The modification of vasodilation through adenosine triphosphate (ATP)-sensitive K(+) channels induced by antiarrhythmic drugs has not been studied in chronic hypertension. We designed the present study to examine whether mexiletine modulates vasorelaxation via these channels in hypertensive rat aortas. Normotensive and hypertensive rat aortas without endothelium were suspended for isometric force recording. Mexiletine (3 x 10(-5) M) increased vasorelaxation induced by levcromakalim (10(-8)-10(-5) M) in normotensive, but not hypertensive, rat aortas. Mexiletine (10(-5) to 3 x 10(-5) M) also augmented vasorelaxation to sodium nitroprusside (10(-10)-10(-5) M) only in normotensive rat aortas, whereas mexiletine (3 x 10(-5) M) did not affect this vasodilation in aortas treated with an ATP-sensitive K(+) channel antagonist glibenclamide (10(-5) M). A nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide; 10(-3) M) abolished augmented vasorelaxation to sodium nitroprusside induced by mexiletine (3 x 10(-5) M) in normotensive rat aortas, whereas a soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one; 10(-5) M) failed to alter this augmentation of vasorelaxation. These results suggest that mexiletine induces augmentation of vasodilation via ATP-sensitive K(+) channels activated by the opener as well as a nitric oxide donor only in normotensive rat aortas. The vasodilator effects of mexiletine are partly caused by the soluble guanylate cyclase-independent action of nitric oxide on these channels.
Implications: Mexiletine induces augmentation of vasodilation mediated by adenosine triphosphate (ATP)-sensitive K(+) channels activated by the opener as well as a nitric oxide donor in normotensive, but not hypertensive, rat aortas, partly by the soluble guanylate cyclase-independent action of nitric oxide on ATP-sensitive K(+) channels of vascular smooth muscle cells.