Thiol oxidation activates a novel redox-regulated coronary vasodilator mechanism involving inhibition of Ca2+ influx.

Abstract

This study examines the mechanism of relaxation of isolated endothelium-removed bovine coronary arteries (BCAs) to the thiol oxidant diamide. BCAs precontracted with KCl or the thromboxane A(2) receptor agonist U46619 showed a concentration-dependent reversible relaxation on exposure to 10 micromol/L to 1 mmol/L diamide. This relaxation was enhanced by an inhibitor of glutathione reductase, and it was not altered by severe hypoxia, the presence of inhibitors of soluble guanylate cyclase, K(+) channels, tyrosine kinases, or probes that modulate levels of superoxide. The relaxation was almost eliminated when BCAs were precontracted with a phorbol ester that causes a contraction that is largely independent of extracellular Ca(2+). The initial transient contraction elicited by 5-hydroxytryptamine in Ca(2+)-free solution was not altered by the presence of 1 mmol/L diamide; however, a subsequent tonic contraction on addition of CaCl(2) was inhibited by diamide. Diamide also inhibited contractions caused by the addition of CaCl(2) to Ca(2+)-free Krebs' buffer containing Bay K8644 (an L-type Ca(2+) channel opener) or KCl. Relaxation to diamide was attenuated by L-type Ca(2+) channel blockers (nifedipine and diltiazem). Thus, thiol oxidation elicited by diamide appears to activate a novel redox-regulated vasodilator mechanism that seems to inhibit extracellular Ca(2+) influx.