Role of endothelin ETB receptor in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats.
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.
Nishida
Masahiro
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Tatasuki, Japan.
Okada
Yuka
Y
Akiyoshi
Kenji
K
Eshiro
Keiko
K
Takoaka
Masanori
M
Gariepy
Cheryl E
CE
Yanagisawa
Masashi
M
Matsumura
Yasuo
Y
D000818:Animals; D030801:Animals, Genetically Modified; D000077868:Atrasentan; D065131:Endothelin B Receptor Antagonists; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D016686:Monocrotaline / Q000633:toxicity*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011922:Rats, Mutant Strains; D044023:Receptor, Endothelin B / Q000172:deficiency / Q000502:physiology*; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology
D065131:Endothelin B Receptor Antagonists; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D016686:Monocrotaline; D000077868:Atrasentan