Testing the "redirection hypothesis" of prostaglandin metabolism in the kidney.
Furosemide increases the synthesis of two major renal eicosanoids, prostacyclin (PGI2) and thromboxane A2 (TXA2), by stimulating the release of arachidonic acid which in turn is metabolized to PGG2/PGH2, then to PGI2 and TXA2. PGI2 may mediate, in part, the early increment in plasma renin activity (PRA) after furosemide. We hypothesized that thromboxane synthetase inhibition should direct prostaglandin endoperoxide metabolism toward PGI2, thereby enhancing the effects of furosemide on renin release. Furosemide (2.0 mg . kg-1 i.v.) was injected into Sprague-Dawley rats pretreated either with vehicle or with U-63,557A (a thromboxane synthetase inhibitor, 2 mg/kg-1 followed by 2 mg/kg-1 X hr-1). Urinary 6ketoPGF1 alpha and thromboxane B2 (TXB2), reflecting renal synthesis of PGI2 and TXA2, as well as PRA and serum TXB2, were measured. Serum TXB2 was reduced by 96% after U-63,557A. U-63,557A did not affect the basal PRA. Furosemide increased PRA in both vehicle and U63,557A treated rats. However, the PRA-increment at 10, 20 and 40 min following furosemide administration was greater in U-63,557A-treated rats than in vehicle-treated rats and urine 6ketoPGF1 alpha excretion rates were increased. These effects of thromboxane synthesis inhibition are consistent with a redirection of renal PG synthesis toward PGI2 and further suggest that such redirection can be physiologically relevant.
Datar
S
S
McCauley
F A
FA
Wilson
T W
TW
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D004347:Drug Interactions; D005665:Furosemide / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001572:Benzofurans; D011453:Prostaglandins; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D005665:Furosemide; D012083:Renin; D013930:Thromboxane-A Synthase; C039936:furegrelate