| Co-Investigator(Kenkyū-buntansha) |
MIYAUCHI Takashi University of Tsukuba, Institute of Basic Medical Sciences, Professor, 臨床医学系, 講師 (60222329)
MIWA Yoshihiro University of Tsukuba, Institute of Basic Medical Sciences, Assistant Professor, 基礎医学系, 講師 (70263845)
SAKURAI Takeshi University of Tsukuba, Institute of Basic Medical Sciences, Associate Professor, 基礎医学系, 助教授 (60251055)
MURATA Sakae Insti. Drug Develop., Tanabe Pharmaceut. Comp. Chief, 循環薬理部, 部長
KASUYA Yoshitoshi Grad.Sch. Med. Chiba Univ. Associate Professor, 大学院・医学研究科・高次機能系分子生体機構学, 助教授 (70221877)
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| Research Abstract |
The aim of this research project is to develop new therapeutic drugs for the treatment of chronic circulatory diseases e.g. chronic heart failure, pulmonary hypertension, etc., by paying special attention on the role of endothelin (ET) as an endogenous factor in the development, maintenance and aggravation of the diseases. For this purpose, various animal models of chronic circulatory diseases were utilized. In cardiac tissues of rats with chronic heart Mure due to coronary artery occlusion, the expression of ET-1 mRNA and the content of ET-1 peptide were significantly increased, and the expression of ET_A receptors was also elevated, indicating that the ET system was markedly enhanced in the failing heart. ETA receptor antagonist decreased the left ventricular +dp/dt/pmax in rats with myocardial infarction soon after coronary occlusion, suggesting that endogenous ET-1 is playing an important role for maintaining cardiac function at the acute phase. However, if the stimulation by ET-1 continues for a long period, the heart would gradually bear overload, thereby resulting in chronic heart, failure with marked hypertrophy 'and flbrosis, I.e. so-called cardiac remodeling. An identical phenomenon was also observed in hamster with cardiomyopathy, an animal model of non-ischemic heart failure. Impairment of cardiac metabolism by the inhibition of mitochondrial Respiratory pathway in cultured cardiomyocytes, an in vitro model of heart failure, ET-1 production was markedly enhanced via expression of HIF-1 α.
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