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
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