Abstract |
We investigated the role of endothelin ETB receptor in the development of monocrotaline-induced pulmonary hypertension, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ETB receptor gene. Three weeks after injection of saline or monocrotaline (60 mg/kg, s.c.), hemodynamics, cardiac hypertrophy and endothelin-1 levels in right ventricle were determined. Monocrotaline produced a marked pulmonary hypertension associated with increases in right ventricular pressure and hypertrophy, pulmonary arterial medial thickening and the endothelin-1 levels. The monocrotaline-induced alterations tended to be enhanced in ETB-deficient homozygous rats, compared with cases in wild-type rats. The treatment with selective ETA receptor antagonist ABT-627 [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)- pyrrolidine-3R- carboxylic acid] for 3 weeks (10 mg/kg/day, twice daily) almost completely suppressed the monocrotaline-induced pulmonary hypertension and related organ damage both in ETB-deficient and wild-type animals to the same levels. Thus, we suggest that the antagonism of the ETA receptor is essential for the protection from monocrotaline-induced pulmonary hypertension, irrespective of the presence of the ETB receptors, although a protective role of ETB receptor-mediated action in the pathogenesis of this disease model cannot be ruled out.
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Authors | Masahiro Nishida, Yuka Okada, Kenji Akiyoshi, Keiko Eshiro, Masanori Takoaka, Cheryl E Gariepy, Masashi Yanagisawa, Yasuo Matsumura |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 496
Issue 1-3
Pg. 159-65
(Aug 02 2004)
ISSN: 0014-2999 [Print] Netherlands |
PMID | 15359489
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Endothelin B Receptor Antagonists
- Pyrrolidines
- Receptor, Endothelin B
- Monocrotaline
- Atrasentan
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Topics |
- Animals
- Animals, Genetically Modified
- Atrasentan
- Endothelin B Receptor Antagonists
- Hypertension, Pulmonary
(chemically induced, physiopathology, prevention & control)
- Monocrotaline
(toxicity)
- Pulmonary Artery
(drug effects, physiology)
- Pyrrolidines
(pharmacology, therapeutic use)
- Rats
- Rats, Mutant Strains
- Receptor, Endothelin B
(deficiency, physiology)
- Ventricular Function, Right
(drug effects, physiology)
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