Nonpeptide endothelin receptor antagonists. V: Prevention and reversal of acute renal failure in the rat by SB 209670.

Abstract

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)

• Authors: M Gellai, M Jugus, T Fletcher, P Nambi, E H Ohlstein, J D Elliott, D P Brooks
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 275 Issue 1 Pg. 200-6 (Oct 1995) ISSN: 0022-3565 [Print] United States
• PMID: 7562550 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Endothelin Receptor Antagonists
• Indans
• 1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-

Topics

• Acute Kidney Injury (drug therapy, etiology, prevention & control)
• Animals
• Drug Evaluation, Preclinical
• Endothelin Receptor Antagonists
• Indans (therapeutic use)
• Ischemia (complications)
• Kidney (blood supply, metabolism)
• Male
• Rats
• Rats, Sprague-Dawley
• Time Factors