [NECA] and bradykinin) at reperfusion reduced infarct size concomitant with Erk1/2 phosphorylation in rabbits, and these salutary actions were abolished by pretreatment with the selective MEK-1 inhibitor PD 098059.14 Another A1/A2 receptor agonist (AMP579) also exerted protective effects during reperfusion through an Erk1/ 2-mediated mechanism.21,85 Brief, repetitive administration of isoflurane before and during early reperfusion reduced infarct size in rabbits,86 and these cardioprotective actions were abolished by pretreatment with PD 098059. These findings indicated that postconditioning produced by isoflurane was mediated by Erk1/2 activation in vivo.86 Erk1/2 was also previously implicated in ischemic and opioid-induced preconditioning.87 Reductions in infarct size and Erk1/2 phosphorylation produced by administration of desflurane before ischemia and reperfusion were abolished by a selective Erk1/2 inhibitor.88

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Erk1/2 was also shown to trigger isoflurane preconditioning concomitant with enhanced expression of hypoxia-inducible factor-1␣ (HIF-1␣) and vascular endothelial growth factor (VEGF) in rats.89 HIF-1␣ is a DNA-binding protein whose activity is influenced by intracellular oxygen tension90 and acts as a central regulator of oxygen homeostasis.91 HIF-1␣ also upregulates transcription of VEGF by binding to specific promoter sequences and stabilizing VEGF translation during hypoxic conditions.92,93 VEGF is an angiogenic protein known to mediate coronary collateral development in response to chronic myocardial ischemia.94,95 VEGF-mediated activation of PKC may play an important role in isoflurane preconditioning through Erk1/2-related signaling. Whether anesthetic postconditioning also stimulates HIF-1␣ and VEGF transcription and translation or produces VEGF-induced activation of PKC has yet to be defined, but such a contention appears very likely to be based on the recent findings during isoflurane preconditioning.89 Both PI3K-Akt96 and Erk1/297 phosphorylate and thereby activate mTOR and its downstream target p70s6K, an important regulator of protein translation98 and a key inhibitor of GSK-3␤ activity.17 A selective mTOR/p70s6K inhibitor (rapamycin) abolished cardioprotection, and a selective PI3K inhibitor (LY294002) blocked Akt-induced phosphorylation of mTOR/p70s6K during ischemic postconditioning.15 mTOR/ p70s6K has also been implicated in pharmacologic postconditioning. For example, rapamycin blocked reductions in infarct size produced by the administration of morphine or the ␦1selective opioid agonist BW373U86 5 minutes before reperfusion.23 The activation of mTOR/p70s6K also mediated the cardioprotective effects of the adenosine A1/A2 agonist NECA99 and insulin25,100,101 during reperfusion. The protective effects of isoflurane against infarction during early reperfusion were mediated by mTOR/p70s6K in rabbits.86 LY294002 abolished isoflurane-induced phosphorylation of mTOR/p70s6K in infarct-remodeled rat myocardium when the volatile agent was administered during the first 15 minutes of reperfusion.67 These data suggested that anesthetic postconditioning retains its protective effects in diseased myocardium through activation of the PI3K-Akt-mTOR/p70s6K axis. PI3K-Akt activates eNOS by phosphorylation of the Ser1177 residue, thereby increasing the formation of NO.102,103 A central role for eNOS-derived NO has been shown in postconditioning by ischemia,12,15 G protein-coupled receptor ligands (eg, NECA and bradykinin),104 and insulin.26 The nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) but not selective inducible or neuronal NOS antagonists abolished reductions in infarct size (Fig 3) produced by administration of isoflurane before and during early reperfusion in rabbits, suggesting that eNOS mediates isoflurane postconditioning.86 Isoflurane inhaled at the onset of reperfusion enhanced the cardioprotective effect of ischemic postconditioning through a NO-dependent mechanism. In addition, isoflurane postconditioning enhanced expression of eNOS in a PI3K-dependent manner in infarct-remodeled rat myocardium.67 Collectively, these findings provided strong evidence that NO produced by eNOS mediates anesthetic postconditioning through PI3K-mediated signaling. eNOS also acted as a trigger and mediator of delayed preconditioning by isoflurane in a similar rabbit model of ischemia-reperfusion injury, suggesting that eNOS plays a

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Fig 3. Histograms showing infarct size (IF) presented as a percentage of left ventricular area at risk (AAR) in rabbits receiving 0.9% saline (control, CON) or brief administration of 1.0 MAC isoflurane (ISO) before and during early reperfusion after prolonged coronary artery occlusion in the absence or presence of pretreatment with the nonselective NOS inhibitor L-NAME, the selective inducible NOS inhibitor aminoguanidine hydrochloride (AG), or the selective neuronal NOS inhibitor 7-nitroindazole (7-NI). Data are mean ⴞ standard deviation. *Significantly (p < 0.05) different from CON.

central role in another form of volatile anesthetic-induced cardioprotection as well.105 The mechanisms responsible for the cardioprotective actions of eNOS-derived NO in postconditioning by volatile agents remain to be defined. NO appears to be an important regulator of apoptosis; has been shown to preserve the Erk1/2 activity in response to growth factor stimulation in endothelial cells;106 nitrosates and inactivates several caspases known to execute the cell suicide program107; and blocks metabolism of the antiapoptotic protein Bcl-2, thereby preventing mitochondrial disruption and cytochrome c release108 through inhibition of mitochondrial permeability transition.109 Whether these proposed intracellular actions of eNOS-derived NO mediate anesthetic postconditioning is currently unknown. The mPTP is nonspecific channel located on the inner mitochondrial membrane. Opening of the mPTP abolishes the mitochondrial membrane potential (⌬⌿m), inhibits oxidative phosphorylation, produces mitochondrial swelling, and facilitates the release or activation of several apoptotic proteins including cytochrome c.110,111 These actions rapidly produce cell death. The mPTP was originally proposed to consist of 3 major components: a voltage-dependent anion channel, the adenine nucleotide translocase, and cyclophilin D, a cis/trans peptidyl-propyl isomerase contained within the mitochondrial matrix.19 Cyclophilin D was initially shown to bind to the adenine nucleotide translocase during elevated intramitochondrial Ca2⫹ concentration, thereby preventing nucleotide transport and forming the channel of the mPTP.112 However, more recent studies conducted using knockout mouse models suggest that neither the voltage-dependent anion channel nor the adenine nucleotide translocase is required for mPTP formation.113,114 Instead, it has become clear based on investigations conducted in mice lacking cyclophilin D that this enzyme is a critical mediator of the mPTP.115-117 The immunosuppressant drug cyclosporin A has been shown to bind to cyclophilin D and thereby inhibit the mPTP.118-121 Opening of mPTP appears to occur specifically at the onset of reperfusion,110 in part as a consequence of intramitochondrial Ca2⫹ overload, the presence of cytotoxic oxygen-derived free radicals, and large quantities of inorganic phosphate accumulated because of exhausted adenine nucleotide (eg, ATP and adenosine diphosphate) metab-

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olism.122 Notably, many of these factors associated with mPTP opening are known to occur during reperfusion injury. In contrast, the presence of adenine nucleotides, Mg2⫹ and other matrix cations (eg, Mn2⫹), and acidosis inhibits mitochondrial permeability transition. Opening of the mPTP has been strongly implicated as an end-effector in myocardial necrosis and apoptosis resulting from reperfusion injury,18,20,122 and the activation of the PI3KAkt and Erk1/2 signaling pathways may exert profound regulatory control over the transition state of the mitochondrial pore.17,19 The administration of cyclosporin A before global ischemia and reperfusion caused reductions in myocardial infarct size that were similar to those produced by ischemic preconditioning in isolated rat hearts.123 Ischemic preconditioning was shown to directly inhibit mPTP opening as shown using a [3H]2-deoxyglucose entrapment technique.124 Importantly, these actions of ischemic preconditioning on mitochondrial permeability transition occurred specifically during reperfusion.124 Analogously, delayed mPTP opening in response to Ca2⫹ overload was observed in isolated mitochondria obtained from rabbit hearts exposed to ischemic preconditioning, cyclosporin A, or a more cyclophilin D-selective cyclosporin A derivative without immunosuppressant properties (NIM811125).126 Delayed ischemic preconditioning was also shown to regulate the mPTP by enhancing expression of the antiapoptotic protein Bcl-2.127 Furthermore, a role for mPTP inhibition was suggested during pharmacologic preconditioning produced by the selective mitochondrial KATP channel agonist diazoxide123 or volatile anesthetics.128 Piriou et al128 showed that desflurane preconditioning in vivo improved the resistance of the mPTP to Ca2⫹-induced opening in mitochondria isolated from xylazine-ketamine anesthetized, acutely instrumented rabbits. These latter data were the first to suggest a role for the mPTP in cardioprotection by volatile anesthetics. Because mPTP opening appears to be a reperfusion-dependent phenomenon,110 it is perhaps not surprising that inhibition of mPTP was also shown to mediate ischemic and anesthetic postconditioning.52,119,120,129,130 The degree of Ca2⫹ overload required to produce mPTP opening was greater in mitochondria isolated from rabbits pretreated with cyclosporin A or NIM811 1 minute before reperfusion as compared with those that were not.119 In addition, administration of cyclosporin A or NIM811 immediately before reperfusion produced reductions in myocardial infarct size that were similar in magnitude to those observed with ischemic preconditioning in vivo.119 Furthermore, ischemic postconditioning and NIM811 reduced infarct size and the quantity of Ca2⫹ loading necessary to open the mPTP to equivalent degrees in intact hearts and isolated mitochondria, respectively.120 A role for mPTP inhibition has also been established during anesthetic postconditioning. Reductions in infarct size produced by the brief administration of isoflurane immediately before and during early reperfusion were abolished by the mPTP opener atractyloside and enhanced by cyclosporin A (Fig 4) in rabbits.52 Similarly, atractyloside and the selective PI3K antagonist LY294002 abolished isoflurane postconditioning in rats.130 LY294002 also inhibited PI3K-induced phosphorylation of Akt and the regulatory enzyme GSK-3␤ and opened mPTP as determined by nicotinamide adenine dinucleotide measurements.130 These data pro-

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Fig 4. Histograms showing infarct size (IF) presented as a percentage of left ventricular area at risk (AAR) in rabbits in the presence (ⴙ) or absence (ⴚ) of postconditioning with isoflurane (ISO, 0.5 or 1.0 MAC) or the mPTP inhibitor cyclosporin A (CsA, 5 or 10 mg/kg). Isoflurane (1.0 but not 0.5 MAC) and cyclosporin A (10 but not 5 mg/kg) reduced infarct size compared with control. The combination of subthreshold doses of isoflurane (0.5 MAC) and cyclosporin A (5 mg/kg) also reduced infarct size to an equivalent degree as 1.0 MAC isoflurane and 10 mg/kg cyclosporin A. Data are mean ⴞ standard deviation. *Significantly (p < 0.05) different from control; †significantly (p < 0.05) different from ISO (0.5 MAC) and CsA (5 mg/kg).

vided strong molecular evidence of the existence of a critical link between the activation of prosurvival signaling and the state of mitochondrial permeability transition during isoflurane postconditioning. Activation of mitochondrial KATP channels has been postulated as is an end-effector of preconditioning by volatile anesthetics131 and has also been shown to mediate anesthetic postconditioning.51,52 Volatile agents either directly activate mitochondrial KATP channels132 or indirectly prime the opening of these channels in response to other signaling molecules (eg, adenosine, PKC, and ROS).133 The opening of mitochondrial KATP channels during ischemic or pharmacologic preconditioning may produce small alterations in intramitochondrial homeostasis134 that promote protection against subsequent ischemic damage through energy-dependent regulation of mitochondrial matrix volume via the mPTP.135 The opening of mitochondrial K⫹ influx pathways favorably regulated matrix volume and improved function during simulated ischemia and reperfusion.136 A selective mitochondrial KATP channel antagonist (5-hydroxydecanoate) inhibited isoflurane postconditioning,52 suggesting that mitochondrial KATP channel opening by brief administration of isoflurane during early reperfusion may be responsible for cardioprotection in rabbits. Mitochondrial KATP channels were also shown to mediate sevoflurane postconditioning in rats.51 A close interaction between mitochondrial KATP channels and mPTP was previously identified during diazoxide123 and desflurane preconditioning.128 Such an interaction was emphasized by the observation that reductions in myocardial infarct size produced by the administration of mPTP inhibitor cyclosporin A before reperfusion were abolished by 5-hydroxydecanoate pretreatment.52 Furthermore, adenine nucleotide translocase (a possible component of the mPTP associated with cyclophilin D) was shown to mediate H⫹ and K⫹ ion flux to the mitochondrial matrix produced by the KATP channels openers diazoxide and pinacidil in isolated rat mitochondria.137 Thus, anesthetic postconditioning may not be solely attributed to the actions of volatile agents on mitochon-

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drial KATP channels alone but may instead be dependent on the interaction between mitochondrial KATP channel opening and mPTP inhibition. GSK-3␤ is an important mediator of cellular function138 whose activation has been implicated in the pathogenesis of diabetes mellitus139 and Alzheimer’s disease.140 The inhibition of GSK-3␤ has been shown to play a critical role in pre- and postconditioning-induced cardioprotection.23,24,141-145 Tong et al141 showed that reductions in infarct size during ischemic preconditioning were associated with phosphorylation and inactivation of GSK-3␤ through a PI3K-dependent mechanism in Langendorff-perfused rat hearts. PI3K-induced inactivation of GSK-3␤ also promoted angiogenic and antiapoptotic signaling through the induction of VEGF, Bcl-2, and survivin in rat myocardium subjected to ischemic preconditioning.144 Similarly, GSK-3␤ inhibition mediated the protective effects of G protein–linked receptor ligands (eg, ␦1 opioid23,24,142 and adenosine subtype 3 [A3]143) administered before ischemia or during early reperfusion. Interestingly, cardioprotection by PI3K-mediated GSK-3␤ inactivation was attenuated in experimental models of chronic hyperglycemia146 and estrogen deficiency associated with aging in female rats.145 These data suggested a mechanism by which diabetes mellitus and postmenopausal reductions in estrogen concentration may be associated with a reduced myocardial tolerance to ischemic events. Juhaszova et al17 showed that GSK-3␤ is a central regulator of several prosurvival signaling enzymes (eg, PI3K, mTOR/p70s6K, and PKC) and, furthermore, that GSK-3␤ inhibition limits mPTP opening during cardioprotection against hypoxia-reoxygenation injury in isolated ventricular myocytes.17 These data strongly suggested that several redundant signaling pathways converge on and regulate the activity of GSK-3␤, thereby favorably modulating mitochondrial permeability transition and producing protection against reperfusion injury.147 Two independent research groups simultaneously reported that GSK-3␤ mediates anesthetic postconditioning in experimental animals. Feng et al130 showed that the administration of 1.5 MAC isoflurane during the first 15 minutes of reperfusion phosphorylated and inactivated GSK-3␤ concomitant with reductions in myocardial infarct size in isolated perfused rat hearts. This isoflurane-induced inhibition of GSK-3␤ and its resultant cardioprotection were abolished by pretreatment with the selective PI3K antagonist LY294002. In contrast, atractyloside failed to inhibit phosphorylation of PI3K and GSK-3␤ by isoflurane, but the drug did block reductions in infarct size produced by exposure to the volatile agent during early reperfusion through its direct actions on the mPTP. Isoflurane also preserved mitochondrial function as indicated by accumulation of the probe MitoTracker Red 580 (Molecular Probes, Invitrogen, Basel, Switzerland) detected using epifluorescence microscopy, and this action was abolished by atractyloside. Collectively, these results indicated that isoflurane postconditioning protects against reperfusion injury in previously normal myocardium by preventing mPTP opening through GSK-3␤ inhibition.130 Similar results were subsequently reported by the same group in infarct-remodeled myocardium.67 Pagel et al148 showed that a selective inhibitor of GSK-3␤ (SB216763) lowered the threshold of isoflurane postconditioning against infarction in rabbits in vivo. The salutary actions of

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effects of GSK-3␤ inhibition were abolished by the mPTP opener atractyloside but not the PI3K or mTOR/p70s6K antagonists wortmannin or rapamycin, respectively.148 These data suggested that isoflurane postconditioning was mediated by the combined actions of the SB216763 and the volatile anesthetic on mPTP and provided pharmacologic evidence suggesting that isoflurane produces a direct inhibitory effect on GSK-3␤ independent of its actions on PI3K and mTOR/p70s6K activity.148 The mechanisms by which anesthetic-induced inhibition of GSK-3␤ favorably affects mPTP to cause protection against ischemia-reperfusion injury have not been clearly elucidated. Activated GSK-3␤ has been shown to bind to and promote the actions of p53,149 and this tumor suppressor protein stimulates the disruption of mitochondria during apoptosis.150 Activated p53 translocates to mitochondria and opens the mPTP by directly interacting with Bax, thereby abolishing ⌬⌿m and causing the release of cytochrome c.151-153 A central role for inhibition of p53 in myocardial and neuronal protection against cellular injury has been characterized. Activation of p53 by hypoxia or ROS154 produced cell suicide by stimulating apoptotic signaling152 and enhancing transcription of additional apoptotic proteins (eg, Bax, apoptosis-inducing factor).155 Enhanced p53 expression was observed after ischemia and reperfusion in isolated rat ventricular myocytes, and ischemic preconditioning substantially mitigated this effect.156 Ischemic preconditioning also attenuated p53 transcription and translation in hippocampal pyramidal neurons in a rat model of global forebrain ischemia and reperfusion.157 Inhibition of p53 using the selective antagonist pifithrin-␣158 or augmented degradation of the protein by PI3K-mediated phosphorylation of murine double minute 2 protein (Mdm2, an oncogenic factor known to facilitate p53 degradation159) protected against ischemic injury in isolated rat hearts.160 Phosphorylated Mdm2 binds p53, inactivating the latter protein by blocking its active site and promoting its subsequent degradation through formation of a ubiquitin complex.161 Thus, ischemic preconditioning abrogated the deleterious actions of p53 by PI3K-mediated phosphorylation of the downstream moiety Mdm2.160 The direct inhibition of p53 using pifithrin-␣ protected against neuronal cell death produced by ischemia.162 The targeted deletion of p53 was also shown to prevent cardiac rupture after infarction in transgenic mice, presumably by simulating the protective effects of ischemic preconditioning via the inhibition of apoptosis.163 Inhibition of p53 was recently shown to enhance anesthetic postconditioning in barbiturate-anesthetized, acutely instrumented rabbits. Venkatapuram et al164 showed that the administration of a dose of pifithrin-␣ that did not affect infarct size alone lowered the end-tidal concentration (from 1.0 to 0.5 MAC) of isoflurane required to produce postconditioning in vivo Fig 5). This action was blocked by atractyloside, indicating that the observed cardioprotection was mediated by the actions of the selective p53 inhibitor and the volatile anesthetic on mPTP. These164 and previous148 results suggested that the administration of isoflurane immediately before and during early reperfusion may affect the interaction between GSK-3␤ and p53 to modulate the transition state of the mPTP. The PI3K dependence of the reduction of isoflurane postconditioning by pifithrin-␣ was also suggested because wortmannin pretreatment blocked decreases in infarct size produced by the combina-

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tion of subthreshold doses of the p53 inhibitor and the volatile agent. PI3K-Akt is known to phosphorylate Mdm2,165 and the activation of Akt by isoflurane54 may facilitate an interaction between phospho-Mdm2 and p53 that leads to the metabolism of the latter apoptotic protein,161 thereby effectively preventing its detrimental association with GSK-3␤. Ischemic preconditioning was shown to activate Mdm2 and enhance phospho-Mdm2-p53 binding in a PI3K-dependent manner,160 but whether anesthetic postconditioning specifically causes phosphorylation of Mdm2 or produces a similar phospho-Mdm2-p53 interaction remains to be formally established. The effects of anesthetic postconditioning on another major regulator of apoptotic signaling during reperfusion have also been preliminarily described in vitro73 and in vivo.166 The antiapoptotic Bcl-2 protein is located in the outer mitochondrial membrane,167 plays a central role in the regulation of transition state of the mPTP,168 and has been implicated in cardioprotection against ischemia-reperfusion injury.169 For example, Bcl-2 reduced ischemia-induced cellular damage by preventing mitochondrial cytochrome c release170 and attenuating intracellular Ca2⫹ overload by maintaining integrity of the endoplasmic reticulum.171 Ischemic preconditioning reduced apoptosis by producing upregulation of Bcl-2 in isolated rat hearts,172 whereas intermittent hypoxia attenuated reperfusion-induced

Fig 5. Histograms showing infarct size (IF) presented as a percentage of left ventricular area at risk (AAR) in rabbits in the presence (ⴙ) or absence (ⴚ) of postconditioning with isoflurane (ISO, 0.5 or 1.0 MAC) or the selective apoptotic protein p53 inhibitor pifithrin-␣ (PIF, 1.5 or 3.0 mg/kg). (A) Isoflurane (1.0 but not 0.5 MAC) and pifithrin-␣ (3.0 but not 1.5 mg/kg) reduced infarct size compared with the control. The combination of subthreshold doses of isoflurane (0.5 MAC) and pifithrin-␣ (1.5 mg/kg) also reduced infarct size to an equivalent degree as 1.0 MAC isoflurane and 3.0 mg/kg pifithrin-␣. (B) This cardioprotective effect was abolished by pretreatment with the mPTP opening atractyloside (ATRA, 5 mg/kg) but not the selective PI3K inhibitor wortmannin (WORT, 0.6 mg/kg), suggesting that the combined cardioprotective actions of isoflurane postconditioning and p53 inhibition occur downstream from PI3K in the signaling pathway. Data are mean ⴞ standard deviation. *Significantly (p < 0.05) different from control; †significantly (p < 0.05) different from ISO (0.5 MAC) and pifithrin-␣ (1.5 mg/kg).

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apoptosis by favorably affecting the ratio of Bcl-2 to apoptotic protein Bax in ventricular myocytes.173 Reductions in ischemiareperfusion injury produced by mild hypothermia in rats were also enhanced expression of Bcl-2.174 The overexpression of Bcl-2 mitigated apoptotic cell death and protected against myocardial ischemia-reperfusion injury in transgenic mice.175 In addition, an important interaction between Bcl-2 and the inhibition of the mPTP was proposed to occur during delayed ischemic preconditioning.127 A selective inhibitor (HA14-1) of Bcl-2 abolished isoflurane-induced Bcl-2 expression and attenuated reductions in apoptosis (eg, cytochrome c release and TUNEL staining) in isolated atrial and ventricular myocytes subjected to hypoxia reoxygenation, hydrogen peroxide, or activated neutrophils.73 HA14-1 inhibited isoflurane and ischemic postconditioning in vivo but did not alter reductions in infarct size produced by the mPTP inhibitor cyclosporin A.166 These data suggested that the salutary actions of isoflurane or preconditioning ischemia during early reperfusion may also occur as a result of modulation of mitochondrial permeability transition mediated upstream by Bcl-2.166 PI3K was shown to phosphorylate and activate Bcl-2 concomitant with inactivation of apoptotic proteins including Bad, Bax, and p53.176 Thus, the activation of PI3K signaling by isoflurane postconditioning may also cause cardioprotective effects by favorably affecting apoptotic protein homeostasis.

In summary, a growing body of evidence suggests that volatile anesthetics exert important cardioprotective effects when these agents are exclusively administered immediately before or during early reperfusion after prolonged coronary artery occlusion. The mechanisms responsible for anesthetic postconditioning have been incompletely described but appear to share many similarities with those recognized for preconditioning (eg, activation of G protein– coupled receptors, PKC, PI3K, Erk1/2, mitochondrial KATP channels, the inhibition of mPTP). However, it has become clear that anesthetic postconditioning activates many components of prosurvival signaling downstream from PI3K and Erk1/2 that favorably affect the transition state of the mPTP to contribute to cardioprotection. Furthermore, anesthetic postconditioning also protects against programmed cell death by selectively activating antiapoptotic while simultaneously inhibiting apoptotic proteins. Whether anesthetic postconditioning protects human myocardium from reperfusion injury in patients with acute coronary artery occlusion is currently unknown. However, ischemic postconditioning has already been shown in patients with acute myocardial infarction,33 and it appears likely based on experimental results accumulated to date that anesthetic postconditioning certainly has the strong potential provide cardioprotection in clinical settings in which reperfusion is a controllable event. This intriguing hypothesis will require controlled clinical trials to confirm.

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