Roles of endothelin ETA and ETB receptors in the pathogenesis of monocrotaline-induced pulmonary hypertension.
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.
Nishida
Masahiro
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
Eshiro
Keiko
K
Okada
Yuka
Y
Takaoka
Masanori
M
Matsumura
Yasuo
Y
D000284:Administration, Oral; D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000188:drug therapy; D007279:Injections, Subcutaneous; D007441:Intubation, Gastrointestinal; D008168:Lung / Q000033:anatomy & histology / Q000098:blood supply; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage / Q000009:adverse effects*; D009929:Organ Size / Q000187:drug effects; D011651:Pulmonary Artery / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000502:physiology*; D013997:Time Factors; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology; D017725:Ventricular Pressure / Q000187:drug effects
C120508:A 192621; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016686:Monocrotaline; D000077868:Atrasentan