Studies on antiplatelet effects of OP-41483, a prostaglandin I2 analog, in experimental animals. II. Mechanism of its antiplatelet effect.
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.
Fujitani
B
B
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Wakitani
K
K
D000244:Adenosine Diphosphate / Q000097:blood; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000097:blood; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D016048:Dideoxyadenosine / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology* / Q000031:analogs & derivatives; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D013931:Thromboxanes / Q000096:biosynthesis
D010975:Platelet Aggregation Inhibitors; D013931:Thromboxanes; D016048:Dideoxyadenosine; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D000242:Cyclic AMP; D013917:Thrombin; D000262:Adenylyl Cyclases; C035847:ataprost; D002118:Calcium