INSULIN-SECRETION AND ITS MODULATION BY ANTIARRHYTHMIC AND SULFONYLUREA DRUGS

Cardiovascular drugs such as antiarrhythmic agents with Vaughan Willia ms class Ia action have been found to induce a sporadic hypoglycemia. Recent investigation has revealed that these drugs induce insulin secr etion from pancreatic beta-cells by inhibiting ATP-sensitive K+ (K-ATP ) channels in a manner similar to sulfonylurea drugs. The mechanism un derlying block of K-ATP channels by antiarrhythmic drugs was different , however, from that of sulfonylureas: firstly, because binding of rad ioactive glibenclamide could not be inhibited by unlabelled antiarrhyt hmic agents, and vice versa; secondly, because the two compounds diffe r in the kinetics and sidedness of drug action-antiarrhythmic drugs ac t on the channel from the inner surface of the cell membrane, whereas glibenclamide binds through the intramembrane pathway; finally, it was shown that functional K-ATP channels in beta-cells are composed of tw o distinct molecules-a sulfonylurea receptor (SUR) and a channel pore- forming subunit, an inwardly-rectifying K channel with two transmembra ne regions (Kir6.2). Antiarrhythmic drugs reversibly inhibit the K+ co nductance displayed by the Kir6.1 (a putative K-ATP channel clone)-tra nsfected NIH3T3 cells. Therefore they appear to interact directly with the pore-forming subunit, thereby inhibiting K-ATP channel currents a nd exerting an insulinotrophic effect.