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

在第一个系列的实验中，我们描述了高血压患者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诱发的去甲肾上腺素释放和大鼠肠系膜动脉血管收缩反应。自发性高血压大鼠（SHR）的抑制作用比年龄匹配的正常Wistar-Kyoto大鼠（WKY）更明显。在第二系列研究中，为了评估高血压、肥胖和糖尿病之间可能的联系，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征，是调节微循环的重要因素。利用电子顺磁共振和自旋标记方法，研究了高血压合并肥胖和糖尿病患者红细胞膜流动性的变化。结果表明，血浆胰岛素水平越高，红细胞的膜流动性越低。这可能表明高胰岛素血症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使用和钙联合使用会降低红细胞的膜流动性。红细胞膜流动性的降低可能引起血液流变学行为和微循环的紊乱，这可能至少在一定程度上有助于高血压的病理生理。一种假说认为胰岛素可能加速红细胞胞内钙代谢和膜功能的异常，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，瘦素通过一氧化氮（NO）和cgmp依赖的机制增加了红细胞的膜流动性，改善了细胞膜的刚性，提示胰岛素和瘦素可能对红细胞的膜微粘度起相反的作用。在这种情况下，我们推测细胞膜功能和钙代谢的异常可能至少在一定程度上参与了高血压合并肥胖和糖尿病的病理生理。少

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