Metabolic regulation of cardiac ATP-sensitive K⁺ channels

Summary

Activation of ATP-sensitive K⁺ (K_ATP) channels has been implicated as a cause of increased cellular K⁺ efflux and action potential duration (APD) shortening during myocardial ischemia, hypoxia, and selective glycolytic inhibition, since selective K_ATP channel antagonists partially or completely block increased cellular K⁺ efflux and APD shortening under these conditions. During substrate-free hypoxia or myocardial ischemia in intact rabbit ventricle, unidirectional K⁺ efflux rate during systole approximately doubled and APD decreased by ≈40% after 10 minutes. In patch-clamped guinea pig ventricular myocytes, similar changes could be produced by activation of <0.5% of the maximal K_ATP channel conductance. Furthermore, from studying the desensitizing 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 sufficient 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 saponin-permeabilized ventricular myocytes, K_ATP channels were preferentially suppressed by glycolytic ATP production compared to ATP generated by mitochondria or by the creatinine kinase reaction, and functional glycolytic enzymes were found to be associated with K_ATP channels in excised membrane patches. We hypothesize that sarcolemma-associated glycolytic enzymes may be important in maintaining a high local cytosolic ATP/ADP ratio in the vicinity of K_ATP channels, where sarcolemmal ATPases are tending to depress the local ATP/ADP ratio.