METABOLIC-REGULATION OF CARDIAC ATP-SENSITIVE K+ CHANNELS

Activation of ATP-sensitive K+ (K(ATP)) channels has been implicated a s a cause of increased cellular K+ efflux and action potential duratio n (APD) shortening during myocardial ischemia, hypoxia, and selective glycolytic inhibition, since selective K(ATP) channel antagonists part ially or completely block increased cellular K+ efflux and APD shorten ing under these conditions. During substrate-free hypoxia or myocardia l ischemia in intact rabbit ventricle, unidirectional K+ efflux rate d uring systole approximately doubled and APD decreased by almost-equal- to 40% after 10 minutes. In patch-clamped guinea pig ventricular myocy tes, similar changes could be produced by activation of <0.5% of the m aximal K(ATP) channel conductance. Furthermore, from studying the dese nsitizing effects of ADP(i) on the ATP sensitivity of K(ATP) channels in excised inside-out patches, it was estimated that the rapid changes in the cytosolic ATP/ADP ratio during ischemia and hypoxia were of su fficient magnitude to activate K(ATP) channels to this degree. During selective glycolytic inhibition, however, the global cytosolic ATP/ADP ratio in intact heart remained normal despite an increase in cellular K+ efflux comparable to ischemia and hypoxia. In patch-clamped saponi n-permeabilized ventricular myocytes. K(ATP) channels were preferentia lly suppressed by glycolytic ATP production compared to ATP generated by mitochondria or by the creatinine kinase reaction, and functional g lycolytic enzymes were found to be associated with K(ATP) channels in excised membrane patches. We hypothesize that sarcolemma-associated gl ycolytic enzymes may be important in maintaining a high local cytosoli c ATP/ADP ratio in the vicinity of K(ATP) channels, where sarcolemmal ATPases are tending to depress the local ATP/ADP ratio.