Abstract

In some but not all arterial beds, smooth muscle cell calcium-activated K⁺ channels (K_Ca channels) play a central role in the mediation of the vasodilator response to nitric oxide (NO) and other nitrates. We investigated the effect of nitrates on K_Ca channels in the relaxation of human coronary arteries by means of isometric contraction experiments in arterial rings. We also measured whole-cell currents in freshly isolated human coronary artery vascular smooth muscle cells via the patch-clamp technique. Sodium nitroprusside, diethylamine-nitric oxide complex sodium salt and isosorbide mononitratre completely relaxed rings preconstricted with 5 μM serotonin and produced dose-dependent relaxations of 5 μM serotonin-preconstricted human rings. The relaxations were inhibited by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-oxyl 3-oxide (10 μM), which neutralizes nitric oxide. The K_Ca channel blockers iberiotoxin (100 nM) and tetraethylammonium ions (1 mM) significantly inhibited SNP-induced relaxations of human coronary arteries. Moreover, in the patch-clamp experiments, SNP (1 μM) stimulated K_Ca currents and spontaneous transient outward K⁺ currents carried by Ca spark activated K_Cachannels. The SNP-induced (1 μM) K_Ca current was strongly inhibited by iberiotoxin (100 nM). These data show that activation of K_Ca channels in smooth muscle cells contributes to the vasodilating actions of nitrates and nitric oxide in human coronary arteries. This finding may have unique clinical significance for the development of antianginal and antihypertensive drugs that selectively target K⁺ channels and Ca sparks..