title: Differential effects of sulfonylurea derivatives on vascular ATP-sensitive potassium channels.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Engbersen
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Miriam A
authors.initials: MA
authors.lastname: van Gestel
authors.forename: Helene L M
authors.initials: HL
authors.lastname: Siero
authors.forename: Miek M
authors.initials: MM
authors.lastname: Moons
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D054086:KATP Channels / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D054086:KATP Channels; D013453:Sulfonylurea Compounds; D010656:Phenylephrine