【作者】 石伟彬；

【导师】 刘光耀； 杨成明；

【作者基本信息】 第三军医大学 ， 内科学， 2002， 硕士

【摘要】 高血压是严重威胁人类健康的常见病之一, 高血压及其所引起的并发症不仅给患者造成巨大的身心痛苦，而且给家庭和社会带来了沉重的经济负担和社会问题。但其发病具体机制仍不清楚。循环高胰岛素血症和胰岛素抵抗在高血压发病中起重要作用。新近研究表明：脑内广泛分布且能自身合成胰岛素和胰岛素受体。另一方面亦证实自发性高血压大鼠(Spontaneous Hypertensive Rat,SHR)下丘脑胰岛素含量显著高于正常血压Wistar大鼠，侧脑室和下丘脑腹内侧核微量注入胰岛素可抑制交感神经系统活性和洋地黄类物质释放而降低血压、减慢心率。中枢神经系统在高血压的发生发展中起重要作用。因此深入探讨中枢神经系统内胰岛素和胰岛素受体的变化及与高血压的关系有助于高血压发病机制的研究并为临床诊治提供实验理论依据。本实验利用自发性高血压大鼠、胰岛素抵抗高血压大鼠(Insulin resisrance hypertensive rat，IRH)及正常血压Wistar大鼠模型，采用放射免疫分析、受体放射配基分析、逆转录PCR和微量注射方法检测各组大鼠下丘脑胰岛素含量、胰岛素受体最大结合容量和平衡解离常数、胰岛素mRNA以及下丘脑前区微量注射胰岛素的平均动脉血压(Mean Arteria Pressure，MAP)的变化等指标。结果与结论：1. 中枢神经系统中胰岛素分布广泛，但分布不均匀，下丘脑、嗅球和海马中最高，大脑皮层、小脑最低。下丘脑胰岛素含量SHR高于正常血压大鼠，而血浆胰岛素与Wistar大鼠无明显变化，胰岛素水平与血压未见相<WP=8>关性。2. 高蔗糖热量饮食复制出胰岛素抵抗高血压动物模型，其血浆胰岛素水平显著高于SHR和正常血压大鼠，血压显著高于正常饮食组而血糖无显著改变。3. SHR下丘脑胰岛素受体Bmax代偿性下调，KD值无显著变化，胰岛素受体mRNA定量分析显示低于其余两组大鼠。下丘脑胰岛素受体数目代偿性下调，其下调可能主要是受体基因表达减少。4. SHR下丘脑前区微量注入0.2pmol胰岛素，在注射后一小时MAP显著下降，其余各组MAP和血糖均无变化。下丘脑胰岛素在高血压发生发展过程起到保护作用，抑制血压的过度升高。其具体机制尚有待深入研究。更多还原

【Abstract】 Hypertension is one of the diseases seriously threatening health of human beings. Hypertension and its complications can cause not only patients’ tremendous agony in body and mind, but also a heavy burden to their families and the society. But the pathogenesis remains unclear. Insulin resistance and hyperinsulinmia plays an important role in the development of hypertension. It has been hypothesized from the experimental researches that insulin and insulin receptor are widely distributed and can be synthesized in the central nervous system. On the other hand, previous studies have shown that the central insulin concentration of spontaneous hypertensive rats was higher than that of Wistar rats. And microinjections of insulin into the ventromedial nucleus in the hypothalamus and the lateral ventricle can cause vasodepression and bradycardia via the suppression of both sympathetic nervous system activities and the release of digitalis-like substances. Central nervous system has an important role in the development of hypertension. A deeper understanding of the relationship between the central insulin, insulin receptor and blood pressure will be helpful to explain the pathogenesis of hypertension and offer an experimental basis in the treatment of hypertension.In this study, we have investigated the concentration of insulin in hypothalamus, the Bmax and KD of InsR in cellualr membrane from hypothalamus, InsR mRNA and effects of microinjection of insulin into anterior hypothalamic area on blood pressure and blood glucose at different blood pressure by means of RIA (radioimmunoassay), RBA (radioligand<WP=6>binding assay of receptor), RT-PCR and microinjection. The main results are as follows:⑴ The insulin was widely and unequally distributed in the rat brain. The insulin concentrations in hypothalamus, hippocampus and olfactory bulb were higher than those in cerebral cortex and midbrain, but much lower in medulla oblongata. The insulin concentration in hypothalamus of SHR was higher than that in Wistar (P<0.05), but the plasma insulin concentration was similar without significant difference. The insulin concentration was not associated with blood pressure in any part of brain. ⑵ With high sucrose diets, the animal model of insulin resistance had been set up successfully in the Wistar rats and the concentration of insulin in plasma was higher than that of SHR and IRH. (P<0.05), the blood pressure was also higher than that of Wistar rats.⑶The quantity of insulin receptor in the hypothalamus was a down- regulated in response to the increased concentration of insulin in SHR, which maybe result from the decreased expression of the InsR mRNA, without changes found in its KD.⑷Microinjection of insulin (0.2pmol) into anterior hypothalamic area significantly decreased mean arterial pressure in SHR group, but not in other groups. Blood glucose concentration was not affected by the microinjection of insulin in all groups. The insulin in the hypothalamus may be a negative feedback to the high arterial pressure and has a protective effect on inhibiting the continuous increase of arterial pressure during the development of hypertension. But the mechanism needs further investigation .更多还原