Inhibition of human platelet aggregation by nitric oxide donor drugs: Relative contribution of cGMP-independent mechanisms

Inhibition of platelet activation by nitric oxide (NO) is not exclusively c GMP-dependent. Here, we tested whether inhibition of platelet aggregation b y structurally distinct NO donors is mediated by different mechanisms, part ly determined by the site of NO release. Glyceryl trinitrate (GTN), sodium nitroprusside (SNP), S-nitrosoglutathione (GSNO), diethylamine diazeniumdio late (DEA/NO), and a novel S-nitrosothiol, RIG200, were examined in ADP (8 muM)- and collagen (2.5 mug/ml)-activated human platelet rich plasma. GTN w as a poor inhibitor of aggregation whilst the other NO donors inhibited agg regation, irrespective of agonist. These effects were abolished by the NO s cavenger, hemoglobin (Hb; 10 muM, P < 0.05, n = 6), except with high concen trations of DEA/NO, when NO concentrations exceeded the capacity of Hb. How ever, experiments with the soluble guanylate cyclase inhibitor, ODQ (100 <m u>M), indicated that only SNP-mediated inhibit-ion was exclusively cGMP-dep endent. Furthermore, the cGMP-independent effects of S-nitrosothiols were d istinct from those of DEA/NO, suggesting that different NO-related mediator s (e.g., nitrosonium and peroxynitrite, respectively) are responsible for t heir actions. (C) 2000 Academic Press.