on October 21, 2002
Published online before print October 21, 2002, doi: 10.1161/01.HYP.0000039748.88581.A0
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 6, 2002
From HELIOS Klinikum-Berlin, Franz Volhard Clinic and
Medical Faculty of the Charité, Humboldt University of Berlin
(D.N.M., A.M., R.D., A.F., B.P., F.C.L.); Max Delbrück Center for
Molecular Medicine (D.N.M., F.C.L.), Berlin-Buch; the Department of
Medicine-Nephrology, Hannover Medical School (J.-K.P.,
H.H.), Hannover; and Hoffmann-La Roche Ltd (B.-M.L., D.B.-K., S.M.,
H.D., J.D.A.), Basel,
Switzerland. * To whom correspondence should be addressed. E-mail: luft{at}fvk-berlin.de.
Abstract—We
tested the hypothesis that endothelin-converting enzyme (ECE)
inhibition ameliorates end-organ damage in rats harboring both human
renin and human angiotensinogen genes (dTGR). Hypertension
develops in the animals, and they die by age 7 weeks of heart and
kidney failure. Three groups were studied: dTGR (n=12) receiving
vehicle, dTGR receiving ECE inhibitor (RO0687629; 30 mg/kg
by gavage; n=10), and Sprague-Dawley control rats (SD; n=10) receiving
vehicle, all after week 4, with euthanasia at week 7. Systolic
blood pressure was not reduced by ECE inhibitor compared
with dTGR (205±6 versus 206±6 mm Hg at week 7, respectively).
In contrast, ECE inhibitor treatment significantly reduced
mortality rate to 20% (2 of 10), whereas untreated dTGR had a 52%
mortality rate (7 of 12). ECE inhibitor treatment
ameliorated cardiac damage and reduced left ventricular ECE
activity below SD levels. Echocardiography at week
7 showed reduced cardiac hypertrophy (4.8±0.2 versus
5.7±0.2 mg/g, P<0.01) and
increased left ventricular cavity diameter (5.5±0.3 versus
3.1±0.1 mm, P<0.001) and
filling volume (0.42±0.04 versus 0.16±0.06 mL,
P<0.05) after ECE
inhibitor compared with untreated dTGR. ECE
inhibitor treatment also reduced cardiac fibrosis, tissue
factor expression, left ventricular basic fibroblast growth
factor mRNA levels, and immunostaining in the vessel
wall, independent of high blood pressure. In contrast, the ECE
inhibitor treatment showed no renoprotective effect. These
data are the first to show that ECE inhibition reduces
angiotensin II-induced cardiac damage.
Revised on August 27, 2002
Endothelin-Converting Enzyme Inhibition
Ameliorates Angiotensin II-Induced Cardiac
Damage
Dominik N. Muller;
Key words: angiotensin II • enzymes • fibrosis • hypertrophy
This article has been cited by other articles:
 |
|
 |
|
  Y. Ikeda, K.-i. Aihara, T. Sato, M. Akaike, M. Yoshizumi, Y. Suzaki, Y. Izawa, M. Fujimura, S. Hashizume, M. Kato, et al. Androgen Receptor Gene Knockout Male Mice Exhibit Impaired Cardiac Growth and Exacerbation of Angiotensin II-induced Cardiac Fibrosis J. Biol. Chem., August 19, 2005; 280(33): 29661 - 29666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Pollock Endothelin, Angiotensin, and Oxidative Stress in Hypertension Hypertension, April 1, 2005; 45(4): 477 - 480. [Full Text] [PDF]
|
|
|
|
 |
|
 N. G Perez, M. C Villa-Abrille, E. A Aiello, R. A Dulce, H. E Cingolani, and M. C Camilion de Hurtado A low dose of angiotensin II increases inotropism through activation of reverse Na+/Ca2+ exchange by endothelin release Cardiovasc Res, December 1, 2003; 60(3): 589 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chen, Z. A. Khan, M. Cukiernik, and S. Chakrabarti Differential activation of NF-kappa B and AP-1 in increased fibronectin synthesis in target organs of diabetic complications Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1089 - E1097. [Abstract] [Full Text] [PDF]
|
|