ABSTRACT
BACKGROUND: Endothelin-1 (ET-1) receptor antagonist is expected to improve the prognosis of patients with heart failure, but the role of the ET(B) receptor in cardiac function and structure is complicated. In the present study the NADPH diaphorase activity and ET-1 content in the failing heart treated with ET(A) or ET(B) receptor antagonist were evaluated in a model of dilated cardiomyopathy. METHODS AND RESULTS: Selective ET(A) receptor antagonist, ABT-627 (10 mg/kg per day), or selective ET(B) antagonist, A-192621 (30 mg/kg per day), was given to 22-week-old J2N-k cardiomyopathic hamsters for 8 weeks. The effects of ABT-627 and A-192621 on cardiac function, left ventricular (LV) histology, ET-1 content and NADPH diaphorase activity in the LV were evaluated. Treatment with ABT-627, but not A-192621, significantly decreased ET-1 content and NADPH diaphorase activity. Although the improvement of LV function was modest, ABT-627 prevented tissue damage in J2N-k hamsters. In contrast, A-192621 worsened the degeneration of cardiomyocytes despite improving hemodynamic parameters. CONCLUSIONS: Selective ET(A) antagonist, but not ET(B) antagonist, reduced the ET-1 content as well as the NADPH diaphorase activity, and preserved the fine structure of LV myocardium in cardiomyopathic hamsters. Long-term blockade of ET(B) receptor might worsen the degeneration of cardiomyocytes through the ET-1/ET(A) system even if LV function could be improved.
Subject(s)
Cardiomyopathy, Dilated/drug therapy , Endothelin B Receptor Antagonists , Muscle Cells/pathology , Myocardium/pathology , Pyrrolidines/therapeutic use , Ventricular Function, Left/physiology , Animals , Atrasentan , Cardiomyopathy, Dilated/pathology , Cricetinae , Disease Models, Animal , Heart/drug effects , Heart Function Tests , Male , Muscle Cells/drug effects , Ventricular Function, Left/drug effectsABSTRACT
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.
Subject(s)
Hypertension, Pulmonary/physiopathology , Monocrotaline/toxicity , Receptor, Endothelin B/physiology , Animals , Animals, Genetically Modified , Atrasentan , Endothelin B Receptor Antagonists , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/prevention & control , Pulmonary Artery/drug effects , Pulmonary Artery/physiology , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Rats , Rats, Mutant Strains , Receptor, Endothelin B/deficiency , Ventricular Function, Right/drug effects , Ventricular Function, Right/physiologyABSTRACT
The functional roles of endothelin ETA and ETB receptors in the development of monocrotaline (MCT)-induced pulmonary hypertension were investigated using MCT-treated rats in the absence or presence of a daily administration of A-192621, a selective ETB receptor antagonist, ABT-627, a selective ETA receptor antagonist, or a combination of both drugs. Four weeks after the injection of saline or MCT (60 mg/kg, s.c.), cardiac hypertrophy, right ventricular systolic pressure and morphologic changes of pulmonary arteries were evaluated. Compared with the control animals, MCT produced marked pulmonary hypertension associated with increases in right ventricular pressure and hypertrophy, and pulmonary arterial medial thickening. These MCT-induced alterations were markedly suppressed by daily treatment with ABT-627 for 4 weeks (10 mg/kg/d, twice daily), whereas treatment with A-192621 significantly aggravated the above MCT-induced pathologic changes. The blockade of both receptor subtypes by a combination of A-192621 and ABT-627 also significantly improved the MCT-induced pathologic changes, to the same extent as with ABT-627 administration. Thus, an exaggerated response to MCT during ETB receptor blockade also seems to be mediated by ETA receptor activation, thereby suggesting that ETA receptor-mediated action is exclusively contributive to the pathogenesis of MCT-induced pulmonary hypertension, although we cannot rule out a protective role of ETB receptor-mediated action.
