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CARDIOVASCULAR ANESTHESIA

The Role of Mitochondrial and Sarcolemmal K_ATP Channels in Canine Ethanol-Induced Preconditioning In Vivo

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

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

Chronic consumption of small doses of ethanol protects myocardium from ischemic injury. We tested the hypothesis that mitochondrial and sarcolem-mal adenosine triphosphate-dependent potassium (K_ATP) channels mediate these beneficial effects. Dogs (n = 76) were fed with ethanol (1.5 g/kg) or water mixed with dry food bid for 6 or 12 wk, fasted overnight before experimentation, and instrumented for measurement of hemodynamics. Dogs received intracoronary saline (vehicle), 5-hydroxydecano-ate (a mitochondrial K_ATP channel antagonist; 6.75 mg/kg over 45 min), or HMR-1098 (a sarcolemmal K_ATP channel antagonist; 45 µg/kg over 45 min) and were subjected to a 60 min coronary artery occlusion followed by 3 h of reperfusion. A final group of dogs was pretreated with ethanol and chow for 6 wk before occlusion and reperfusion. Myocardial infarct size and transmural coronary collateral blood flow were measured with triphenyltetrazolium chloride staining and radioactive microspheres, respectively. The area at risk of infarction was similar between groups. A 12-wk pretreatment with ethanol significantly reduced infarct size to 13% ± 2% (mean ± SEM; n = 8) of the area at risk compared with control experiments (25% ± 2%; n = 8), but a 6-wk pretreatment did not (21% ± 2%; n = 8). 5-hydroxydecanoate and HMR-1098 abolished the protective effects of 12-wk ethanol pretreatment (24% ± 2% and 29% ± 3%, respectively; n = 8 for each group) but had no effect in dogs that did not receive ethanol (22% ± 2% and 23% ± 4%, respectively; n = 8 for each group). No differences in hemodynamics or transmural coronary collateral blood flow were observed between the groups. The results indicate that mitochondrial and sarcolemmal K_ATP channels mediate ethanol-induced preconditioning in dogs independent of alterations in systemic hemodynamics or coronary collateral blood flow.

IMPLICATIONS: Mitochondrial and sarcolemmal K_ATP channels mediate ethanol-induced preconditioning independent of alterations in systemic hemodynamics or coronary collateral perfusion in vivo.

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