Physiol. Res. 53: 581-593, 2004


Chronic Endothelin Receptor Blockade Reduces End-Organ Damage Independently of Blood Pressure Effects
in Salt-Loaded Heterozygous Ren-2 Transgenic Rats


M. OPOČENSKÝ1,2, P. DVOŘÁK2,3, J. MALÝ1, H. J. KRAMER4, A. BÄCKER4,
L. KOPKAN1,2, Z. VERNEROVÁ5, V. TESAŘ6, T. ZIMA6, M. BADER7,
D. GANTEN7, J. JANDA3, I. VANĚČKOVÁ1,2

1 Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 2Center for Experimental Cardiovascular Research, 3Department of Pediatrics, Second Medical Faculty, Charles University, Prague, Czech Republic, 4Section of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany, 5Department of Pathology, Third Medical Faculty, Charles University, 6Department of Nephrology, First Department of Medicine, First Medical Faculty, Charles University, Prague, Czech Republic and 7Max Delbrück Center for Molecular Medicine and Franz Volhard Clinic, Berlin-Buch, Germany

Received December 19, 2003
Accepted February 9, 2004



Summary
The present study was performed to evaluate the role of an interaction between the endothelin (ET) and the renin-angiotensin systems (RAS) in the development and maintenance of hypertension and in hypertension-associated end-organ damage in heterozygous male and female transgenic rats harboring the mouse Ren-2 renin gene (TGR). Twenty-eight days old heterozygous TGR and age-matched transgene-negative normotensive Hannover Sprague-Dawley rats (HanSD) were randomly assigned to groups with normal-salt (NS) or high-salt (HS) intake. Nonselective ETA/ETB receptor blockade was achieved with bosentan (100 mg.kg-1.day-1). All male and female HanSD as well as heterozygous TGR on NS exhibited 100 % survival rate until 180 days of age (end of experiment). HS diet in heterozygous TGR induced a transition from benign to malignant phase hypertension. The survival rates in male and in female heterozygous TGR on the HS diet were 46 % and 80 %, respectively, and were significantly improved by administration of bosentan to 76 % and 97 %, respectively. Treatment with bosentan did not influence either the course of hypertension (measured by plethysmography in conscious animals) or the final levels of blood pressure (measured by a direct method in anesthetized rats) in any of the experimental groups of HanSD or TGR. Administration of bosentan in heterozygous TGR fed the HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR. Our data show that the ET receptor blockade markedly improves the survival rate and ameliorates end-organ damage in heterozygous TGR exposed to HS diet. These findings indicate that the interaction between the RAS and ET systems plays an important role in the development of hypertension-associated end-organ damage in TGR exposed to salt-loading.


Key words
Hypertension • Endothelin system • Renin-angiotensin system • Bosentan • End-organ damage


© 2004 by the Institute of Physiology, Czech Academy of Sciences