title: 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.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Iesaki
authors.forename: M S
authors.initials: MS
authors.lastname: Wolin
mesh_terms: D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002121:Calcium Channel Blockers; D002122:Calcium Chloride / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D003958:Diamide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006321:Heart; D009119:Muscle Contraction / Q000187:drug effects; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D026902:Potassium Channel Blockers; D011189:Potassium Chloride / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D013438:Sulfhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D013438:Sulfhydryl Compounds; D003958:Diamide; D011189:Potassium Chloride; D005980:Glutathione Reductase; D011505:Protein-Tyrosine Kinases; D006162:Guanylate Cyclase; D002122:Calcium Chloride; D010100:Oxygen; D002118:Calcium