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Attenuation of pulmonary vascular hypertension and cardiac hypertrophy with sitaxsentan sodium, an orally active ET(A) receptor antagonist.
- Source :
-
Pulmonary pharmacology & therapeutics [Pulm Pharmacol Ther] 2000; Vol. 13 (2), pp. 87-97. - Publication Year :
- 2000
-
Abstract
- Effects of sitaxsentan (TBC11251), an orally active, highly selective antagonist of endothelin A receptors, were examined on the development and maintenance of pulmonary hypertension, pulmonary vascular remodeling, and cardiac hypertrophy in the rat. The pulmonary vasoconstrictor response to acute hypoxia (10% O(2)for 90 min) was prevented with sitaxsentan (5 mg/kg infused iv 10 min prior to the onset of hypoxia) while BQ-788 (a specific endothelin B receptor antagonist) was without effect. The same dose of sitaxsentan delivered iv 50 min after the onset of hypoxia reversed the established pulmonary vasoconstriction. In a 2-week model of hypoxia using 10% O(2), treatment with sitaxsentan (15 mg/kg per day in drinking water) attenuated pulmonary hypertension and the associated right ventricular hypertrophy, and prevented the remodeling of small pulmonary arteries (50-100 microM) without affecting systemic arterial blood pressure or heart rate. Institution of sitaxsentan treatment (15 and 30 mg/kg per day in drinking water) for 4 weeks after 2 weeks of untreated hypoxia produced a significant, dose dependent reversal of the established pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling despite continued hypoxic exposure. Sitaxsentan blocked increased plasma endothelin levels in the prevention protocol but did not affect the established elevated levels in the intervention study. Sitaxsentan dose dependently (10 and 50 mg/kg per day in the drinking water) attenuated right ventricular systolic pressure, right heart hypertrophy, and pulmonary vascular remodeling observed 3 weeks after a single subcutaneous injection of monocrotaline. These findings support the hypothesis that endothelin-1 plays a significant role in the development of pulmonary hypertension, pulmonary vascular remodeling, and the associated cardiac hypertrophy, and further suggest that specific endothelin-A receptor blockade may be useful in the treatment of pulmonary hypertension of diverse etiologies.<br /> (Copyright 2000 Academic Press.)
- Subjects :
- Animals
Cardiomegaly blood
Disease Models, Animal
Endothelin-1 blood
Hypertension, Pulmonary blood
Hypertrophy prevention & control
Hypoxia blood
Hypoxia physiopathology
Male
Monocrotaline therapeutic use
Oxygen metabolism
Rats
Rats, Sprague-Dawley
Receptor, Endothelin A
Vasoconstriction drug effects
Weight Gain drug effects
Cardiomegaly prevention & control
Endothelin Receptor Antagonists
Hypertension, Pulmonary prevention & control
Isoxazoles therapeutic use
Thiophenes therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1094-5539
- Volume :
- 13
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Pulmonary pharmacology & therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 10799286
- Full Text :
- https://doi.org/10.1006/pupt.2000.0237