Prostaglandin H2/thromboxane A2 pathway in platelet aggregation and activity of Dahl salt-sensitive rat--a sulotroban study.
It has been postulated that the main proaggregatory effect of thromboxane A2 (TxA2) is mediated by an inhibition of adenylate cyclase/cAMP complex, an effect similar to that of Na+ ion. The possibility of a modulation of the effect of Na+ on in vivo and in vitro platelet function of Dahl salt-sensitive (Dahl-S) and Dahl salt-resistant (Dahl-R) rats was investigated. Sulotroban, a powerful antagonist of prostaglandin peroxides and TxA2 was administered at doses of 1, 3 and 10 micrograms/kg/min. In vivo platelet activity was estimated on the basis of bleeding time and thrombocytopenia produced by i.v. bolus injection of 100 micrograms/kg collagen, and by plasma measurement of the stable prostacyclin and TxA2 analogs. In vitro aggregation was induced by collagen at concentrations of 10, 20, 30 and 40 micrograms/ml. Main blood pressure was measured directly in common carotid artery. The results showed that sulotroban did not produce hypotensive effects but did increase the bleeding time almost 2-fold. Plasma TxA2 levels were significantly increased in both Dahl-S and Dahl-R rats. The inhibition of collagen-induced aggregation and thrombocytopenia by sulotroban was negligible on Dahl-R rats but significant in Dahl-S rats. The results suggested a blocking effect of sulotroban not only on stimulus/receptor TxA2 complex but also on the inhibitory unit of adenylate cyclase complex, confirming this pathway of TxA2-induced aggregation.
Somova
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Department of Human Physiology and Physiological Chemistry, University of Durban-Westville, South Africa.
D000818:Animals; D001760:Bleeding Time; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010976:Platelet Count; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000097:blood* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000097:blood / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000097:blood* / Q000502:physiology
D010975:Platelet Aggregation Inhibitors; D011463:Prostaglandins H; D013449:Sulfonamides; D044262:Prostaglandin H2; D013928:Thromboxane A2; C040624:sulotroban; D003094:Collagen; D012964:Sodium