Myocardial ATP-sensitive potassium channels and ischemia/reperfusion injury

Ischemic heart disease claims more worldwide lives than any other single disease, and myocardial infarction is commonly the initial manifestation of ischemic heart disease. As recovery following an infarction is inversely related to the size of infarction, understanding the basic mechanisms of myocardial ischemia/reperfusion injury is obligatory for novel treatments aimed at salvaging heart tissue. The purpose of these experiments was to determine if gender, acute exercise, and chronic exercise training provide intrinsic cardioprotection following in vitro ischemia/reperfusion, and to examine the mechanism(s) by which the protection was afforded. Our data indicate that susceptibility to ischemia/reperfusion injury is sex dependent in the rat, with females having significantly smaller infarcted areas than male counterparts. Acute treadmill running (1 or 5 days) led to reduced infarct size in both sexes, with the protection occurring faster in males than females. The protection following short-term running was sustainable over months of exercise in females, as both 12 and 20 weeks elicited a ∼20% reduction in infarct size. Several putative mechanisms were explored to understand the molecular basis of the sex-dependent and exercise-induced protection. Increased manganese superoxide dismutase protein expression was observed in sedentary females (when compared to males) and was enhanced by chronic running, but did not increase following acute exercise in either sex. These experiments provided the first demonstration that exercise-induced protection can be attained without increased expression of manganese superoxide dismutase. Our experiments also provide novel insight that myocardial ischemia/reperfusion injury may be critically dependent on the expression and activity of ATP-sensitive potassium (KATP) channels. Increased expression of KATP channel subunits was observed in hearts from sedentary female rats (when compared to sedentary males) and correlated very closely to the protection elicited by both acute and chronic treadmill running. A protective role of KATP channels was confirmed by blocking the sarcolemmal (but not the mitochondrial) isoform of the KATP channel during ischemia/reperfusion. Pharmacological blockade of sarcolemmal KATP channels abolished both the enhanced cardioprotection afforded by chronic exercise and intrinsic protection of female (as compared to male) hearts. These data indicate that the sarcolemmal KATP channel population plays an important role in protecting the myocardium from ischemia/reperfusion injury, and channel agonists may eventually serve as novel therapy for patients experiencing a heart attack.