The effect of endothelium-derived relaxing factor (EDRF) and related compounds on platelet aggregation in response to physiological and pathological levels of arterial wall shear stress (30-120 dyne/cm(2)) was investigated. Platelets in plasma, or washed platelets, aggregated markedly in response to shear stresses generated by a cone-plate viscometer. Pre-treatment of platelets with the S-nitrosothiol compounds S-nitroso-N-acetylcysteine or S-nitrosocysteine, or with nitric oxide (NO) or SIN-1 (which is non-enzymatically metabolized to NO), resulted in decreased platelet aggregation in response to shear stress. Non-hydrolyzable analogues of cyclic guanosine 3',5'-monophosphate (cGMP) also inhibited shear stress-induced platelet aggregation, and specific pharmacological manipulations of NO and cGMP (with methylene blue or the cGMP phosphodiesterase inhibitor M&B 22 984) resulted in alterations of intraplatelet levels of cGMP that correlated with the degree of inhibition of shear stress-induced platelet aggregation. These results demonstrate that EDRF and related compounds inhibit platelet aggregation that is initiated by shear stress, and suggest that this physiologically relevant mechanism of platelet aggregation may be regulated by intraplatelet cGMP.
