Inhibitory Effects of Lidocaine and Mexiletine on Vasorelaxation Mediated by Adenosine Triphosphate–sensitive K+Channels and the Role of Kinases in the Porcine Coronary Artery

Abstract

Effects of antiarrhythmic drugs on coronary vasodilation mediated by K channels have not been studied. Modulator roles of protein kinase C and tyrosine kinase in the activity of K channels have also been unclear in the coronary artery. The current study examined whether lidocaine and mexiletine in the porcine coronary artery modify the vasorelaxation mediated by adenosine triphosphate-sensitive K channels via activation of protein kinase C and tyrosine kinase. Porcine coronary arteries without endothelium were suspended for isometric force recording, and vasorelaxation to levcromakalim (10 to 10 m) was obtained. Changes in membrane potentials produced by levcromakalim (10 m) were also recorded. Glibenclamide completely abolished vasorelaxation as well as hyperpolarization in response to levcromakalim. Lidocaine and mexiletine significantly reduced these responses. Calphostin C, Go 6976, genistein, and erbstatin A partly restored vasorelaxation or hyperpolarization in response to levcromakalim in arteries treated with mexiletine but not in those with lidocaine, whereas these inhibitors did not alter the vasorelaxation to levcromakalim. Phorbol 12-myristate 13-acetate produced reduction of vasorelaxation in response to levcromakalim, which is recovered by calphostin C or Go 6976. Therefore, lidocaine and mexiletine inhibit vasorelaxation mediated by the activation of adenosine triphosphate-sensitive K channels in the coronary artery. Protein kinase C and tyrosine kinase seem to have roles in the inhibitory effect of mexiletine but not in that of lidocaine. Class Ib antiarrhythmic drugs may reduce coronary vasodilation mediated by adenosine triphosphate-sensitive K channels via the differential modulator effects on these kinases.