Pharmacological evidence that captopril possesses an endothelium- mediated component of vasodilation: effect of sulfhydryl groups on endothelium-derived relaxing factor

JE Goldschmidt and RJ Tallarida

Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania.

Captopril, an angiotensin-converting enzyme inhibitor, reportedly can scavenge superoxide anion (O2-), a property attributed to its sulfhydryl group. The present investigation, using rabbit aortic rings precontracted with either norepinephrine or clonidine, was designed to determine whether captopril possesses an endothelium-dependent component of vasodilation related to its ability to protect endothelium- derived relaxing factor (EDRF) from superoxide-mediated destruction. Also studied were enalaprilat, a nonsulfhydryl angiotensin-converting enzyme-inhibitor, superoxide dismutase, and the sulfhydryl compounds glutathione (GSH), N-2-mercaptopropionylglycine (MPG) and N- acetylcysteine (NAC). Captopril, but not enalaprilat, caused dose- dependent relaxations in preconstricted aortic rings containing an intact endothelium. Rings denuded of endothelium were unresponsive to any dose of captopril. Captopril's vasodilation was not related to prostaglandin influence but was associated with an increase in cyclic GMP. Superoxide dismutase, GSH, MPG and NAC also produced endothelium- dependent relaxations similar to captopril. It was also demonstrated that endothelium-dependent relaxations to acetylcholine were enhanced by captopril, GSH, MPG and NAC but not by enalaprilat. In another set of experiments, the ability of captopril to inhibit superoxide-mediated inactivation of EDRF was examined. Pyrogallol, a potent generator of O2- , and superoxide dismutase, a scavenger of O2-, were used as a basis for comparing a possible scavenging effect of captopril. In preconstricted rings, pyrogallol elicited endothelium-dependent contractions that were attenuated by both captopril and superoxide dismutase. Similar effects were found with GSH, MPG and NAC but not with enalaprilat. These results suggest that captopril's endothelium- dependent vasodilation is due to its sulfhydryl group and the ability of the latter to scavenge O2-, thereby protecting EDRF.

Volume 257, Issue 3, pp. 1136-1145, 06/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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