Open AccessStudies on Antiplatelet Effects of OP-41483, a Prostaglandin l2 Analog, in Experimental Animals II. Mechanism of Its Antiplatelet Effect
Author(s) -
Buichi Fujitani,
Korekiyo Wakitani
Publication year - 1990
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.53.25
Subject(s) - platelet , chemistry , cyclase , adenylate kinase , thromboxane a2 , prostaglandin , dissociation constant , thromboxane , thrombin , ic50 , biochemistry , medicine , endocrinology , biophysics , receptor , in vitro , biology
The mechanism for the inhibition of platelet functions by a prostaglandin I2 analog, OP-41483, was studied with guinea pig platelets. OP-41483, and PGI2 as well, inhibited aggregation, ADP release and thromboxane formation of platelets with IC50 values of 4.3-5.8 ng/ml and 0.6-0.9 ng/ml, respectively. The ligand binding study using [3H]-OP-41483 suggested that OP-41483 bound with different affinities to two classes of binding sites on platelets. The dissociation constant of OP-41483 for the higher affinity site corresponded to the IC50 values of its antiplatelet effect. PGI2 as well as OP-41483 displaced [3H]-OP-41483 previously bound to platelets, thus indicating that both agents exerted their antiplatelet effects by binding to the same site on platelets. OP-41483 and PGI2 activated adenylate cyclase and raised cyclic AMP levels in platelets. However, their inhibitory effect on platelet aggregation was not fully antagonized by an adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA), at a concentration completely inhibiting the increase of cyclic AMP. Moreover, this DDA-resistant effect of OP-41483 disappeared in the presence of calcium chloride (10(-4)-10(-3) M). OP-41483 and PGI2 inhibited thrombin-induced Ca++ influx into platelets. The inhibition of Ca++ influx was not reversed by DDA. Based on these results, we speculate that the inhibitory effects of OP-41483 and PGI2 on platelet functions are produced through dual mechanisms: one mediated by activation of adenylate cyclase and the other by an inhibition of Ca++ influx; and these two mechanisms seem to be independent of each other.