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

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.