Reversal of postischemic acute renal failure with a selective endothelinA receptor antagonist in the rat.
Studies were designed to examine the effect of a selective endothelinA (ETA) receptor antagonist, BQ123, on severe postischemic acute renal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in uninephectomized, chronically instrumented rats by 45-min renal artery occlusion. BQ123 (0.1 mg/kg.min) or vehicle was infused intravenously for 3 h on the day after ischemia. Measurements before infusion (24 h control) showed a 98% decrease in glomerular filtration rate (GFR), increase in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicle-treated rats died in 4 d because of continuous deterioration of renal function, resulting in an increase of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ123 significantly improved survival rate (75%) by markedly improving tubular reabsorption of Na+ and moderately increasing GFR and K+ excretion. Plasma K+ returned to basal levels by the 5th d after ischemia. Improved tubular function was followed by gradual recovery in GFR and urinary concentrating mechanism. Additional data from renal clearance studies in rats with moderate ARF (30-min ischemia) and in normal rats with intact kidneys showed that ETA receptor blockade increases Na+ reabsorption and has no effect on renal hemodynamics. These results indicate that in the rat, the ETA receptor subtype mediates tubular epithelial function, and it plays a significant role in the pathogenesis of ischemia-induced ARF. Treatment with the selective ETA receptor antagonist reverses deteriorating tubular function in established ARF, an effect of possible therapeutic significance.
Gellai
M
M
SmithKline Beecham Pharmaceuticals, Department of Renal Pharmacology, King of Prussia, Pennsylvania 19406.
Jugus
M
M
Fletcher
T
T
DeWolf
R
R
Nambi
P
P
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007511:Ischemia / Q000150:complications / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D009392:Nephrectomy; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011188:Potassium / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000502:physiology; D012964:Sodium / Q000652:urine; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D012964:Sodium; D011188:Potassium; C072247:cyclo(Trp-Asp-Pro-Val-Leu)