Role of endothelin ET B receptor in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats

Masahiro Nishida, Yuka Okada, Kenji Akiyoshi, Keiko Eshiro, Masanori Takaoka, Cheryl E. Gariepy, Masashi Yanagisawa, Yasuo Matsumura

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

We investigated the role of endothelin ET B 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 ET B 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. These monocrotaline-induced alterations tended to be enhanced in ET B-deficient homozygous rats, compared with cases in wild-type rats. The treatment with the selective ET A 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 ET B-deficient and wild-type animals to the same levels. Thus, we suggest that the antagonism of the ET A receptor is essential for the protection from monocrotaline-induced pulmonary hypertension, irrespective of the presence of the ET B receptors, although a protective role of ET B receptor-mediated action in the pathogenesis of this disease model cannot be ruled out.

Original languageEnglish (US)
Pages (from-to)159-165
Number of pages7
JournalEuropean Journal of Pharmacology
Volume496
Issue number1-3
DOIs
StatePublished - Aug 2 2004

Keywords

  • ET receptor
  • ET receptor
  • ET receptor-deficient rat
  • Endothlin-1
  • Monocrotaline
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Pharmacology

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