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CARDIOVASCULAR ANESTHESIA

Inhibition of Mitochondrial Permeability Transition Enhances Isoflurane-Induced Cardioprotection During Early Reperfusion: The Role of Mitochondrial K_ATP Channels

Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), the Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, and the Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin

Address correspondence and reprint requests to Paul S. Pagel, MD, PhD, Medical College of Wisconsin, MEB-M4280, 8701 Watertown Plank Road, Milwaukee, WI 53226. Address e-mail to pspagel{at}mcw.edu.

	Abstract

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Inhibition of the mitochondrial permeability transition pore (mPTP) mediates the protective effects of brief, repetitive ischemic episodes during early reperfusion after prolonged coronary artery occlusion. Brief exposure to isoflurane immediately before and during early reperfusion also produces cardioprotection, but whether mPTP is involved in this beneficial effect is unknown. We tested the hypothesis that mPTP mediates isoflurane-induced postconditioning and also examined the role of mitochondrial K_ATP (mK_ATP) channels in this process. Rabbits (n = 102) subjected to a 30-min coronary occlusion followed by 3 h reperfusion received 0.9% saline (control), isoflurane (0.5 or 1.0 MAC) administered for 3 min before and 2 min after reperfusion, or the mPTP inhibitor cyclosporin A (CsA, 5 or 10 mg/kg) in the presence or absence of the mPTP opener atractyloside (5 mg/kg) or the selective mK_ATP channel antagonist 5-hydroxydecanoate (5-HD; 10 mg/kg). Other rabbits received 0.5 MAC isoflurane plus 5 mg/kg CsA in the presence and absence of atractyloside or 5-HD. Isoflurane (1.0 but not 0.5 MAC) and CsA (10 but not 5 mg/kg) reduced (P < 0.05) infarct size (21% ± 4%, 44% ± 6%, 24% ± 3%, and 43% ± 6%, respectively, mean ± sd of left ventricular area at risk; triphenyltetrazolium staining) as compared with control (42% ± 7%). Isoflurane (0.5 MAC) plus CsA (5 mg/kg) was also protective (27% ± 4%). Neither atractyloside nor 5-HD alone affected infarct size, but these drugs abolished protection by 1.0 MAC isoflurane, 10 mg/kg CsA, and 0.5 MAC isoflurane plus 5 mg/kg CsA. The results indicate that mPTP inhibition enhances, whereas opening abolishes, isoflurane-induced postconditioning. This isoflurane-induced inhibition of mitochondrial permeability transition is dependent on activation of mitochondrial K_ATP channels in vivo.

	Introduction

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A transition in mitochondrial permeability caused by opening of the mitochondrial permeability transition pore (mPTP) has been strongly implicated in myocardial necrosis and apoptosis resulting from ischemia-reperfusion injury (1–4). The mPTP is located on the inner mitochondrial membrane, and opening of the pore abolishes the mitochondrial membrane potential, inhibits oxidative phosphorylation, and facilitates the release or activation of several proapoptotic proteins including cytochrome c (4). These actions rapidly contribute to cell death. Opening of mPTP appears to occur specifically at the onset of reperfusion (5), in part as a consequence of intracellular calcium overload and the presence of large quantities of cytotoxic oxygen-derived free radicals (6). Previous studies demonstrated that the protective effects of classical (7,8) and delayed (9) ischemic preconditioning were mediated by inhibition of mitochondrial permeability transition. Similarly, a role for mPTP inhibition was also suggested in pharmacological preconditioning produced by the selective mitochondrial adenosine triphosphate-dependent potassium (mK_ATP) channel agonist diazoxide (7) and the volatile anesthetic desflurane (10). Most recently, inhibition of mPTP was shown to mediate the protective effects of repetitive, brief ischemic episodes conducted during early reperfusion after prolonged coronary artery occlusion (11–13), a phenomenon termed "ischemic postconditioning" (14,15).

Volatile anesthetics also exert important cardioprotective effects when administered solely during early reperfusion (16–19). This observation may be clinically relevant because the precise timing of coronary artery occlusion is unknown in the majority of patients with acute myocardial infarction. Our laboratory recently demonstrated that this "anesthetic-induced postconditioning" reduces myocardial infarct size by activating the pro-survival phosphatidylinositol-3-kinase (PI3K)-Akt signaling cascade (18,19). Several of the downstream signaling components of the PI3K-Akt pathway may act to prevent cellular damage by inhibiting mPTP opening on reperfusion (20,21). A critical interaction between mPTP and mK_ATP channels has also been proposed (7,22). Thus, the current investigation tested the hypothesis that mPTP mediates cardioprotection produced by isoflurane during early reperfusion. We further examined the hypothesis that isoflurane-induced postconditioning is dependent on mK_ATP channel activation in vivo.

	Methods

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All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin. Furthermore, all conformed to the Guiding Principles in the Care and Use of Animals (23) of the American Physiologic Society and were in accordance with the Guide for the Care and Use of Laboratory Animals (24).

Male New Zealand white rabbits weighing between 2.5 and 3.0 kg were anesthetized with IV sodium pentobarbital (30 mg/kg) as previously described (18). Briefly, a tracheostomy was performed through a midline incision, and each rabbit’s lungs were ventilated with positive pressure using an air-oxygen mixture (fractional inspired oxygen concentration = 0.33). Heparin-filled catheters were inserted into the right carotid artery and the left jugular vein for measurement of arterial blood pressure and fluid or drug administration, respectively. A thoracotomy was performed at the left fourth intercostal space, and the heart was suspended in a pericardial cradle. A prominent branch of the left anterior descending coronary artery (LAD) was identified, and a silk ligature was placed around this vessel approximately halfway between the base and the apex for the production of coronary artery occlusion and reperfusion. IV heparin (500 U) was administered immediately before LAD occlusion. Coronary artery occlusion was verified by the presence of epicardial cyanosis and regional dyskinesia in the ischemic zone, and reperfusion was confirmed by observing an epicardial hyperemic response. Hemodynamic data were continuously recorded on a polygraph throughout each experiment.

The experimental design is illustrated in Figure 1. Baseline hemodynamic data and arterial blood gas tensions were recorded 30 min after instrumentation was completed. All rabbits underwent a 30 min LAD occlusion followed by 3 h of reperfusion. In separate experimental groups, rabbits (n = 7 to 8 per group) were randomly assigned to receive 0.9% saline (control), isoflurane (0.5 or 1.0 minimum alveolar concentration [MAC]; 1.0 MAC = 2.05% in the rabbit) administered for 3 min before and 2 min after reperfusion, the mPTP inhibitor cyclosporin A (CsA) (5 or 10 mg/kg) in the presence or absence of the mPTP opener atractyloside (5 mg/kg), or the selective mK_ATP channel antagonist 5-hydroxydecanoate (5-HD; 10 mg/kg). Isoflurane was administered for 3 min before reperfusion to establish a blood concentration of the volatile anesthetic when the coronary blood flow was restored. Additional groups of rabbits received the combination of 0.5 MAC isoflurane and 5 mg/kg CsA in the presence and absence of atractyloside or 5-HD. CsA was dissolved in 2 mL of a 50% ethanol-polyethylene glycol mixture and administered over 2 min as an IV infusion 5 min before reperfusion. Atractyloside was dissolved in 2 mL of distilled water and administered over 2 min as an IV infusion 30 min before coronary artery occlusion. 5-HD was dissolved in 0.9% saline and administered IV 10 min before reperfusion.

View larger version (13K): [in this window] [in a new window]   Figure 1. Schematic illustration depicting the experimental protocol. ATR = atractyloside; ISO = isoflurane; CsA = cyclosporin A; 5-HD = 5 hydroxydecanoate.

Myocardial infarct size was measured as previously described (25). Briefly, the LAD was reoccluded at the completion of each experiment and 3 mL of patent blue dye was injected IV. The left ventricular (LV) area at risk (AAR) for infarction was separated from surrounding normal areas (stained blue), and the 2 regions were incubated at 37°C for 20 min in 1% 2,3,5-triphenyltetrazolium chloride in 0.1 M phosphate buffer adjusted to pH 7.4. Infarcted and noninfarcted myocardium within the AAR were carefully separated and weighed after storage overnight in 10% formaldehyde. Myocardial infarct size was expressed as a percentage of the AAR (Fig. 2). Rabbits that developed intractable ventricular fibrillation and those with an AAR <15% of total LV mass were excluded from subsequent analysis.

View larger version (44K): [in this window] [in a new window]   Figure 2. Histograms depicting myocardial infarct size displayed as a percentage of the left ventricular area at risk in rabbits receiving isoflurane (ISO, 0.5 or 1.0 MAC), cyclosporin A (CsA, 5 or 10 mg/kg), or the combination of 0.5 MAC ISO and 5 mg/kg CsA (panel A). Infarct size in rabbits receiving atractyloside (ATR) or 5-hydroxydecanoate (5-HD) in the presence or absence of 1.0 MAC ISO, 10 mg/kg CsA, or the combination of 0.5 MAC ISO and 5 mg/kg CsA are also depicted (panels B and C, respectively). All data are mean ± sd *Significantly (P < 0.05) different from control (CON).

Statistical analysis of data within and between groups was performed with analysis of variance for repeated measures followed by the Student-Newman-Keuls test. Changes were considered statistically significant when P < 0.05. All data are expressed as mean ± sd.

	Results

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One-hundred-ten rabbits were instrumented to obtain 102 successful experiments. Three rabbits were excluded because of technical problems during instrumentation. Five rabbits were excluded because intractable ventricular fibrillation occurred during or immediately after LAD occlusion (1 5 mg/kg CsA, 1 10 mg/kg CsA, 1 atractyloside alone, 2 atractyloside + 0.5 MAC isoflurane + 5 mg/kg CsA). Baseline hemodynamics were similar among groups (Table 1). Coronary artery occlusion significantly (P < 0.05) decreased rate-pressure product in most experimental groups. Decreases in heart rate, mean arterial blood pressure, and rate-pressure product were observed during reperfusion in many experimental groups.

Body weight, LV mass, AAR weight, and the ratio of AAR to LV mass were similar among groups (Table 2). Brief exposure to isoflurane (1.0 but not 0.5 MAC) significantly (P < 0.05) reduced infarct size (21% ± 4% and 44% ± 6% of LV AAR, respectively) as compared with control (42 ± 7%). Ten but not 5 mg/kg CsA also reduced infarct size (24% ± 3% and 43% ± 6%, respectively). The combination of 0.5 MAC isoflurane and 5 mg/kg CsA protected against infarction (27% ± 4%). Atractyloside alone did not affect infarct size (46% ± 2%), but abolished the protection produced by 1.0 MAC isoflurane (45% ± 5%), 10 mg/kg CsA (43% ± 4%), and the combination of 0.5 MAC isoflurane and 5 mg/kg CsA (46% ± 2%). 5-HD alone did not alter infarct size (44% ± 3%). In contrast, 5-HD blocked the cardioprotection produced by 1.0 MAC isoflurane (46% ± 3%), 10 mg/kg CsA (46% ± 3%), and the combination of 0.5 MAC isoflurane and 5 mg/kg CsA (44% ± 4%).

	Discussion

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The current results confirm previous findings (18,19) demonstrating that brief exposure to 1.0 but not 0.5 MAC isoflurane immediately before and during early reperfusion protects against myocardial infarction. This cardioprotective effect was abolished by pretreatment with the mPTP opener atractyloside or mK_ATP antagonist 5-HD. These results indicate, for the first time, that isoflurane-induced postconditioning produces inhibition of mitochondrial permeability transition and mK_ATP channel activation and support the recent observations demonstrating a link between inhibition of mPTP and mK_ATP channels during desflurane-induced preconditioning (10). The current results also confirm previous findings (7,12,26) demonstrating that administration of the mPTP inhibitor CsA before reperfusion reduces irreversible ischemic injury. Interestingly, the protective effect of CsA was abolished by 5-HD pretreatment, suggesting an important relationship between mPTP and the mK_ATP channel. Such an interaction between mitochondrial permeability transition and the mK_ATP channel was previously suggested by findings indicating that diazoxide-induced preconditioning was inhibited by atractyloside (7). The current findings further demonstrate that CsA, when administered in a dose that does not alter infarct size alone, enhances isoflurane-induced postconditioning. The protective effects of the combination of subthreshold doses of CsA and isoflurane during early reperfusion were abolished by pretreatment with atractyloside or 5-HD, indicating that the observed decrease in the extent of infarction was mediated by mPTP and mK_ATP channels.

The mechanisms by which administration of isoflurane before and during early reperfusion inhibits mitochondrial permeability transition have yet to be clearly elucidated. Our laboratory recently demonstrated that the cardioprotective effect of isoflurane during early reperfusion was mediated by activation of the PI3K-Akt signaling cascade in an identical rabbit model (18,19). The PI3K-Akt pathway has been shown to play a major role in cell survival during reperfusion by activating the downstream enzymes endothelial nitric oxide synthase (eNOS) and 70 kDa ribosomal protein s6 kinase (p70s6K), favorably affecting the balance between pro-apoptotic proteins (e.g., Bad, Bax) and anti-apoptotic proteins (e.g., B cell lymphoma-2 [Bcl-2]) and inhibiting caspase formation and glycogen synthase kinase-3ß activity (20,27). Recent preliminary data from our laboratory demonstrated that eNOS and p70s6K play essential roles in isoflurane-induced protection against myocardial infarction during early reperfusion (28). These proteins may directly inhibit mPTP by producing nitric oxide (29) or indirectly alter mitochondrial permeability transition by attenuating the effects of glycogen synthase kinase-3ß (27).

Bcl-2 is specifically located in the outer mitochondrial membrane (30), and a close relationship between the activity of this protein and inhibition of mitochondrial permeability transition has been previous demonstrated during delayed ischemic preconditioning (9). Bcl-2 attenuates cellular injury by inhibiting mitochondrial cytochrome c translocation into the cytosol (31), presumably by preventing mPTP opening (20). We have recently shown that isoflurane enhances Akt activity and Bcl-2 expression and reduces cytochrome c translocation in atrial and ventricular myocytes subjected to simulated reperfusion injury in vitro (32). Taken together, our current and previous (32) data suggest that inhibition of mitochondrial permeability transition by isoflurane during early reperfusion may be mediated by the actions of the volatile anesthetic on Bcl-2, but further investigation will be required to confirm this hypothesis in the intact heart. Several cardioprotective signaling elements, including Akt and p70s6K, also converge on glycogen synthase kinase-3ß, and inhibition of this protein reduces mitochondrial permeability transition and decreases cardiac myocyte injury in vitro (27,33). Whether isoflurane inhibits mPTP by attenuating glycogen synthase kinase-3ß activity through PI3K-Akt signaling is unknown. This hypothesis is being actively investigated by our laboratory. However, such a mechanism for the beneficial actions of isoflurane during early reperfusion certainly appears to be very plausible based on recent evidence that PI3K- and p70s6K-dependent inhibition of glycogen synthase kinase-3ß activity mediates opioid-induced cardioprotection during reperfusion (34).

Experimental evidence has implicated mK_ATP channel activation as an end-effector during preconditioning by isoflurane and other volatile anesthetics (35). Isoflurane either directly activates mK_ATP channels (36,37) or indirectly primes the opening of these channels in response to other signaling molecules in vitro (38). Opening of mK_ATP channels during ischemic or pharmacological preconditioning may produce small alterations in intramitochondrial homeostasis (39) that promote protection against subsequent ischemic damage through energy-dependent regulation of mitochondrial matrix volume (20,22). A very recent study (40) provides additional support for this contention, as opening of mitochondrial K⁺ influx pathways were shown to favorably regulate matrix volume and improve function during simulated ischemia and reperfusion. Thus, the current results indicating that isoflurane-induced postconditioning is inhibited by 5-HD suggest that mK_ATP channel opening by brief administration of isoflurane during early reperfusion may be directly responsible for cardioprotection. Nevertheless, a close interaction between mK_ATP channels and mPTP was previously identified during diazoxide- and desflurane-induced preconditioning (7,10). Thus, it appears highly likely that isoflurane-induced postconditioning may not be solely attributed to the actions of the volatile anesthetic on mK_ATP channels alone but rather is dependent on this interaction between mK_ATP channel opening and mPTP inhibition.

The current results must be interpreted within the constraints of several potential limitations. CsA has been previously shown to be a relatively selective inhibitor of mPTP (2), but this drug may also affect other proteins implicated in cardioprotection (41,42) and such actions cannot be completely excluded from the analysis. Nevertheless, a recent study demonstrated that equivalent doses of the CsA and its nonimmunosuppressive, more specific derivative NIM811 (10 mg/kg) produce similar reductions in myocardial necrosis and apoptosis when administered immediately before reperfusion in a nearly identical rabbit model (12). Myocardial infarct size is determined primarily by the size of the AAR and extent of coronary collateral perfusion. The AAR expressed as a percentage of total LV mass was similar among groups in the current investigation. Rabbits have also been shown to possess little if any coronary collateral blood flow (43). Thus, it appears unlikely that differences in collateral perfusion among groups account for the observed results. However, coronary collateral blood flow was not specifically quantified in the current investigation. The reductions in myocardial infarct size produced by brief administration of isoflurane during early reperfusion and their inhibition by atractyloside or 5-HD in the presence and absence of CsA occurred independent of changes in major determinants of myocardial oxygen consumption. However, the current results require qualification because coronary venous oxygen tension was not directly measured and myocardial oxygen consumption was not calculated in the current investigation. The results also require qualification because we did not examine the actions of isoflurane, CsA, atractyloside, or 5-HD on mPTP activity in isolated mitochondria. Nevertheless, our pharmacological data obtained in rabbits strongly suggest a central role for mPTP inhibition and mK_ATP channel activation in isoflurane-induced postconditioning.

In summary, the current results confirm that brief exposure to isoflurane immediately before and during early reperfusion reduces myocardial infarct size in barbiturate-anesthetized, acutely instrumented rabbits. The findings also indicate that mPTP inhibition enhances, whereas opening abolishes, this isoflurane-induced postconditioning against infarction. This cardioprotective effect is dependent on mK_ATP channel activation in vivo.

The authors thank David A. Schwabe BSEE (Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin) for technical assistance and Mary Lorence-Hanke AA (Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin) for assistance in preparation of the manuscript.

	Footnotes

 
Supported, in part, by American Heart Association Greater Midwest Affiliate grant AHA 0265259Z (to Dr. Weihrauch) and National Institutes of Health grants HL 054820 (to Dr. Warltier), GM 008377 (to Dr. Warltier), GM 066730 (to Dr. Warltier), and HL 063705 (to Dr. Kersten) from the United States Public Health Service (Bethesda, MD).

Accepted for publication July 20, 2005.

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				P. S. Pagel, J. G. Krolikowski, D. A. Neff, D. Weihrauch, M. Bienengraeber, J. R. Kersten, and D. C. Warltier Inhibition of glycogen synthase kinase enhances isoflurane-induced protection against myocardial infarction during early reperfusion in vivo. Anesth. Analg., May 1, 2006; 102(5): 1348 - 1354. [Abstract] [Full Text] [PDF]

				C. Wang, D. A. Neff, J. G. Krolikowski, D. Weihrauch, M. Bienengraeber, D. C. Warltier, J. R. Kersten, and P. S. Pagel The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesth. Analg., May 1, 2006; 102(5): 1355 - 1360. [Abstract] [Full Text] [PDF]

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999