Involvement of brain function in the development of hypertension and hyperinsulinemia

在肥胖人和肥胖动物中，高胰岛素血症引起的胰岛素抵抗是诱发高血压的致病因素之一。本研究旨在探讨高血压与高胰岛素血症的相互作用中脑功能的参与，特别是从组胺能的角度来看，即在这些病理症状中下丘脑组胺功能受损。结果：1)STZ诱导的糖尿病（DM）大鼠食量增加，体重下降。糖尿病大鼠高血糖和胰岛素缺乏时下丘脑神经元组胺浓度降低。神经元组胺的减少是由于组胺合成酶组氨酸脱羧酶（HDC）失活所致。2)胰岛素诱导的低血糖，而不是胰岛素本身，激活了下丘脑的组胺转换。3)肥胖的扎克鼠下丘脑几乎检测不到神经元组胺，而瘦弱的扎克鼠下丘脑检测到神经元组胺更多。肥胖的扎克鼠的HDC活性也有所下降。这些结果表明，血糖水平调节下丘脑神经元组胺的周转率。因此，在患有高胰岛素血症但血糖正常的肥胖zucker患者中，一些非代谢因素的遗传因素似乎极有可能诱发下丘脑组胺神经元系统的功能障碍。事实上，我们最近已经澄清了下丘脑瘦素受体的异常导致组胺能神经元系统保持低活性。4)肿瘤坏死因子- α (TNFalpha)主要由脂肪组织分泌，参与胰岛素抵抗的发展，不影响组胺神经元的活性，而脑室内（i.c.v）给予细胞因子可减少食物摄入量。白细胞介素-1 β也能减少食物摄入，但对食物摄入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中的脂溶作用。6)组胺神经元的激活产生胰岛素分泌的双相反应，即由于葡萄糖水平升高的直接刺激而快速加速，由于下丘脑的间接调节而随后抑制。7)胰岛素静脉注射对肾上腺交感神经传出电生理活动无影响。静脉注射组胺，而不是胰岛素，增加了大鼠的血压水平。综上所述，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并导致血压升高。本研究结果提示，下丘脑组胺与代谢因子如葡萄糖浓度、高胰岛素血症和强分泌瘦素之间的长期相互作用可能导致胰岛素抵抗

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