Donepezil Markedly Improves Long-Term Survival in Rats With Chronic Heart Failure After Extensive Myocardial Infarction
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概要
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Background: Vagal activation by electrical stimulation has been shown to improve the long-term survival of rats with chronic heart failure (CHF) after extensive myocardial infarction (MI). Acetylcholinesterase inhibition increases synaptic acetylcholine, and can disproportionately increase vagal tone. To develop an alternative therapy for CHF using a clinically available drug, the present study investigated whether oral donepezil, an acetylcholinesterase inhitor, could reproduce the beneficial effects of electrical vagal stimulation in rats. Methods and Results: At 2 weeks after ligation of the proximal left coronary artery, resulting in extensive MI, surviving rats were randomly assigned to donepezil-treated and untreated groups. Donepezil treatment started 14 days after MI significantly decreased the heart rate (325±6 vs. 355±10beats/min, P<0.05) and improved 140-day survival (29% to 54%, P=0.03) by preventing pump failure (cardiac index: +29%, P<0.001; left ventricular+dp/dtmax: +18%, P<0.01; left ventricular end-diastolic pressue: −26%, P<0.01) and cardiac remodeling (biventricular weight: 2.73±0.04 vs. 3.06±0.08g/kg, P<0.001). In addition, donepezil treatment lowered the levels of plasma arginine vasopressin, brain natriuretic peptide, catecholamine, and tissue pro-inflammation markers. Conclusions: Oral donepezil markedly improved the long-term survival of CHF rats by preventing pump failure and cardiac remodeling, indicating that donepezil may be a new alternative therapy for CHF.
著者
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Uemura Kazunori
Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute
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Zheng Can
Department Of Cardiovascular Control Kochi Medical School
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Kawada Toru
Department Of Cardiovascular Dynamics Advanced Medical Engineering Center
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Li Meihua
Department Of Cardiovascular Dynamics Advanced Medical Engineering Center National Cardiovascular Ce
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Sugimachi Masaru
Department Of Artificial Organ Medicine Division Of Surgical Medicine Osaka University Graduate Scho
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Inagaki Masashi
Department Of Cardiovascular Dynamics National Cardiovascular Center
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Shishido Toshiaki
Department of Cardiovascular Control, Faculty of Medicine, Kochi University
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Inagaki Masashi
Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center
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Kawada Toru
Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center
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