Thromboxane synthase inhibition enhances furosemide-induced renal vasodilation.
The effects of furegrelate (a thromboxane synthase inhibitor), indomethacin, and the combination on urine volume (V), para-aminohippurate clearance (CPAH), and mean arterial pressure (MAP) before and after intravenous furosemide were examined in Sprague-Dawley rats. Prior to furosemide, none of the treatments changed MAP, V, or CPAH. Furosemide increased urine volume from 16 +/- 7 to 148 +/- 25 microL.min-1. Concomitant administration of furegrelate or indomethacin did not affect furosemide-induced diuresis, but the combination of indomethacin, furegrelate, and furosemide caused increased diuresis (to 254 +/- 40 microliters.min-1, p < 0.05, compared with furosemide alone). Furosemide alone or with the other drugs had no effect on mean arterial pressure. CPAH was increased from 3.0 +/- 0.4 to 4.6 +/- 0.8 ml.min-1.100g-1 (p < 0.05, n = 6) by furosemide, and to an even greater extent (6.7 +/- 0.8, n = 6) after pretreatment with furegrelate. Pretreatment with indomethacin alone or in combination with furegrelate abolished the furosemide-induced CPAH increment. Urine excretion of the prostacyclin hydrolysis product 6-ketoprostaglandin F1 alpha was increased by furosemide in the presence of furegrelate. Given that the transient renal vasodilation with furosemide is due to prostanoid precursor release, these results are consistent with redirection of arachidonate metabolism toward vasodilator prostaglandins by furegrelate.
Wilson
T W
TW
Cardiovascular Risk Factor Reduction Unit, University of Saskatchewan, Saskatoon.
Badahman
A H
AH
Kaushal
R D
RD
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004347:Drug Interactions; D005665:Furosemide / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014664:Vasodilation / Q000187:drug effects*; D010130:p-Aminohippuric Acid / Q000652:urine
D001572:Benzofurans; D015121:6-Ketoprostaglandin F1 alpha; D005665:Furosemide; D013930:Thromboxane-A Synthase; C039936:furegrelate; D007213:Indomethacin; D010130:p-Aminohippuric Acid