Circulation, Vol 90, 2510-2518, Copyright © 1994 by American Heart Association
JR Teerlink, BM Loffler, P Hess, JP Maire, M Clozel and JP Clozel
BACKGROUND--Endothelin (ET) is a potent vasoconstrictor, and its
concentration is increased in patients with heart failure. The purpose of
this study was to investigate the role of endothelin in heart failure by
use of a rat model. METHODS AND RESULTS--Experiments were performed on rats
at 1 through 16 weeks after sham operation or coronary artery ligation.
Rats with left ventricular end-diastolic pressures > 15 mm Hg were
considered to have chronic heart failure (CHF), while the others were
considered to have uncomplicated myocardial infarction (MI). There were
increased ET-1 concentrations in CHF rats at weeks 1 to 16 (Sham, 20 +/-
0.5 pg/mL, n = 45; CHF, 31 +/- 2 pg/mL, n = 50; P < .001) and transient
increases in ET-3 concentrations at week 1 in both the MI and CHF groups.
There were no significant increases in big ET-1 concentrations, suggesting
an increased conversion of ET-1 from big ET-1 in the CHF group. At weeks 2
through 8, oral administration of the mixed (ETA and ETB) endothelin
receptor antagonist bosentan significantly decreased mean arterial pressure
in conscious CHF rats, an effect that increased over time. Furthermore,
bosentan had an additive effect to the angiotensin- converting enzyme
inhibitor cilazapril. CONCLUSIONS--Endothelin plays a role in the
maintenance of blood pressure in CHF rats, as evidenced by the significant
reduction in mean arterial pressure after oral administration of bosentan.
Therefore, endothelin antagonists may be useful therapeutic agents in the
treatment of CHF.
ARTICLES
Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan)
Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
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