title: Openers of calcium-activated potassium channels and endothelium-dependent hyperpolarizations in the guinea pig carotid artery.
abstract: This study was designed to determine whether putative openers of calcium-activated potassium channels of small and/or intermediate conductance (SK(Ca) and IK(Ca)) induce vascular smooth muscle hyperpolarizations and to identify the underlying mechanisms. The membrane potential of guinea pig carotid artery smooth muscle cells was recorded with intracellular microelectrodes in the presence of N(omega)-nitro-L-arginine and indomethacin. Acetylcholine and NS-309 produced endothelium-dependent hyperpolarizations. The effects of acetylcholine were partially and significantly inhibited by apamin. The combinations of charybdotoxin plus apamin and TRAM-34 plus apamin markedly and significantly reduced these hyperpolarizations. 1-ethyl-2-benzimidazolinone (1-EBIO) induced hyperpolarizations that were unaffected by TRAM-34 but partially inhibited by charybdotoxin, apamin, TRAM-34 plus apamin, and charybdotoxin plus apamin. Riluzole produced only marginal hyperpolarizations. Therefore, in the guinea pig carotid artery, endothelium-dependent hyperpolarization to acetylcholine involves the activation of both SK(Ca) and IK(Ca), with a predominant role for the former channel. 1-EBIO is a non-selective and weak opener of SK(Ca), while riluzole is virtually ineffective. By contrast, NS-309 is a reasonably potent and selective opener of both SK(Ca) and IK(Ca), and this compound mimics the endothelium-dependent hyperpolarizations to acetylcholine.
authors.affiliation: Département Angiologie, Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France.
authors.forename: V
authors.initials: V
authors.lastname: Leuranguer
authors.forename: P
authors.initials: P
authors.lastname: Gluais
authors.forename: P M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: T J
authors.initials: TJ
authors.lastname: Verbeuren
authors.forename: M
authors.initials: M
authors.lastname: Félétou
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology*; D002339:Carotid Arteries / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D019782:Riluzole / Q000494:pharmacology
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D001562:Benzimidazoles; D001685:Biological Factors; D007211:Indoles; D010091:Oximes; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; C411671:TRAM 34; C067410:endothelium-dependent hyperpolarization factor; D019782:Riluzole; C102635:1-ethyl-2-benzimidazolinone; D000109:Acetylcholine