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

Abstract

IntroductionBrief periods of ischemia that precede sustained ischemia lead to a reduction of infarct size (1-4). This phenomenon is known as ischemic preconditioning (IPC) and the mechanisms underlying it remain unclear, despite extensive study (5-7). Sarcolemmal ATP-sensitive potassium (sarcK ATP ) channels were proposed to play an important role in the cardioprotective effect, because potassium channel openers (KCOs) mimicked the cardioprotection and the K ATP channel blocker glibenclamide abolished the IPC (8-13). Since the discovery of sarcK ATP channels (14), it has been recognized that activation of these channels may serve an endogenous cardioprotective mechanism: action potential shortening due to K ATP channel activation is expected to reduce Ca 2+ influx in ischemic heart cells, producing a cardioplegic effect. However, recent studies indicate that mitochondria harbor another type of K ATP channel (15,16), and activation of the mitochondrial K ATP (mitoK ATP ) channel rather than the sarcK ATP channel has been proposed to underlie the cardioprotective effect of IPC or . Because the mitoK ATP channel has yet to be identified at a molecular level, the existing evidence is almost entirely based on pharmacological studies.The molecular structure of sarcK ATP channels has been clarified by cloning members of the inwardly rectifying K + channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the receptors for sulfonylureas (SUR1, SUR2A, and SUR2B) (21,22). Accumulating evidence indicates that native sarcK ATP channels are composed of these two structurally distinct subunits. Various combinations of Kir6.0 and SUR convey the heterogeneity in channel properties observed in native cells of various tissues, such as heart, pancreatic β cells, skeletal and smooth muscles, and neurons (22). Cardiac sarcK ATP channels have been suggested in a reconstitution study to comprise SUR2A and Kir6.2 (23). Our recent functional study using Kir6.2-deficient mice has provided direct evidence that Kir6.2 forms the pore region of cardiac sarcK ATP channels but not of vascular sarcK ATP channels (24). Although the molecular identity of mitoK ATP channel remains unclear, experiments using dominant negative gene transfer have indicated that neither Kir6.1 nor Kir6.2 is a functionally important part of the mitoK ATP channel in native heart cells (25). Despite the paucity of molecular tools available to probe the role of mitoK ATP channels, Kir6.2-deficient mice are potentially useful to define the pathophysiological significance 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 ventric...

Volatile anesthetic-induced cardiac preconditioning

“…These fi ndings have led to a widespread opinion that the cardioprotective effects of preconditioning are dependent on the opening of the mitoK ATP channel. However, the results of more recent studies suggest that the potential involvement of sarcK ATP channels in cardioprotection should not be ignored [49,64,65].…”

Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism

“…Toyoda et al [13] found that while glibenclamide blocked IPC protection measured both from infarct size and recovery of contractile function, 5-HD affected only infarct size and HMR 1883 only functional recovery. Finally, strong evidence for a major role of sarcoK ATP in the mouse heart has come from knockout of its pore-forming subunit Kir6.2, which abolishes the protective effect of IPC [14].…”

An abundant, truncated human sulfonylurea receptor 1 splice variant has prodiabetic properties and impairs sulfonylurea action

“…Blockage of cardiac K ATP channels impairs ischemic preconditioning and extends infarction areas [46]. Thus, cardiac K ATP channels are considered to represent an endogenous cardioprotective mechanism usually attributed to SUR2A/Kir6.2-containing channels [47].…”