Exhibition of anti-platelet effect of isocarbacyclin methyl ester and its free acid via an increase in cAMP in platelets.
Isocarbacyclin methyl ester (CAS 88931-51-5, TEI-9090) and its free acid (CAS 88911-35-7, TEI-7165) are chemically stable analogues of prostaglandin (PG) I2. The cAMP increasing activities of TEI-9090 and TEI-7165 were investigated. TEI-9090, TEI-7165, PGI2, and PGE1 caused the accumulation of cAMP in rabbit and human platelets. The effects of TEI-9090, TEI-7165, and PGE1 were longer lasting than the effect of PGI2. Each drug concentration-dependently increased the cAMP level in rabbit and human platelets. The order of cAMP-increasing activity was PGI2 > PGE1 = TEI-9090 = TEI-7165 in rabbit platelets and PGI2 > TEI-9090 = TEI-7165 > PGE1 in human platelets. The antiplatelet aggregation activity of TEI-9090 in rabbit and human platelets was remarkably decreased by the addition of an esterase inhibitor, diisopropyl fluorophosphate (DFP). However, this activity of TEI-7165 was not affected by the inhibitor. In the presence of DFP, the cAMP accumulation by TEI-9090 in rabbit platelets was almost completely inhibited but that by TEI-7165 was not inhibited. These results suggest that TEI-9090 is deesterified to TEI-7165 and that this free acid then inhibits platelet aggregation via an increase in the cAMP level in the platelets.
D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007531:Isoflurophate / Q000494:pharmacology; D008297:Male; D010277:Parasympathomimetics / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D014407:Tumor Cells, Cultured
D010277:Parasympathomimetics; D010975:Platelet Aggregation Inhibitors; D007531:Isoflurophate; C052840:TEI 9090; C041946:9-O-methanoprostaglandin I; D011464:Epoprostenol; D000242:Cyclic AMP; D000527:Alprostadil