The effects of ethanol on cyclic GMP (cGMP) in washed human platelets were studied in the presence and absence of sodium nitroprusside (SNP), nitric oxide donor which stimulates guanylate cyclase. SNP stimulated cGMP accumulation in a dose-dependent fashion. After 1 min exposure to 100 microM SNP, the level of cGMP was approximately four-fold that in vehicle-treated platelets. Alcohol had no effect on basal cGMP, but inhibited SNP-induced cGMP accumulation at 17, 85 and 170 mM. In further experiments, platelets were incubated for 0, 0.5, 1 2 or 5 min with 10 microM SNP, with or without 100 microM zaprinast, a selective cGMP-phosphodiesterase (PDE) inhibitor and 85 mM ethanol. In the presence of zaprinast but not alcohol, cGMP levels rose continuously, to 10-fold the basal level at 5 min. Without zaprinast, cGMP levels were lower and reached a plateau by 2 min. Accumulation of cGMP was attenuated by alcohol 2 and 5 min after SNP addition, both in zaprinast-treated platelets and those without zaprinast. Thus, alcohol inhibits platelet cGMP accumulation stimulated by nitric oxide donor. Its mechanism probably does not involve a major effect on PDE, because the inhibition was observed in the presence or absence of zaprinast. We hypothesize that alcohol inhibits guanylate cyclase, contributing to its complex functional effects in platelets.