2007 Fiscal Year Final Research Report Summary
Mechanism and treatment of endothelial dysfunction in patients with metabolic syndrome and hypertension.
| Project/Area Number |
17590474
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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 | Seinan Jo Gakuin University (2006-2007)
University of the Ryukyus (2005) |
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Principal Investigator |
TAGAWA Tatsuya Seinan Jo Gakuin University, 保健福祉学部, Professor (50347142)
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| Co-Investigator(Kenkyū-buntansha) |
UEDA Shinichiro University of the Ryukyus, 大学院・医学研究科, Professor (80285105)
YAMAKAWA Ken University of the Ryukyus, 大学院・医学研究科, Assistant Professor (00363664)
OHYA Yusuke University of the Ryukyus, 医学部, Associate Professor (30240964)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Hypertension / Diabetes Mellitus / Central Nervous System / Pharmacology |
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| Research Abstract |
OBJECTIVE: 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. METHODS AND RESULTS: Changes in forearm blood flow during intra-arterial infusion of acetylcholine were measured by plethysmography before and after systemic infusion of lipid/heparin in 10 healthy subjects given a single dose of placebo, losartan (50 mg), or perindopril (8 mg). Endothelial function after lipid/heparin infusion was also investigated with the confusion of vitamin C or N^G-monomethyl-L-arginine (L-NMMA). Elevated FFA significantly reduced the response to acetylcholine by 37.7% (P=0.0096) 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
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or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction. CONCLUSIONS: Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resistance, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition in patients with high FFA levels.
A chromosome 1 blood pressure quantitative trait locus (QTL) was introgressed from the stroke-prone spontaneously hypertensive rats (SHRSP) to Wistar-Kyoto (WKY) rats. This congenic strain (WKYpch1.0) showed an exaggerated pressor response to both restraint and cold stress. In this study, we evaluated cardiovascular and sympathetic response to an air-jet stress and also examined the role of the brain RAS in the stress response of WKYpch1.0. We measured mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to air-jet, stress in WKYpch1.0, WKY, and SHRSP. We also examined effects of intracerebroventricular administration of candesartan, an ANG II type 1 receptor blocker, on MAP and HR responses to air-jet stress. Baseline MAP in the WKYpch1.0 and WKY rats were comparable, while it was lower than that in SHRSP rats. Baseline HR did not differ among the strains. In WKYpch1.0, air-jet stress caused greater increase in MAP and RSNA than in WRY. The increase in RSNA was as large as that in SHRSP, whereas the increase in MAP was smaller than in SHRSP. Intracerebroventricular injection of a nondepressor dose of candesartan inhibited the stress-induced pressor response to a greater extent in WKYpch1.0 than in WKY. Intravenous injection of phenylephrine caused a presser effect comparable between WKYpch1.0 and WKY. These results suggest that the chromosome 1 blood pressure QTL congenic rat has a sympathetic hyperreactivity to an air-jet stress, which causes exaggerated pressor responses. The exaggerated response is at least party mediated by the brain RAS. Less
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