Elevation of platelet cyclic AMP level by thromboxane A2/prostaglandin H2 receptor agonists.
Arachidonic acid (AA)- or thromboxane A2/prostaglandin H2 (TXA2/PGH2) analog (STA2 and U-46619)-induced aggregations yielded a bell-shaped dose-response curve. The inhibitory mechanism by high concentrations of the agonists was examined. STA2 elevated cAMP level of platelet in a dose-dependent manner. And the aggregation was affected by metabolic inhibitors of cAMP. AA also rised cAMP level, and the rise was suppressed by indomethacin. These results indicate that the reduction of aggregation by high dose of the agonists is through cAMP elevation. The cAMP elevation was not suppressed by ruling out phospholipase C effects by chelation of cytoplasmic Ca2+ and inhibition of protein kinase C (PKC). These results suggest that the cAMP elevation is not due to activation of phospholipase C-linked TXA2/PGH2 receptor. 13-APA, an antagonist of TXA2/PGH2 receptor, suppressed the cAMP elevation, although ONO-3708, another antagonist, had no effect. As to be expected from this result, inhibitory effect of 13-APA on high STA2 level-induced aggregation was weaker than that of ONO-3708. The antagonists did not inhibit PGE1- or PGD2-induced cAMP elevation. These findings suggest that platelet has adenylate cyclase-linked TXA2/PGH2 receptor.
Ishikawa
Y
Y
Japanese Red Cross Central Blood Center, Tokyo.
Ogawa
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000527:Alprostadil / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology*; D000242:Cyclic AMP / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000187:drug effects; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D013931:Thromboxanes
D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C037866:STA 2; D000242:Cyclic AMP; D000527:Alprostadil; D015230:Prostaglandin D2