Role of cyclic AMP and cyclic GMP as modulators of platelet cytosolic calcium

Abstract

Studies from our laboratory at the University of Minnesota as well as that of others have demonstrated that agonist-mediated receptor stimulation leads to the activation of phospholipase C and formation of second messengers, diacyl glycerol and inositol trisphosphate, and mobilization of cytosolic free calcium. Elevation in intracellular calcium activates phospholipase A2 and release of arachidonic acid. This fatty acid is further converted to active metabolites, prostaglandin endoperoxides, and thromboxanes (TXA 2 ). TXA 2 promote fibrinogen binding, irreversible aggregation, and the release of granule contents, including serotonin and ADP. Agents that promote irreversible aggregation, facilitate fibrinogen binding, and those drugs that dissociate this process do so by lowering the cytosolic calcium levels. Endogenous antagonists such as PGE 1 , PGI 2 , and NO exert their inhibitory effect on platelet function by the action of cyclic nucleotides, cyclic AMP and cyclic GMP. Epinephrine-induced modulation of alpha-adrenergic receptor restores the action of agonists in drug-induced refractory platelets. As far as the role of cyclic nucleotides is considered, the observations are consistent with the concept that cyclic nucleotides participation in the biologic regulation may be modulated by cytoplasmic cations, and that a change in intracellular cyclic nucleotides and appropriate cations serves to promote the participation of both regulatory effectors. Anti-platelet drugs such as aspirin, indomethacin, and PGE 1 do not inhibit platelet interactions with the vessel wall. Based on this collective knowledge, novel antiplatelet drugs should be developed for the prevention of acute vascular events.