中枢性胰岛素-血管紧张素II在果糖超载大鼠血压调节中的相互作用

M.A. Mayer , C. Höcht , J.F. Giani , M.C. Muñoz , A. Carranza , C.A. Taira , F.P. Dominici , A.M. Puyó , B.E. Fernández
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引用次数: 3

摘要

本研究的目的是确定胰岛素是否能够调节胰岛素抵抗果糖超载大鼠脑室内给药血管紧张素II的升压反应。雄性Sprague-Dawley大鼠分为两组:1)对照组(C)连续6周饮用自来水(n = 36);2)果糖处理(F),用果糖溶液(10% w/v)饮用6周(n = 36)。当天实验中,麻醉男性F C和老鼠intracerebroventricularly注射了胰岛素(12亩/小时,n = 15)或林格氏溶液作为车辆(n = 15) 2 h。立即改变平均动脉压(MAP)在回应一个intracerebroventricular subpressor剂量的血管紧张素ⅱ(5 pmol, n = 10)或车辆(n = 5)测定10分钟。然后,下丘脑被移除和Akt ERK1/2磷酸化水平测定。在C的一个子集(n = 10)和F (n = 20)动物,PD98059 (p44/42 MAPK抑制剂)或车辆的流量管理intracerebroventricularly 5μl / min 1分钟。十分钟后,胰岛素(12亩/小时,每组(n = 5)或车辆(林格氏溶液,只有在F组,n = 5)的流量为2 h灌注4μl / h,每15分钟测量和心血管参数。马上以5 pmol/2 μl的angii亚压剂作用10 min(每组n = 5),评价MAP和HR的变化。在其他动物亚群中(每组n = 6),采用Western blotting检测下丘脑AT1和AT2受体水平。脑室内胰岛素预处理增加了C大鼠对血管紧张素II的升压反应。在F大鼠(有或没有胰岛素预处理)中,血管紧张素II的升压反应高于对照组预处理的C动物,但与胰岛素输注后的C动物相似。注射血管紧张素II后,经胰岛素预处理的C大鼠下丘脑磷酸化- erk 1/2水平显著升高,提示MAPK激活可能参与胰岛素增强血压对血管紧张素II的反应。与C相比,F大鼠的下丘脑磷酸化- erk 1/2水平显著升高,这表明基础MAPK激活可能在这些动物中观察到的对血管紧张素II的增强反应中起作用。最后,在F大鼠中,无论是在载药还是胰岛素输注后,血管紧张素II注射与下丘脑磷酸化- erk 1/2水平的相似升高相关,与注射胰岛素预处理的C动物血管紧张素II后观察到的结果相当。与C相比,ERK 1/2阻断显著降低了F大鼠的MAP。此外,ERK 1/2抑制完全消除了F大鼠和胰岛素预处理C动物的Ang II加压反应。这些结果提示,胰岛素-血管紧张素II在下丘脑水平的相互作用可能与胰岛素抵抗状态下观察到的血压升高有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Central insulin–angiotensin II interaction in blood pressure regulation in fructose overloaded rats

The aim of the present study was to determine if insulin is able to modulate the pressor response to intracerebroventricularly administered angiotensin II in insulin resistant fructose overloaded rats.

Male Sprague-Dawley rats were divided into two groups: 1) Control group (C) with tap water to drink for 6 weeks (n = 36); and 2) fructose treated (F), with fructose solution (10% w/v) to drink for 6 weeks (n = 36). On the day of the experiment, anesthetized male C and F rats were intracerebroventricularly infused with insulin (12 mU/h, n = 15) or Ringer's solution as vehicle (n = 15) for 2 h. Immediately, changes in mean arterial pressure (MAP) in response to an intracerebroventricular subpressor dose of angiotensin II (5 pmol, n = 10) or vehicle (n = 5) were measured for 10 min. Then, hypothalami were removed and Akt and ERK1/2 phosphorylation levels were determined. In a subset of C (n = 10) and F (n = 20) animals, PD98059 (p44/42 MAPK inhibitor) or vehicle was administered intracerebroventricularly at a flow rate of 5 μl/min for 1 min. Ten minutes later, insulin (12 mU/h, n = 5 for each group) or vehicle (Ringer's solution, only in the F group, n = 5) was perfused for 2 h at a flow rate of 4 μl/h, and cardiovascular parameters were measured every 15 min. Immediately, changes in MAP and HR in response to a subpressor dose of Ang II (5 pmol/2 μl) were evaluated for 10 min (n = 5 for each group). In other subset of animals (n = 6 for each group), AT1 and AT2 hypothalamic receptor levels were measured by Western blotting.

Intracerebroventricular insulin pre-treatment increased the pressor response to angiotensin II in C rats. In F rats (with or without insulin pretreatment), the pressor response to angiotensin II was higher than that in vehicle pre-treated C animals, but similar to that observed in C after insulin infusion. In C rats phospho-ERK 1/2 hypothalamic levels significantly increased after angiotensin II injection in insulin pretreated animals compared to vehicle pre-treated rats, suggesting that MAPK activation might be involved in insulin potentiation of blood pressure response to angiotensin II in the brain. Phospho-ERK 1/2 hypothalamic levels were significantly increased in vehicle treated F rats compared to C, suggesting that basal MAPK activation might play a role in the enhanced response to angiotensin II observed in these animals. Finally, in F rats, either after vehicle or insulin infusion, angiotensin II injection was associated with a similar increase in phospho-ERK 1/2 hypothalamic levels, comparable to that observed after angiotensin II injection in insulin pre-treated C animals. ERK 1/2 blockade significantly reduced MAP in F rats compared to C. Moreover, ERK 1/2 inhibition completely abolished the Ang II pressor response in F rats and in insulin pre-treated C animals. All these findings suggest that insulin–angiotensin II interaction at hypothalamic level might be involved in the increase in blood pressure observed in the insulin resistant state.

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来源期刊
Regulatory Peptides
Regulatory Peptides 医学-内分泌学与代谢
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审稿时长
2 months
期刊介绍: Regulatory Peptides provides a medium for the rapid publication of interdisciplinary studies on the physiology and pathology of peptides of the gut, endocrine and nervous systems which regulate cell or tissue function. Articles emphasizing these objectives may be based on either fundamental or clinical observations obtained through the disciplines of morphology, cytochemistry, biochemistry, physiology, pathology, pharmacology or psychology.
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