INTERACTION OF SULFONYLUREA DERIVATIVES WITH VASCULAR ATP-SENSITIVE POTASSIUM CHANNELS IN HUMANS

Cardiovascular adenosine-5'-triphosphate-sensitive potassium (K-ATP) c hannels have been reported to play an important role in endogenous car dioprotective mechanisms. Sulphonylurea derivatives can inhibit these cardioprotective mechanisms in animal models. We investigated whether therapeutic concentrations of sulphonylurea derivatives can block vasc ular K-ATP channels in humans. The forearm vasodilator responses to ad ministration of the specific K-ATP channel opener diazoxide into the b rachial artery of healthy male volunteers were recorded by venous occl usion plethysmography. This procedure was repeated with concomitant in traarterial infusion of:1) the sulphonylurea derivative glibenclamide (0.33 or 3.3 mu g . min(-1). dl(-1), both n = 12), 2) the new sulphony lurea derivative glimepiride (2.5 mu g . min(-1) dl(-1), n = 12) or 3) placebo (n = 12). The effects of glibenclamide on the vasodilator res ponses to sodium nitroprusside were also studied (n = 12). Glibenclami de significantly inhibited the diazoxide-induced increase in forearm b lood now ratio (ANOVA with repeated measures: p < 0.01). During the hi ghest diazoxide dose this ratio (mean+/-SEM) was lowered from 892+/-16 5 to 449+/-105%, and from 1044+/-248 to 663+/-114% by low- and high-do se glibenclamide, respectively. In contrast, neither glimepiride nor p lacebo attenuate diazoxide-induced vasodilation. Furthermore, glibencl amide did not affect nitroprusside-induced side-induced vasodilation. We conclude that therapeutic concentrations of the classical sulphonyl urea derivative glibenclamide result in significant blockade of vascul ar K-ATP channels in humans. The newly developed glimepiride seems to be devoid of these properties.