The objective of this study was to ascertain whether the vasodilator effect of organic nitrates and nitrites, NaNO2, nitroprusside and NO could be attributed to the formation and action of short-acting intermediate S-nitrosothiols. Recent studies from this and other laboratories have suggested that cyclic GMP may be involved in the vascular smooth muscle relaxant re-sponse to nitrogen oxide-containing vasodilator drugs. In this study, partially purified guanylate cyclase from bovine coronary artery was activated by glyceryl trinitrate, isosorbide dinitrate, pentaerythritol tetranitrate, amyl nitrite, NaNO2, nitroprusside and NO, but this enzyme activation required the presence of-SH groups in the form of added thiols. Glyceryl trinitrate reacted with cysteine or coronary arterial soluble fraction to form N02. Glyceryl trinitrate, amyl nitrite, NaNO2, nitroprus-side and NO reacted with cysteine under specified conditions to form S-nitrosocysteine. S-nitrosocysteine and other S-nitrosothiols markedly activated guanylate cyclase, elevated cyclic GMP levels in precontracted strips of bovine coronary artery before eliciting relaxation and caused a profound but shortlived decrease in systemic arterial pressure when injected iv in the anesthetized cat. Methylene blue inhibited the effects of S-nitrosothiols as well as those of the nitrogen oxide-containing vasodilators on guanylate cyclase activity, coronary arterial cyclic GMP accumulation and coronary arterial tone. The de-creases in systemic arterial pressure elicited by S-nitrosothiols, nitroprusside and glyceryl trinitrate yielded parallel dose-re-sponse curves which were unaffected by propranolol. More-over, the S-nitrosothiols closely resembled nitroprusside and glyceryl trinitrate with respect to certain hemodynamic effects such as onset and duration of their effects on blood pressure and cardiac output. The finding that the/2 for decomposition of S-nitrosothiols is decreased by over 500-fold at 37#{176} Cin the presence of oxygen supports our hypothesis that the vasodi-lator action of organic nitrates and nitrites, NaNO2, nitroprusside and NO are attributed, at least in part, to the formation of active, unstable, intermediate S-nitrosothiols.

The vasodepressor action of organic nitrates and nitrites has been known for over 130 years. Sodium nitroprusside, an inorganic nitroso compound(nitroferricyanide), has been employed sporadically as a hypotensive drug for over 50 years. Despite the widespread clinical use ofsuch vasodilators in the treatment ofangina, acute congestive heart failure and hypertensive emergencies, their mechanisms of action remain uncertain. An important advance on the mechanism of vasodilator action of