title: YM598, an orally active ET(A) receptor antagonist, ameliorates the progression of cardiopulmonary changes and both-side heart failure in rats with cor pulmonale and myocardial infarction.
abstract: The effects of the novel, selective endothelin-A (ETA) receptor antagonist YM598 on both-side heart failure were investigated. Right-side heart failure secondary to pulmonary hypertension was produced by a single subcutaneous injection of 60 mg/kg monocrotaline, and post-ischemic congestive left-side heart failure (CHF) produced by surgical left coronary artery ligation. In right-side heart failure rats, oral YM598 (0.1 and 1 mg/kg for 4 weeks), but not bosentan (30 mg/kg), significantly inhibited the progression of pulmonary hypertension and the development of right ventricular hypertrophy. YM598 also improved hypoxemia and morphological pulmonary lesions in these rats. In CHF rats, moreover, long-term oral administration of YM598 (1 mg/kg/day for approximately 30 weeks) significantly ameliorated their poor survival rate (P < 0.05). In the measurement of cardio-hemodynamic parameters, YM598 improved the contractile/diastolic capacity of the left ventricle and the preload in the right ventricle to the levels seen in sham-operated rats. YM598 also markedly inhibited both ventricular hypertrophy and pulmonary congestion, as well as lowering high plasma brain natriuretic peptide levels in CHF rats. These findings suggest that YM598 may have a clinical benefit with regards to ameliorating the cardiopulmonary changes of right-side heart failure, and the cardiac dysfunction and mortality/morbidity of CHF.
authors.affiliation: Pharmacology Laboratories, Institute for Drug DiscoveryResearch, Yamanouchi Pharmaceutical Co., Ltd, Tsukuba, Ibaraki, Japan. fujimori@yamanouchi.co.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Fujimori
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyauchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakai
authors.forename: Hironori
authors.initials: H
authors.lastname: Yuyama
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Iemitsu
authors.forename: Masanao
authors.initials: M
authors.lastname: Sanagi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Sudoh
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Goto
authors.forename: Hisataka
authors.initials: H
authors.lastname: Shikama
authors.forename: Iwao
authors.initials: I
authors.lastname: Yamaguchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003331:Coronary Vessels / Q000601:surgery; D004195:Disease Models, Animal; D018450:Disease Progression; D065130:Endothelin A Receptor Antagonists; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008026:Ligation; D008297:Male; D016686:Monocrotaline; D009203:Myocardial Infarction / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011660:Pulmonary Heart Disease / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D002317:Cardiovascular Agents; D065130:Endothelin A Receptor Antagonists; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D016686:Monocrotaline