| Project/Area Number |
10670653
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Osaka University |
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Principal Investigator |
MASUYAMA Tohru Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70273670)
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| Co-Investigator(Kenkyū-buntansha) |
DOI Reiko Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
YAMAMOTO Kazuhiro Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (90303966)
HORI Masatsugu Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (20124779)
MIWA Takeshi Osaka University, Genome Information Research Center, Associate Professor, 遺伝情報実験施設, 助教授 (20174229)
近藤 寛也 大阪大学, 医学部, リサーチアソシエイト (40294102)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | isolated diastolic heart failure / hypertension / hypertrophy / fibrosis / renin-angiotensin system |
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| Research Abstract |
In spite of frequent occurrence of isolated diastolic heart failure with preserved systolic function, our understanding of its pathophysiology is limited because an animal model for isolated diastolic heart failure has not been established. We have demonstrated that Dahl-Iwai salt-sensitive (Dahl-S) rats fed on high salt diet from 7 weeks old develop hypertension followed by compensated LV hypertrophy (LVH) at 13 weeks and isolated diastolic heart failure at 19 weeks. At the failing stage in this model (19 weeks), progressive fibrosis and an increase in LV ACE mRNA were observed. We further studied whether the local renin-angiotensin system (RAS) was associated with transition to isolated diastolic heart failure by studying effects of chronic administration Angiotensin II type 1 receptor (AT1-R) antagonist (Candesartan Cilexetil) on LV geometry and function. Dahl-S rats were placed on high salt diet with or without oral administration Candesartan Cilexetil (1mg/kg/day). An increase in the LV mass/weight in the treated rats at 13 weeks was comparable to that in the untreated rats, but a further increase thereafter was observed only in the untreated rats. At 19 weeks, the elevation of LVEDP and myocardial fibrosis were observed in the untreated rats, and Candesartan Cilexetil prevented these changes. Thus, AT1-R antagonist Candesartan Cilexetil did not restrain initial adaptive LVH up to compensated stage, but prevented non-adaptive excessive LVH thereafter and myocardial fibrosis, which benefited in stopping or at least in delaying the transition to decompensation. In conclusion, cardiac RAS seems to play an important role in facilitating excessive LV hypertrophy and myocardial fibrosis that closely link to isolated diastolic heart failure.
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