Nonpeptide endothelin receptor antagonists. III. Effect of SB 209670 and BQ123 on acute renal failure in anesthetized dogs.
Endothelin (ET) is a potent vasoconstrictor that has been implicated in the pathogenesis of acute renal failure (ARF). In order to investigate the potential role of ET in ARF in the dog, the effect of a mixed ETA and ETB receptor antagonist, (+/-)-SB 209670, [(1RS-2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-5- (prop-1-yloxy) indane-2-carboxylic acid], and a selective ETA antagonist, BQ123, were evaluated in anesthetized uninephrectomized dogs undergoing 60 min of renal occlusion. (+/-)-SB 209670 (1 microgram/kg/min) and BQ123 (10 micrograms/kg/min) were infused directly into the renal artery (intrarenal) for 30 min before renal occlusion, during occlusion and for 60 min after reperfusion at doses that inhibited the renal vasoconstrictor effects of intrarenal renal artery infusions of ET-1. Renal occlusion resulted in a significant reduction in inulin clearance (from 26.2 +/- 1.8 to 3.2 +/- 1.1 ml/min). This response was significantly (P < .05) attenuated by (+/-)-SB 209670 (from 23.5 +/- 2.2 to 7.6 +/- 2.0 ml/min) but not by BQ123 (from 23.5 +/- 1.7 to 4.9 +/- 1.2 ml/min). Endogenous creatinine clearance showed the same pattern. After renal artery occlusion, fractional sodium and fractional potassium excretions were increased significantly. (+/-)-SB 209670, but not BQ123, resulted in a significant reduction in fractional sodium; however, neither compound altered fractional potassium excretion. The data suggest that ET receptor antagonists, possibly by altering tubular sodium reabsorption, may be beneficial in ischemia-induced ARF.
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
D P
DP
Brooks
P D
PD
dePalma
M
M
Gellai
P
P
Nambi
E H
EH
Ohlstein
J D
JD
Elliott
J G
JG
Gleason
R R
RR
Ruffolo
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007511:Ischemia / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D012079:Renal Circulation / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; D010456:Peptides, Cyclic; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; C072247:cyclo(Trp-Asp-Pro-Val-Leu)