Studies on inhibition of human platelet function by sodium nitroprusside. kinetic evaluation of the effect on aggregation and cyclic nucleotide content

In this study, we explored the ability of sodium nitroprusside to inhibit t he aggregation of human platelets in platelet-rich plasma (PRP) and whole b lood and its effects on intracellular levels of guanosine 3',5'-cyclic mono phosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). The exper iments investigated dose-dependent effects of nitroprusside starting from c oncentrations in the range of circulating levels achievable in vivo during drug administration in humans. Furthermore, we investigated the timecourse of both antiaggregating action and the influence on cyclic nucleotide synth esis. Results showed that sodium nitroprusside inhibited the aggregation in duced by adenosine 5-diphosphate (ADP) and collagen starting from concentra tion as low as 2 mu mol/l. The IC50 value for ADP-induced aggregation in PR P was 18.7 +/- 2.4 mu mol/l. The inhibition of platelet aggregation showed a time-dependent behaviour and was not reversible within 90 min. The accumu lation of intraplatelet cGMP in the presence of sodium nitroprusside exhibi ted a comparable time-course characterized by an early increase, a steady s tate and a late further increase. The time-course of cAMP synthesis was ver y similar to that of cGMP. Our data evidenced a long-lasting inhibition of platelet responses by sodium nitroprusside and excluded a desensitization o f platelet guanylyl cyclase after 3-h exposure to nitric oxide (NO). Furthe rmore, they indicated a role of cAMP accumulation in the antiaggregating ef fects of nitroso donor: the simultaneous increase of intracellular content of cAMP and cGMP can synergize in the reduction of the platelet responses. (C) 2001 Elsevier Science Ltd. All rights reserved.