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Involvement of brain function in the development of hypertension and hyperinsulinemia

脑功能参与高血压和高胰岛素血症的发生

基本信息

批准号：
06670731
负责人：
YOSHIMATSU Hironobu
金额：
$ 0.83万
依托单位：
OITA MEDICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

In obese humans as well as obese animals, insulin resistance resultant of hyperinsulinemia is one of the pathogenetic factors which induces hypertension. The present study aims to investigate involvement of brain function in the interaction of hypertension with hyperinsulinemia particularly from a histaminergic point of view, i.e., impaired hypothalamic histamine functions in those pathological symptoms. Results : 1) Diabetic (DM) rats induced by streptozotosin (STZ) increased, food intake and decreasd body weight. Concentration of hypothalamic neuronal histamine decreased under the hyperglycemic and insulin deficient conditions in the DM rats. The reduction of neuronal histamine was resulted from inactivation of histamine synthesizing enzyme, histidine decarboxylase enzyme (HDC). 2) Insulin-induced hypoglycemia, but not insulin per se, activated histamine turnover in the hypothalamus. 3) Neuronal histamine was hrdly detectable in the hypothalamus of the obese Zucker compared with that … More in the lean littermates hypothalanus. HDC activity decreased as well in the obese Zucker. These results indicate that blood glucose levels, modulate a turnover rate of hypothalamic neuronal histamine. Consequently, in the obese Zuckers with hyperinsulinemia, but with normoglycemia, some genetic factor other thana metabolic one seems is highly probable to induce dysfunction of the histamine neuron system in the hypothalamus. In fact, we have recently clarified that abnormalities of leptin receptor in the hypothalamus cause to maintain low activity of histaminergic neuron system. 4) Tumor necrosis factor-alpha (TNFalpha), which was predominantly secreted from the adipose tissue and involved in the development of insulin resistance, did not affect activity of histamine neuron while intracerebroventriculer (i.c.v) administration of the cytokine decreased food intake. Interleukin-1beta decreased food intake as well, but the suppressive effect on food intake was regulated by hypothalamic neuronal histamine. 5) According to a in vivo microdialysis study, activation of a hypothalamic histamine system enhanced lipolytic action in the adipose tissue through a sympathetic nervous system. 6) Activation of histamine neuron produced biphasic responses in insulin secretion, i.e., rapid acceleration due to direct stimulation of the increased glucose level and succeeding suppression due to indirect modulation of the hypothalamus. 7) Insulin i.c.v.infusion did not affect electrophysiological activity of efferent adrenal sympathetic nerve. Icv infusion of histamine, but not insulin, increased blood presser level in rats. Taken together, it is not likely that acute change in central insulin level may affect histamine neuronal activity and resultant increase in blood pressuer. The present findings suggest that chronic interaction between hypothalamic histamine, metabolic factor such as glucose concentration, hyperinsulinemia and potent secretion of leption may cause insulin resistance Less

在肥胖的人和肥胖的动物中，由高胰岛素血症引起的胰岛素抵抗是导致高血压的发病因素之一。本研究旨在从组胺能的角度探讨脑功能在高血压和高胰岛素血症相互作用中的作用，即在这些病理症状中下丘脑组胺功能受损。结果：1)链脲佐菌素(STZ)诱导的糖尿病(DM)大鼠进食量增加，体重下降。糖尿病大鼠在高血糖和胰岛素缺乏条件下，下丘脑神经元组胺浓度降低。神经元组胺的减少是组胺合成酶组氨酸脱羧酶(HDC)失活的结果。2)胰岛素诱导的低血糖，而不是胰岛素本身，激活了下丘脑组胺的转换。3)与…相比，肥胖的Zucker的下丘脑中可检测到更多的神经元组胺更多的是在精干的下丘脑。肥胖的Zucker的HDC活性也降低了。这些结果表明，血糖水平，调节了下丘脑神经元组胺的周转率。因此，在有高胰岛素血症但血糖正常的肥胖Zucker中，除代谢因素外的其他遗传因素很可能导致下丘脑组胺神经系统功能障碍。事实上，我们最近已经阐明，下丘脑中瘦素受体的异常导致组胺能神经元系统保持低活性。4)主要由脂肪组织分泌并参与胰岛素抵抗形成的肿瘤坏死因子-α(TNFpha)不影响组胺神经元的活动，而侧脑室(i.c.v)注射该细胞因子可减少摄食量。白介素1β也减少摄食量，但对摄食量的抑制作用是由下丘脑神经元组胺调节的。5)根据体内微透析研究，下丘脑组胺系统的激活通过交感神经系统增强了脂肪组织的脂肪分解作用。6)组胺神经元的激活引起胰岛素分泌的双相反应，即直接刺激血糖升高引起的快速加速和下丘脑的间接调节引起的抑制。7)静脉注射胰岛素不影响传出肾上腺交感神经的电生理活动。脑室注射组胺，而不是胰岛素，可提高大鼠的血压水平。总而言之，中枢胰岛素水平的急性变化不太可能影响组胺神经元活动，从而导致血压升高。目前的研究结果表明，下丘脑组胺、代谢因素如葡萄糖浓度、高胰岛素血症和促排血素的有效分泌之间的长期相互作用可能会导致胰岛素抵抗减轻。