Effect of furegrelate on renal plasma flow after angiotensin II infusion.
We had previously shown that selective thromboxane synthetase inhibition with furegrelate increases urinary excretion of 6-ketoPGF1 alpha, the hydrolysis product of prostacyclin after stimulation of renal prostaglandin synthesis with furosemide. The present study assessed the functional significance of this "redirection" of prostaglandin formation using a more physiologic stimulus, angiotensin II. Sprague-Dawley rats (n = 27) were fitted with a transabdominal bladder cannula. Five days later they were given angiotensin II (10 mg.kg-1.min-1) by intravenous infusion. After 30 min, an infusion of furegrelate, 2 mg/kg, then 2 mg.kg-1.h-1, (n = 9); indomethacin, 2 mg/kg, then 2 mg.kg-1.h-1 (n = 9); or vehicle, 250 microL, then 0.018 mL/min (n = 9) was begun for 60 min. Clearance of [14C]para-aminohippuric acid was taken as a measure of renal plasma flow. Angiotensin II raised the mean arterial pressure in all groups. Administration of furegrelate or indomethacin did not change mean arterial pressure or heart rate. Angiotensin II reduced [14C]p-aminohippuric acid clearance by about 32% (1.42 +/- 0.18 to 0.97 +/- 0.07 mL.min-1.100 g-1, p less than 0.05). Furegrelate attenuated this renal vasoconstriction (0.97 +/- 0.07 to 1.38 +/- 0.17 mL.min-1.100 g-1, p less than 0.05), while indomethacin increased it by a further 32% (1.78 +/- 0.12 to 1.20 +/- 0.12 mL.min-1.100 g-1, p less than 0.05). Vehicle alone had no effect. Furegrelate reduced serum thromboxane B2 by 90% (6.52 +/- 0.030 to 0.7 +/- 0.21 ng/100 microL, p less than 0.05), while indomethacin reduced it by 73% (5.9 +/- 0.99 to 1.4 +/- 0.20 ng/100 microL, p less than 0.05). We conclude that furegrelate attenuates the renal vasoconstriction of angiotensin II, presumably by enhancing the formation of vasodilator prostaglandins.
Kaushal
R D
RD
Department of Pharmacology, University of Saskatchewan, Saskatoon, Canada.
Wilson
T W
TW
D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D010130:p-Aminohippuric Acid / Q000097:blood
D001572:Benzofurans; D000804:Angiotensin II; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase; C039936:furegrelate; D007213:Indomethacin; D010130:p-Aminohippuric Acid