Antiplatelet functions of a stable prostacyclin analog, SM-10906 are exerted by its inhibitory effect on inositol 1,4,5-trisphosphate production and cytosolic Ca++ increase in rat platelets stimulated by thrombin.
The mechanism of the antiplatelet functions of SM-10906, the active form of the 3-oxa-methano-prostaglandin (PG) I1 analog SM-10902, was examined in rat platelets. SM-10906 activated adenylate cyclase in crude membrane fractions, and inhibited platelet aggregation and release of adenine nucleotides stimulated by thrombin. SM-10906 also inhibited malondialdehyde production induced by thrombin, but not that induced by arachidonic acid. This may account for its inhibitory effects on phospholipase A2. SM-10906 prevented thrombin-induced inositol 1,4,5-trisphosphate production, Ca++ mobilization from intracellular Ca storage and 45Ca++ influx into platelets, which were all reversed by pretreatment with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine. PGI2 and PGE1 have the same antiplatelet profiles in the order of PGI2 > or = SM-10906 > PGE1. These results indicate that SM-10906 as well as PGI2 and PGE1 may exert antiplatelet activities by stimulating adenylate cyclase to prevent thrombin-induced phospholipase C and A2 activations and increase in cytosolic Ca++ level.
Research Center, Sumitomo Pharmaceuticals Co., Osaka, Japan.
T
T
Nishimura
T
T
Yamamoto
Y
Y
Komuro
Y
Y
Hara
D000262:Adenylyl Cyclases / Q000378:metabolism; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; C086699:SM 10906; D015544:Inositol 1,4,5-Trisphosphate; D011464:Epoprostenol; D013917:Thrombin; D000262:Adenylyl Cyclases; D000527:Alprostadil; D002118:Calcium