Endogenous Activation of Mitochondrial K ATP Channels Protects Human Failing Myocardium From Hydroxyl Radical–Induced Stunning

Abstract

Rationale : During reperfusion of ischemic myocardium, a burst of hydroxyl radicals (ȮH) induces contractile dysfunction (“myocardial stunning”), and ȮH in the plasma of patients after myocardial infarction predict the development of heart failure. The effects of ȮH on myocardial function in patients with heart failure; however, have never been assessed. Furthermore, although ATP-dependent K + channels (K ATP channels) are implicated in myocardial protection during ischemia/reperfusion (“ischemic preconditioning”), their role in heart failure has hardly been elucidated. Objective : To investigate the effects of ȮH on cardiac contractile function in human failing myocardium, and to clarify the role of K ATP channels during this response. Methods and Results : In isolated left ventricular trabeculae of nonfailing hearts, ȮH (produced by Fe 3+ -nitrilotriacetic acid and H 2 O 2 ) induced substantial systolic and diastolic dysfunction, whereas in failing myocardium, stunning was virtually absent. Although in failing myocardium, protein expression of sarcolemmal K ATP channels (Kir6.2/SUR2) was ≈2-fold upregulated, their blockade with HMR-1098 did not impair contractile function in the presence of ȮH. In contrast, when blocking mitochondrial K ATP channels during ȮH exposure (with 5-HD), failing myocardium developed contractile dysfunction to a degree that was comparable to ȮH-induced stunning in nonfailing myocardium without K ATP channel blockade. Conclusions : Human failing left ventricular myocardium is resistant to ȮH-induced stunning, and this resistance is related to endogenous activation of putative mitochondrial K ATP channels. Given that certain sulfonylurea drugs that also block mitochondrial K ATP channels (eg, glibenclamide) are frequently used for the treatment of diabetes, our results imply that in patients with heart failure and diabetes, these drugs may impair left ventricular function during ischemia/reperfusion.