Cardioprotective Effect of Diazoxide Is Mediated by Activation of Sarcolemmal but Not Mitochondrial ATP-Sensitive Potassium Channels in Mice

Abstract

Background— We recently demonstrated that the sarcolemmal ATP-sensitive potassium (sarcK ATP ) channel plays a key role in cardioprotection against ischemia/reperfusion injuries in Kir6.2-knockout (KO) mice. In the present study, we evaluated the effects of diazoxide, a mitochondrial ATP-sensitive potassium (mitoK ATP ) channel opener, on ischemia-induced myocardial stunning in sarcK ATP channel-deficient mice. Methods and Results— Langendorff-perfused hearts of wild-type (WT) and KO mice were subjected to global ischemia/reperfusion. Diazoxide improved the recovery of contractile function in WT hearts but not in KO hearts. Treatment with HMR1098 (a sarcK ATP channel blocker) but not 5-hydroxydecanoate (a mitoK ATP channel blocker) abolished the cardioprotective effect of diazoxide in WT hearts. In coronary-perfused WT ventricular muscle preparations, action potential shortening during ischemia was accelerated in the presence of diazoxide. Conclusions— Diazoxide enhances action potential shortening during ischemia by activating sarcK ATP channels and provides cardioprotection in mouse hearts.