Cibenzoline Has an Inhibitory Effect on Vasorelaxation Mediated by Adenosine Triphosphate-Sensitive K+ Channels in the Rat Carotid Artery

Abstract

Studies in cardiac myocytes have shown that cibenzoline reduces adenosine triphosphate (ATP)-sensitive K+ currents, suggesting that this class Ia antiarrhythmic drug may modify the activity of ATP-sensitive K+ channels in these preparations. The effects of class Ia antiarrhythmic drugs on vasodilation mediated by ion channels have not been studied. Therefore, we designed this study to examine whether cibenzoline may produce changes in vasorelaxation in response to a selective ATP-sensitive K+ channel opener, levcromakalim, in the isolated rat carotid artery. Rings of rat carotid arteries without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative fashion. During submaximal contraction to phenylephrine (3 × 10−7 M), vasorelaxation in response to levcromakalim (10−8 to 10−5 M) or 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10−10 to 10−5 M) was obtained. During contraction to phenylephrine, levcromakalim induced concentration-dependent vasorelaxation. A selective ATP-sensitive K+ channel antagonist, glibenclamide (5 × 10−6 M), completely abolished vasorelaxation in response to levcromakalim, whereas a selective Ca2+-dependent K+ channel antagonist, iberiotoxin (5 × 10−8 M), did not affect the relaxation. Cibenzoline (10−6 to 10−5 M) significantly reduced vasorelaxation to levcromakalim in a concentration-dependent fashion. In contrast, cibenzoline (10−5 M) did not alter vasorelaxation to a nitric oxide donor, NOC-7. These results suggest that from the clinically relevant concentrations, a novel class Ia antiarrhythmic drug, cibenzoline, impairs carotid vasodilation mediated by ATP-sensitive K+ channels.