Differential effects of sulfonylurea derivatives on vascular ATP-sensitive potassium channels

Sulfonylurea drugs exert their insulinotropic action by inhibiting ATP-sensitive potassium channels in the pancreas. However, these channels are also expressed in myocardial and vascular smooth muscle, implicating possible detrimental cardiovascular effects. Aim of the present study was to investigate the inhibitory potency of various widely used sulfonylurea drugs in resistance arteries. Isolated mesenteric and renal resistance arteries mounted in a myograph and isolated perfused kidneys were used to measure drug responses. Pinacidil induced a dose-dependent relaxation of phenylephrine preconstricted mesenteric and renal arteries (pEC(50)=6.10 ± 0.01 and 5.66 ± 0.03, respectively). Schild plot analysis of pinacidil relaxation curves in mesenteric arteries in the presence of sulfonylurea antagonists revealed the following order of potency: glimepiride (pA(2)=7.22) ≥ glibenclamide (pA(2)=7.05) > glipizide (pA(2)=5.25) > gliclazide (pA(2)=4.31). The effects of glibenclamide in renal arteries were comparable. Furthermore, glibenclamide produced similar constrictive properties in isolated renal arteries as in isolated perfused whole kidneys. We conclude that sulfonylurea drugs exert differential effects on vascular smooth muscle K(ATP) channels. Our results suggest that glibenclamide and glimepiride will interact with these channels at therapeutic concentrations.