Role of sarcolemmal KATP channels in cardioprotection against ischemia/reperfusion injury in mice

Abstract

Recently it has been postulated that mitochondrial ATP-sensitive K + (mitoK ATP ) channels rather than sarcolemmal K ATP (sarcK ATP ) channels are important as end effectors and/or triggers of ischemic preconditioning (IPC).To define the pathophysiological significance of sarcK ATP channels, we conducted functional experiments using Kir6.2-deficient(KO) mice.Metabolic inhibition with glucose-free, dinitrophenol-containing solution activated sarcK ATP current and shortened the action potential duration in ventricular cells isolated from wild-type (WT) but not KO mice.MitoK ATP channel function was preserved in KO ventricular cells.In anesthetized mice, IPC reduced the infarct size in WT but not KO mice.Following global ischemia/reperfusion, the increase of left ventricular end-diastolic pressure during ischemia was more marked, and the recovery of contractile function was worse, in KO hearts than in WT hearts.Treatment with HMR1098, a sarcK ATP channel blocker, but not 5-hydroxydecanoate, a mitoK ATP channel blocker, produced a deterioration of contractile function in WT hearts comparable to that of KO hearts.These findings suggest that sarcKATP channels figures prominently in modulating ischemia/reperfusion injury in the mouse.The rapid heart rate of the mouse (>600 beats per minute) may magnify the relative importance of sarcK ATP channels during ischemia, prompting caution in the extrapolation of the conclusions to larger mammals.