Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation.
Recent studies have suggested that cyclic GMP accumulation in platelets mediates the antiaggregatory effects of certain nitrogen oxide-containing agents such as sodium nitroprusside, nitric oxide, nitrosoguanidines, and related agents. The vasodilator effect of these agents may involve the formation of S-nitrosothiol intermediates which relax vascular smooth muscle, elevate tissue levels of cyclic GMP, and activate guanylate cyclase. The purpose of this study was to investigate the effects of various synthetic S-nitrosothiols on human platelet aggregation. The S-nitroso derivatives of N-acetylpenicillamine, cysteine, and beta-D-thioglucose inhibited human platelet aggregation in a concentration-dependent fashion when ADP, collagen, U46619, or sodium arachidonate was employed as the aggregating agent. The antiaggregatory effects of the S-nitrosothiols were associated with a rapid and marked increase in intracellular platelet cyclic GMP levels, whereas cyclic AMP levels remained unchanged. Additionally, S-nitrosothiols disaggregated platelets which had been aggregated while concomitantly elevating platelet cyclic GMP levels. Moreover, guanylate cyclase, partially purified from the soluble fraction of human platelets, was markedly activated by S-nitrosothiols in a heme-dependent manner. Methemoglobin, a hemoprotein with a high affinity for nitric oxide, partially reversed the antiaggregatory effects, attenuated the accumulation of cyclic GMP, and inhibited the activation of guanylate cyclase by S-nitrosothiols. These data are consistent with the hypothesis that S-nitrosothiols could serve as active intermediates in the inhibitory action of sodium nitroprusside, nitric oxide, and related nitrogen oxides on platelet aggregation.
D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000097:blood*; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000097:blood*; D006418:Heme / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009603:Nitroso Compounds / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D012995:Solubility; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D006418:Heme; D000242:Cyclic AMP; D006162:Guanylate Cyclase