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Differential Effects of Endothelin-1 Antagonists on Erythropoietin-Induced Hypertension in Renal Failure

Research Centre and Division of Nephrology, CHUQ, L'Hôtel-Dieu de Québec Hospital and Department of Medicine, Laval University, Quebec, Canada.

Correspondence to Dr. Marcel Lebel, Centre de Recherche, CHUQ - L'Hôtel-Dieu de Québec, 11 Côte du Palais, Quebec, Canada G1R 2J6. Phone: 418-691-5580; Fax: 418-691-5429; E-mail: marcel.lebel{at}crhdq.ulaval.ca

Abstract. Recently, it was reported that blood vessel immuno-reactive endothelin-1 (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1 receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ET_A and nonselective ET_A/ET_B receptor antagonists are equally effective. Renal failure was induced by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and hypertension. After a 4-wk stabilization period, the animals received either rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4 wk. In protocol A, half of the rats in each group were simultaneously treated with the ET_A/ET_B receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ET_A receptor antagonist LU135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk after the onset of treatment. Serum creatinine levels and hematocrit were measured before treatment and at the end of the study. Creatinine clearance rates and plasma irET-1 concentrations were determined at the end of the study. rhEPO corrected the anemia, but aggravated the hypertension. There was a slight and similar increase in serum creatinine throughout the treatment period in all groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle (P < 0.05). Treatment with LU135252 corrected the increase in BP in rhEPO-treated rats (160 ± 7 mmHg versus 187 ± 9 mmHg, P < 0.05). In contrast, bosentan did not attenuate the progression of hypertension in rhEPO-treated rats (172 ± 10 mmHg versus 168 ± 9 mmHg, NS). In summary, selective ET_A but not ET_A/ET_B receptor blockade can prevent the aggravation of hypertension in renal failure rats treated with rhEPO. These results suggest that the endothelin system may be involved in the pathogenesis of rhEPO-induced hypertension in uremic rats with a differential role for ET_A and ET_B receptors.

This article has been cited by other articles:

				J. W. Fisher Erythropoietin: Physiology and Pharmacology Update Experimental Biology and Medicine, January 1, 2003; 228(1): 1 - 14. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673