INHIBITION OF HUMAN-PLATELET AGGREGATION BY S-NITROSOTHIOLS - HEME-DEPENDENT ACTIVATION OF SOLUBLE GUANYLATE-CYCLASE AND STIMULATION OF CYCLIC-GMP ACCUMULATION

  • 1 January 1983
    • journal article
    • research article
    • Vol. 23  (3) , 653-664
Abstract
CGMP accumulation in platelets apparently 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 cGMP and activate guanylate cyclase. The effects of various synthetic S-nitrosothiols on human platelet aggregation were investigated. The S-nitroso derivatives of N-acetylpenicillamine, Cys and .beta.-D-thioglucose inhibited human platelet aggregation in a concentration-dependent fashion when ADP, collagen, U46619 [(15S)-hydroxy-11.alpha., 9.alpha.-(epoxymethano)prosta-5Z,13E-dienoic acid], 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 cGMP levels, whereas cAMP levels remained unchanged. S-nitrosothiols disaggregated platelets which were aggregated while concomitantly elevating platelet cGMP levels. 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 cGMP, and inhibited the activation of guanylate cyclase by S-nitrosothiols. S-nitrosothiols may serve as active intermediates in the inhibitory action of sodium nitroprusside, nitric oxide and related nitrogen oxides on platelet aggregation.