on October 2, 2006
Published online before print October 2, 2006, doi: 10.1161/01.HYP.0000245117.57524.d6
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Submitted on January 27, 2006
From the Center for Experimental Medicine (M.O., Z.V., V.E., L. * To whom correspondence should be addressed. E-mail: ivvn{at}medicon.cz.
Abstract--We have recently found in male homozygous hypertensive Ren-2 transgenic rats (TGRs) fed a high-salt diet that early onset selective endothelin (ET) A (ETA) or nonselective ETA/ET B (ETB) receptor blockade improved survival rate and reduced proteinuria, glomerulosclerosis, and cardiac hypertrophy, whereas selective ETA receptor blockade also significantly attenuated the rise in blood pressure. Because antihypertensive therapy in general is known to be more efficient when started at early age, our study was performed to determine whether onset of ET receptor blockade at a later age in animals with established hypertension will have similar protective effects as does early-onset therapy. Male homozygous TGRs and age-matched normotensive Hannover Sprague-Dawley rats were fed a high-salt diet between days 51 and 90 of age. TGRs received vehicle (untreated), the selective ETA receptor blocker atrasentan (ABT-627), or the nonselective ETA/ETB receptor blocker bosentan. Survival rates in untreated and bosentan-treated TGRs were 50% and 64%, respectively, whereas with atrasentan, survival rate of TGR was 96%, thus, similar to 93% in Hannover Sprague-Dawley rats. From day 60 on, systolic blood pressure in atrasentan-treated TGRs was transiently lower (P<0.05) than in untreated or bosentan-treated TGRs. Glomerular podocyte injury was substantially reduced with atrasentan treatment independent of severe hypertension and strongly correlated with survival (P<0.001). Our data indicate that in homozygous TGR ET receptors play an important role also in established hypertension. Selective ETA receptor blockade not only reduces podocyte injury and end-organ damage but also improves growth and survival independently of hypertension.
Revised on February 3, 2006
Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension
Martin Opo
ensk
; 
k 
ervenka; ra ertíková Chábová; 
; ková*
., V..C., I.V.), Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Cardiovascular Research Center (M.O., L.., I.V.), Prague, Czech Republic; Section of Nephrology (H.J.K., A.B.), Medical Policlinic, University of Bonn, Bonn, Germany; Department of Pathology (Z.V., V.E.), Third Medical Faculty, and Department of Nephrology (V..C., V.T.), First Medical Faculty, Charles University, Prague, Czech Republic.
Key words: endothelin-1 • ETA and ETB receptors • bosentan • atrasentan (ABT-627), homozygous transgenic Ren-2 rats • hypertension • end-organ damage • survival rate
Related Article:
Hypertension 2006 48: 834-837.
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