Molecular basis, pharmacology and physiological role of cardiac K(ATP) channels

ATP-dependent potassium (K(ATP)) channels exist in high density in the sarcolemmal membrane of heart muscle cells. Under normoxic conditions these channels are closed, but they become active when the intracellular ATP level falls. This leads to a shortening of the action potential duration, rendering the heart susceptible for life-threatening arrhythmias. Molecular biology has revealed that K(ATP) channels consist of heteromultimers of the inwardly rectifying channel Kir6.2 and the sulfonylurea receptor SUR. To date, three types of SURs were identified, representing the pancreatic (SUR1), the cardiac (SUR2A) and the smooth muscle (SUR2B) K(ATP) channel. In order to develop a novel therapeutic principle against ischemia-induced life-threatening arrhythmias leading to sudden cardiac death, the cardioselective K(ATP) channel blocker HMR 1883 was developed. This substance inhibits the sarcolemmal cardiac K(ATP) channel activated by the channel opener rilmakalim half-maximally at concentrations of 0.6-2.2 micromol/l, and substantially affects pancreatic K(ATP) channels at 9-50 times higher concentrations. K(ATP) channels of the coronary vascular system are only slightly blocked by HMR 1883 when activated by hypoxia. The substance was potently effective in preventing ventricular fibrillation in a conscious dog model, and thus can be considered to be a potential novel drug candidate against sudden cardiac death.