| Project/Area Number |
12670654
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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 | TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
INOUE Hiroshi Toyama Medical and Pharmaceutical University, Faculty of Medicine Professor, 医学部, 教授 (60151619)
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| Co-Investigator(Kenkyū-buntansha) |
TOMODA Fumihiro TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY, Faculty of Medicine, Assistant Professor, 医学部, 助手 (90251884)
NOZAWA Takashi TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY, Faculty of Medicine, Assistant Professor, 医学部, 助手 (00180737)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | myocardial ischemia / heart failure / nearve growth factor / sympathetic nerve / catecholamine / beta-receptor |
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| Research Abstract |
An activation of sympathetic nervous system is one of major pathophysiological abnormalities which progress heart failure. The magnitude of sympathetic activation relates to prognosis in patients with heart failure. Therefore, direct inhibition of sympathetic activity might be an effective approach to therapy of heart failure. In the present study, we investigated. 1) effects of peripheral sympathoinhibition by guanethidine on mortality and cardiac function in rats after myocardial infarction, and 2) effects of nerve growth factor (NGF) and anti-NGF on sympathetic neuronal function in myocardial ischemia-reperfusion injury. NGF is a neurotrophic factor that is necessary for survival and regeneration of peripheral sympathetic nerves. It was shown that NGF is released acutely from the ischemic myocardium.
In chronic treatment with high dose guanethidine (10 mg/kg/day) from 2 days before the induction of myocardial infarction, hemodynamic function was not affected in sham-operated rats des
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pite the depletion of myocardial norepinephrine (NE). The 28-day mortality of infracted rats treated with the high dose guanethidine increased markedly (96%), as compared with infarcted rats without guanethidine (52%). In contrast, low dose guanethidine (1 mg/kg/day) improved the mortality (6%) and inhibited the ventricular remodeling. Cardiac sympathetic neuronal function was assessed by ^<131>I-metaiodobenzylguanedine (MIBG), an analogue of NE, in a rat of 15-min coronary artery occlusion and reperfusion. NGF decreased cardiac MIBG uptake in both ischemic and non-ischemic regions of left ventricle. Anti-NGF however increased it in both regions. MIBG uptake was reduced in ischemic region, but neither NGF nor anti-NGF altered the ischemic/non-ischemic uptake ratio.
In summary, "moderate" sympathoinhibition might be favorable for prognosis or inhibition of ventricular remodeling in heart failure after myocardial infarction, but a powerful sympathoinhibition that depletes myocardial NE might be harmful. A modulation of excess sympathetic nerve activation by anti-NGF may be effective for the treatment of heart failure. Less
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