Pathophysiological functions of ATP-sensitive K+ channels in myocardial ischemia

The ATP-sensitive K+ channels (KATP) are characterized by strong inhibition by intracellular ATP but their activity is also modulated by various intra- and extracellular factors with complicated and undefined mechanism. These factors include a low concentration of ADP (or ATP/ADP ratio), a mildly low pH, G-protein coupled process, adenosine and so on. Intracellular ATP has a ligand action to inhibit the channel activity on the one hand, but on the other ATP is necessary for maintaining the channels in an operative state, probably due to the enzymatic process involving ATP hydrolysis. KATP is inhibited by antidiabetic sulfonylureas and sodium 5-hydroxydecanoate. The channels are activated by the K+ channel openers in an ATP-dependent manner, but may have diverse mechanisms of actions depending on different compounds. The KATP channel openings are responsible for shortening the action potential duration (APD) and partial K(+)-efflux during early ischemia. The discrepancy between the high sensitivity of intracellular ATP to inhibit KATP in cell-free, inside-out patches and millimolar orders of myocardial ATP concentration determined by the biochemical techniques may cast some doubts on the actual openings of this channel. It can be explained by the presence of cofactors to stimulate channel opening, heterogeneity or compartmentation of ATP distribution in the cell, the properties and high density of KATP, or a combination of these factors. The opening of KATP during ischemia may contribute to the development and aggravation of serious arrhythmias to some extent, but their opening also protects cellular damage, limits infarct size and improves recovery of cardiac function during reperfusion, acting as a cardioprotection mechanism. KATP opening may mimick the effects of ischemic preconditioning, but its effect may be variable among different animal species and experimental conditions. Further studies are necessary to clarify the actual role of channel opening and the molecular mechanism.