Differential effect of a selective cyclooxygenase-2 inhibitor versus indomethacin on renal blood flow in conscious volume-depleted dogs.
Renal effects of a selective cyclooxygenase-2 (COX-2) inhibitor [MF-Tricyclic; 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone] were studied in control and volume-depleted conscious dogs. MF-Tricyclic was compared with the nonselective COX-1/COX-2 inhibitor indomethacin. Six instrumented male dogs were randomly selected to receive MF-Tricyclic or indomethacin at 10 mg/kg. Volume depletion was effected by a sodium-restricted diet (14 days) with administration of furosemide (7.5 mg/kg, i.v.) the day before the experiment. Indomethacin ablated systemic COX-1 activity (p < 0.05), whereas MF-Tricyclic did not affect this activity. Each compound achieved plasma concentrations in excess of their respective median inhibitory concentrations (IC50 values) against canine COX-2. In controls, neither compound affected mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF), fractional excretion (FE) Na+, or FE K+. In volume-depleted dogs, indomethacin reduced RBF (p < 0.05), whereas MF-Tricyclic did not affect this parameter. Indices of renal function in volume-depleted dogs were not affected. These data are consistent with the view that the effects of indomethacin on RBF are a consequence of inhibition of COX-1 activity. Furthermore, in these studies, short-term administration of a selective COX-2 inhibitor was without deleterious effects on renal function.
Black
S C
SC
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada.
Brideau
C
C
Cirino
M
M
Belley
M
M
Bosquet
J
J
Chan
C C
CC
Rodger
I W
IW
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000652:urine; D004285:Dogs; D005663:Furans / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007213:Indomethacin / Q000097:blood / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects*; D012083:Renin / Q000097:blood
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin; D015232:Dinoprostone; D007213:Indomethacin