Sorrogate biomarker for evaluation of cardiovascular drugs
| Project/Area Number |
16590439
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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 |
Applied pharmacology
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| Research Institution | University of the Ryukyus |
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Principal Investigator |
UEDA Shinichiro University of the Ryukyus, Graduate School of Medicine, Professor, 大学院医学研究科, 教授 (80285105)
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| Co-Investigator(Kenkyū-buntansha) |
OHOYA Yusuke University of the Ryukyus, Faculty of Medicine, Associate Professor, 医学部, 助教授 (30240964)
URATA Hidenori Fukuoka University Chikushi Hospital, Professor, 筑紫病院, 教授 (30289524)
田川 辰也 琉球大学, 大学院・医学研究科, 助教授 (50347142)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | Free fatty acid / Endothelial function / Renin-angiotensin / Nitric Oxide / Post-prandial endothelial dysfunction / alpha glucosidase inhibitor / Oxidative stress / Insulin resistance / HOMA-IR / 高脂肪食 / PWV / 脈波伝播速度 |
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| Research Abstract |
1. FFA induced endothelial dysfunction in humans experimental model mimicking metabolic syndrome/insulin sensitivity and possible roles in evaluating anti atherosclerotic effect of drugs. An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction. Elevated FFA significantly reduced the response to acetylcholine without L-NMMA., but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction. Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resista
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nce, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition inpatients with high FFA levels. Our other study in rats and isolated vessels suggest that FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatia or NADPH oxidase inhibitors.
2. Postprandial endothelial dysfunction and alpha glucosidase inhibitor We evaluated effect of acarbose on post-prandial glucose and lipid metabolism and endothelial function. Patients with impaired glucose tolerance received the single dose of 100mg of acarbose or placebo in cross-over design before test meal. Metabolic parameters including serum glucose, triglyceride, and remnant lipoprotein were measured and endothelial function was evaluated by the measurement of changes in forearm blood flow during reactive hyperemia before and after the test meal. There were significant elevation in metabolic parameters and endothelial function was significantly impaired in patients with impaired glucose tolerance but not in healthy subjects. The single dose acarbose significantly inhibited the elevation in metabolic parameters and prevented post-prandial endothelial dysfunction in patients with impaired-glucose tolerance. Our results suggest that acarbose may improve post--prandial metabolic abnormalities and, consequently, improve endothelial function in subjects with impaired glucose tolerance. On the other hand, Postprandial endothelial function in normal volunteers was impaired only after high-fat diet, but not after high-carbohydrate and standard test meal. Since such endothelial dysfunction after high-fat meal was closely correlated with FFA concentrations, postprandial 'state could be hazardous mostly through acute hyperlipacidenia in healthy subjects. Less
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Report
(4 results)
Research Products
(26 results)
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[Book] 血圧2006
Author(s)
植田 真一郎
Total Pages
138
Publisher
先端医学社
Related Report
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