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(Hypertension. 2006;48:965.)
© 2006 American Heart Association, Inc.

Original Articles

Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension

Martin Opoensk; Herbert J. Kramer; Angela Bäcker; Zdenka Vernerová; Václav Eis; Ludk ervenka; Vra ertíková Chábová; Vladimír Tesa; Ivana Vanková

From the Center for Experimental Medicine (M.O., Z.V., V.E., L.., 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.

Correspondence to Ivana Vaneckova, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, CZ-140 21, Prague 4, Czech Republic. E-mail ivvn{at}medicon.cz

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 (ET_A) or nonselective ET_A/ET B (ET_B) receptor blockade improved survival rate and reduced proteinuria, glomerulosclerosis, and cardiac hypertrophy, whereas selective ET_A 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 ET_A receptor blocker atrasentan (ABT-627), or the nonselective ET_A/ET_B 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 ET_A receptor blockade not only reduces podocyte injury and end-organ damage but also improves growth and survival independently of hypertension.

Key Words: endothelin-1 • ET_A and ET_B receptors • bosentan • atrasentan (ABT-627), homozygous transgenic Ren-2 rats • hypertension • end-organ damage • survival rate

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Role of Endothelin Receptors for Renal Protection and Survival in Hypertension: Waiting for Clinical Trials

Matthias Barton, John J. Mullins, Matthew A. Bailey, and Matthias Kretzler
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