Endothelins modulate in vitro aggregation of human platelets in a bi-directional manner. Thus endothelin-1 has been shown to act as a potentiator of primary aggregation and an inhibitor of secondary aggregation. The endothelin receptors and corresponding second messengers which cause these effects have not yet been characterised. This study investigated the effect of endothelin-1, an agonist at both the ETA and the ETB receptors and sarafotoxin (SRTX) S6c, a selective ETB agonist, on human platelet cyclic nucleotide levels. Neither endothelin-1 (10(-11) -10(-7) M) nor SRTX S6c (10(-11) -10(-7) M) significantly altered platelet cAMP levels. In contrast, both agonists produced a dose-dependent increase in platelet cGMP. From these data, we conclude that activation of the ETB receptor in human platelets is responsible for an increase in platelet cGMP and may contribute to the inhibition of platelet aggregation caused by the endothelins.