Renal protection by a dual ETA/ETB endothelin antagonist, L-754,142, after aortic cross-clamping in the dog

• Published in: Journal of the American Society of Nephrology 1997-07, Vol.8 (7), p.1061-1071
• Main Authors: KRAUSE, S. M, WALSH, T. F, GREENLEE, W. J, RANAEI, R, WILLIAMS, D. L, KIVLIGHN, S. D
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Acute Kidney Injury - etiology; Acute Kidney Injury - prevention & control; Animals; Aorta - surgery; Biological and medical sciences; Constriction; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Endothelin-1 - physiology; Female; Glomerular Filtration Rate - drug effects; Hemodynamics - drug effects; Ischemia - drug therapy; Ischemia - physiopathology; Kidney - blood supply; Kidney - drug effects; Kidney - physiopathology; Male; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Postoperative Complications - etiology; Postoperative Complications - prevention & control; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin - physiology; Renal Circulation - drug effects; Renal failure; Vascular Resistance - drug effects
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.V871061

Renal insufficiency is a significant complication that occurs after surgical procedures, requiring cross-clamping of the aorta. The mechanism for this renal dysfunction is currently not known, but studies suggest a potential role of endothelin in mediating the insufficiency. Accordingly, the role of endothelin was assessed using the nonpeptidyl, dual ETA/ETB endothelin antagonist L-754,142 in a model of renal insufficiency in the anesthetized dog induced by cross-clamping the suprarenal aorta for 60 min, followed by 2 h of reperfusion. In vehicle-treated animals (saline, n = 8) after 2 h of reperfusion, plasma [ET-1] increased 66% and renal blood flow (RBF) was reduced by 38% compared with baseline. This decline was associated with an 84% increase in renal vascular resistance and a 54% reduction in GFR (baseline, 46 +/- 5 ml/min; 21 +/- 3 ml/min at 2 h; P < 0.01) and sodium reabsorption (baseline, 6.7 +/- 0.7 microEq/min; 3.0 +/- 0.5 microEq/min at 2 h, P < 0.01). After baseline measurements, pretreatment with L-754,142 at 0.3 mg/kg bolus + 0.1 mg/kg per h continuous infusion (low dose; n = 8) or 3.0 mg/kg bolus + 1 mg/kg per h infusion (high dose; n = 8) initiated 45 min before aortic cross-clamp led to a dose-dependent normalization of RBF and renal vascular resistance within 2 h of cross-clamp removal. GFR was also improved and returned to within 75% of baseline (P < 0.01 versus vehicle) by 2 h of reperfusion with L-754,142 (baseline, 55 +/- 5 ml/min; 42 +/- 5 ml/min at 2 h with the high dose). The improvement of GFR with L-754,142 treatment was associated with a preservation of sodium reabsorption compared with vehicle-treated animals. This study supports a role of endothelin in the pathogenesis of renal insufficiency after aortic cross-clamping and demonstrates that pretreatment with the dual ETA/ETB endothelin antagonist L-754,142 preserves RBF and sodium reabsorption, leading to a significant improvement in GFR.