The impact of ATP-sensitive K+ channel subtype selectivity of insulin secretagogues for the coronary vasculature and the myocardium

Abstract

Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K+ channel (KATP channel) in the pancreatic beta-cell membrane. KATP channels subserve important functions also in the heart. First, KATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, KATP channels in the sarcolemma of cardiomyocytes (sarcKATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcKATP channels and of KATP channels in the inner membrane of mitochondria (mitoKATP channels) plays a central role in ischemic preconditioning. Opening of sarcKATP channels also underlies the ST-segment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular KATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular KATP channels, being either highly selective (approximately 1,000x; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10-20x; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2x; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested.