1997 Fiscal Year Final Research Report Summary
The study of pathophysiological roles of endothelin in heart failure and cardiac hypertrophy and the development of a new treatment based on these findings
| Project/Area Number |
07407019
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | University of Tsukuba |
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Principal Investigator |
SUGISHITA Yasuro University of Tsukuba Institute of Clinical Medicine Professor, 臨床医学系, 教授 (90010131)
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| Co-Investigator(Kenkyū-buntansha) |
GOTO Katsutoshi University of Tsukuba Institute of Basic Medical Sciences Professor, 基礎医学系, 教授 (30012660)
SAKAI Satoshi University of Tsukuba Institute of Clinical Medicine Research Associate, 臨床医学系, 助手 (30282362)
MIYAUCHI Takashi University of Tsukuba Institute of Clinical Medicine Assistant Professor, 臨床医学系, 講師 (60222329)
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| Project Period (FY) |
1995 – 1997
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| Keywords | heart failure / cardiac hypertrophy / endothelin / endothelin antagonist / cardiovascular pharmacology / pathophysiology / molecular biology |
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| Research Abstract |
Cardiac myocytes as well as vascular endothelium produce endothelin (ET) -1. In the heart, ET-1 induces myocardial hypertrophy and causes cellular injury of cardiac myocytes. In this study, we investigated roles of ET-1 in heart diseases such as chronic heart failure (CHF) and cardiac hypertrophy. We used coronary arteryligated rat model as a CHF model animal (CHF rats). Itwas revealed that production of ET-1 (both peptide and mRNA levels) is increased in the failing heart of the CHF rats. We also obtained the data that the upregulated myocardial ET-1 system may play an aggravating role in the progression of CHF,because long-term (12 weeks) treatment with the ET receptor antagonist BQ-123 greatly improved survival rate of CHF rats. Twelve weeks after BQ-123 application, survival rate of the CHF rats treated with BQ-123 (CHF-BQ rats) was markedly higher than that of the CHF rats treated with saline alone (CHF-saline rats) (85% vs 43%, P<0.01). Hemodynamic parameters of surviving rats were ameliorated by chronic BQ-123 treatment. BQ-123 treatment effectively prevented unfavorable ventricular remodeling of the CHF rats. This beneficial effect was accompanied by amelioration of cardiac dysfunction and amelioration of expression of cardiac genes of molecular markers (ANP mRNA,beta-myosin heavy chain mRNA) for the failing heart. In the hypertrophied left ventricle of the aorta-banded rats, the expression of ET-1 mRNA was significantly increased. Treatment with BQ-123 for 7 days significantly reduced cardiac hypertrophy of the aorta-banded rats. Therefore, myocardial ET-1 was considered to be involved in the progression of cardiac hypertrophy. The present study suggests that endogenous ET-1 is involved in the progression of cardiovascular diseases such as heart failure and cardiac hypertrophy, and that an ET receptor antagonist becomes a new drug for these diseases.
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