Nonpeptide endothelin receptor antagonists. V: Prevention and reversal of acute renal failure in the rat by SB 209670.
The ability of the mixed endothelin (ETA/ETB) receptor antagonist (+/-)-SB 209670 to prevent and reverse ischemia-induced acute renal failure (ARF) was studied in rats with moderate and severe ARF. Uninephrectomized, chronically instrumented Sprague-Dawley rats were used. Moderate and severe ARF was induced by occlusion of the renal artery for 30 and 45 min, respectively. During the 24 hr after 30-min ischemia (moderate ARF), glomerular filtration rate (GFR) decreased by 95%, and fractional excretion of sodium increased from 0.6% to 10%. Infusion of (+/-)-SB 209670 at 10, 30 and 100 micrograms/kg.min for 30 min before, during and 60 min after renal ischemia had a moderate effect on renal function. Thus, with the highest dose, the ischemia-induced reduction in GFR was 70%. This dose, however, had no effect in rats when given before, during and after 45 min of renal ischemia (severe ARF). In contrast, when infused at 30 micrograms/kg.min for 3 hr on the day after ischemia, (+/-)-SB 209670 markedly increased survival rate (75%) in rats with severe ARF by significantly increasing tubular reabsorption of Na+, followed by a slow and gradual increase in GFR and reversal of the increase in plasma K+ concentration. Data from acute renal clearance studies in rats with moderate ARF showed that when infused 24 hr after ischemia, (+/-)-SB 209670 acutely reversed the impairment in sodium reabsorption without increasing GFR or renal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Gellai
M
M
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Jugus
M
M
Fletcher
T
T
Nambi
P
P
Ohlstein
E H
EH
Elliott
J D
JD
Brooks
D P
DP
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D007189:Indans / Q000627:therapeutic use*; D007511:Ischemia / Q000150:complications; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D007189:Indans; 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)-