Delay of the initiation of hypertension in spontaneously hypertensive rats by CV-4151, a specific thromboxane A2 synthetase inhibitor.
When CV-4151, a specific thromboxane (TX) A2 synthetase inhibitor, was given orally to 4 week old (4w) spontaneously hypertensive rats (SHR) daily for 3 weeks, the initiation of hypertension was delayed by about one week. The agent increased urinary excretion of water, sodium and creatinine, reduced that of TXA2 (as TXB2), increased that of PGI2 (as 6-keto-PGF1 alpha) and enhanced urinary PGI2/TXA2. In 4w Wistar-Kyoto rats (WKY) and 18w SHR was established hypertension, the agent had little effect on blood pressure and renal function. In isolated, perfused kidneys of 6w SHR, CV-4151 markedly inhibited both arachidonic acid-induced pressor action and production of TXA2. TXA2 synthetase activity in renal cortical microsomes of 5w SHR was approximately 1.5 times higher than that in age-matched WKY. CV-4151 inhibited TXA2 synthetase activity of medullary and cortical microsomes more effectively in 5w SHR than in age-matched WKY. Thus, in young SHR, the TXA2 synthetase inhibitor seemed to improve renal function by altering the balance of renal TXA2 and PGI2 biosynthesis and subsequently caused a delay in the initiation of hypertension. The present findings lend support to the idea that an imbalance in the renal TXA2-PGI2 biosynthesis may be involved in the initiation of hypertension in SHR.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000209:etiology*; D007668:Kidney / Q000187:drug effects; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011453:Prostaglandins / Q000378:metabolism / Q000652:urine; D011725:Pyridines; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012083:Renin / Q000097:blood; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013931:Thromboxanes / Q000096:biosynthesis*; D014661:Vasoconstriction / Q000187:drug effects
D001095:Arachidonic Acids; D005229:Fatty Acids, Monounsaturated; D011453:Prostaglandins; D011725:Pyridines; D013931:Thromboxanes; D016718:Arachidonic Acid; D013928:Thromboxane A2; D010088:Oxidoreductases; D012083:Renin; D013930:Thromboxane-A Synthase; C045446:isbogrel