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Abnormalities in Membrane Function and Ca-Metabolism, and Their Contribution to the Pathophysiology of Hypertension with Obesity and Diabetes Mellitus

膜功能和钙代谢异常及其对高血压合并肥胖和糖尿病病理生理学的贡献

基本信息

批准号：
15590604
负责人：
TSUDA Kazushi
金额：
$ 2.24万
依托单位：
Wakayama Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

In the first series of the experiments, we describe the results regarding the Ca-sensitivity and neurotransmitter release in hypertension. The Ca channel blocker, nicardipine, significantly inhibited the stimulation-evoked norepinephrine release and vasoconstrictor responses in rat mesenteric arteries. The inhibitory effect was more pronounced in spontaneously hypertensive rats(SHR) than in age-matched normotensive Wistar-Kyoto(WKY) rats.In the second series of the study, in order to assess the possible link among hypertension, obesity and diabetes mellitus, we investigated the mechanisms of actions of insulin and leptin on membrane function in subjects with hypertension. Membrane fluidity is a physicochemical feature of biomembranes and is an important factor modulating microcirculation. Using the electron paramagnetic resonance and spin-labeling method, we examine the alterations in membrane fluidity of erythrocytes in hypertensive subjects with obesity and diabetes mellitus. We demo … More nstrated that the higher plasma insulin level, the lower the membrane fluidity of erythrocytes. This might indicate that hyperinsulinemia is involved in the regulation of membrane fluidity of erythrocytes. In an in vitro study, we showed that insulin alone and in combination with calcium decreased the membrane fluidity of erythrocytes. The decreased membrane fluidity of erythrocytes might cause a disturbance in the blood rheologic behavior and the microcirculation, which could contribute, at least in part, to the pathophysiology of hypertension. One hypothesis is that insulin might accelerate abnormalities in intracellular Ca-metabolism and membrane functionin erythrocytes, which could partially explain the vascular complications in subjects with hyperinsulinemia. On the other hand, it was demonstrated that leptin increased the membrane fluidity of erythrocytes and improved the rigidity of cell membranes via the nitric oxide(NO)-and cGMP-dependent mechanism, suggesting that insulin and leptin may exert opposite effects on membrane microviscosity of erythrocytes.In this context, we speculate that abnormalities in membrane function and Ca-metabolism might contribute, at least in part, to the pathophysiology of hypertension with obesity and diabetes mellitus. Less

在第一系列实验中，我们描述了高血压患者的钙敏感性和神经递质释放的结果。钙通道阻滞剂尼卡地平显著抑制刺激引起的大鼠肠系膜动脉去甲肾上腺素释放和血管收缩反应。这种抑制作用在自发性高血压大鼠(SHR)中比在年龄匹配的正常血压Wistar-京都(WKY)大鼠中更为明显。在第二系列研究中，为了评估高血压、肥胖和糖尿病之间的可能联系，我们研究了胰岛素和瘦素对高血压患者膜功能的作用机制。膜流动性是生物膜的一种物理化学特性，是调节微循环的重要因素。我们用电子顺磁共振和自旋标记方法，检测了高血压合并肥胖和糖尿病患者红细胞膜流动性的变化。我们演示…说明血浆胰岛素水平越高，红细胞膜流动性越低。提示高胰岛素血症可能参与了红细胞膜流动性的调节。在一项体外研究中，我们发现胰岛素单独或与钙联合使用会降低红细胞膜的流动性。红细胞膜流动性降低可能导致血液流变性和微循环紊乱，这至少部分参与了高血压的病理生理过程。一种假说认为，胰岛素可能加速红细胞膜功能和细胞内钙代谢的异常，这可以部分解释高胰岛素血症患者的血管并发症。另一方面，瘦素通过NO和cGMP依赖的机制增加红细胞膜的流动性，改善细胞膜的刚性，提示胰岛素和瘦素可能对红细胞膜的微粘度产生相反的影响，我们推测膜功能和钙代谢的异常可能至少部分参与了高血压合并肥胖和糖尿病的病理生理过程。较少