EFFECTS OF NITROVASODILATORS ON PLATELET CYCLIC-NUCLEOTIDE LEVELS IN RABBIT-BLOOD - ROLE FOR CYCLIC-AMP IN SYNERGISTIC INHIBITION OF PLATELET-FUNCTION BY SIN-1 AND PROSTAGLANDIN-E1

Nitrovasodilators increase both cyclic GMP and cyclic AMP in isolated platelets (Maurice DH, Haslam RJ. Mol Pharmacol 1990;37:671-81). To determine whether this occurs in blood, platelet cyclic[H-3] GMP and cyclic [H-3] AMP were measured in prelabeled rabbit platelets resuspended in modified Tyrode's solution or citrated blood. In the former medium, increases in cyclic [H-3]nucleotides in response to nitroprusside (NP) and 3-morpholinosydnonimine (SIN-1) were maximal by 1 min; in blood, maximal increases were observed only after 10 min and were much smaller. In blood, SIN-1 was more effective than the same concentration of NP. After 10 min, 100-mu-M SIN-1 increased platelet cyclic[H-3] GMP by 475 +/- 58% and cyclic[H-3] AMP by 29 +/- 7% (means +/- SEM, 18 experiments). Supraadditive increases in platelet cyclic[H-3] AMP in blood were observed when SIN-1 was combined with prostaglandin E1 (PGE1). Thus, after 10 min, SIN-1 (100-mu-M), PGE1 (20 nM), and SIN-1 + PGE1 increased cyclic[H-3] AMP by 25 +/- 7, 35 +/- 6, and 130 +/- 17%, respectively (four experiments). In the same experiments, release of platelet [C-14]serotonin by platelet-activating factor (PAF) was inhibited by 22 +/- 5, 2 +/- 2, and 61 +/- 5%, respectively. Increases in platelet cyclic-[H-3] GMP with SIN-1 were unaffected by PGE1. These results suggest that although cyclic GMP may mediate the effects of SIN-1 alone on platelet function, cyclic AMP mediates the synergistic action of SIN-1 and PGE1. M&B 22,948 (a selective cyclic GMP phosphodiesterase inhibitor) enhanced the increases in platelet cyclic[H-3] GMP and cyclic[H-3] AMP caused by SIN-1 and also increased the associated inhibition of [C-14]serotonin release. M&B 22,948 also augmented the synergistic increases in cyclic[H-3] AMP and inhibition of platelet function caused by SIN-1 + PGE1. The results show that a selected nitrovasodilator (e.g., SIN-1), a prostaglandin and a cyclic GMP phosphodiesterase inhibitor can exert synergistic effects on platelets in blood. This may be relevant to the pharmacologic management of thromboembolic disease.