Glutamatergic receptor activation in the rostral ventrolateral medulla mediates the sympathoexcitatory response to hyperinsulinemia.
Glutamatergic receptor activation in the rostral ventrolateral medulla mediates the sympathoexcitatory response to hyperinsulinemia.
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DOI：
10.1161/hypertensionaha.109.146605
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Stocker SD
中科院分区：
文献类型：
--
作者：
Bardgett ME;McCarthy JJ;Stocker SD
高胰岛素血症增加交感神经活动（SNA），并与肥胖症的心血管发病率有关。延髓头端腹外侧区（RVLM）在SNA和动脉血压（ABP）的调节中起着关键作用。许多交感神经兴奋性反应是由RVLM内的血管紧张素能受体激活介导的，并且中枢肾素-血管紧张素和黑皮质素系统都涉及对高胰岛素血症的交感神经兴奋性反应。因此，我们假设RVLM中的一种或多种神经递质介导了对胰岛素的交感兴奋性反应。在α-氯醛糖麻醉的雄性Sprague-Dawley大鼠中，通过输注胰岛素（3.75 mU/kg/min，IV）和50%葡萄糖溶液120 min进行高胰岛素-正常血糖钳夹。血浆胰岛素的生理性增加升高了腰椎SNA，而肾脏SNA、ABP或血糖无变化。在RVLM内微量注射离子型谷氨酸受体拮抗剂犬尿烯酸可显著降低腰段SNA和ABP。选择性阻断NMDA而非非NMDA谷氨酸受体导致腰椎SNA类似的减少。与此形成鲜明对比的是，微量注射血管紧张素II 1型受体拮抗剂氯沙坦或黑素皮质素3/4拮抗剂SHU 9119对腰椎SNA或ABP没有影响。Western blot分析显示，RVLM中胰岛素受体的表达明显低于下丘脑，直接微量注射胰岛素到RVLM中并没有显着增加腰椎SNA。这些结果表明，高胰岛素血症增加腰SNA的激活NMDA依赖性投射到RVLM的多巴胺能。
Hyperinsulinemia increases sympathetic nerve activity (SNA) and has been linked to cardiovascular morbidity in obesity. The rostral ventrolateral medulla (RVLM) plays a key role in the regulation of SNA and arterial blood pressure (ABP). Many sympathoexcitatory responses are mediated by glutamatergic receptor activation within the RVLM, and both the central renin-angiotensin and melanocortin systems are implicated in the sympathoexcitatory response to hyperinsulinemia. Therefore, we hypothesized that one or more of these neurotransmitters in the RVLM mediate the sympathoexcitatory response to insulin. Hyperinsulinemic-euglycemic clamps were performed in α-chloralose anesthetized, male Sprague-Dawley rats by infusion of insulin (3.75 mU/kg/min, IV) and 50% dextrose solution for 120 min. Physiological increases in plasma insulin elevated lumbar SNA with no change in renal SNA, ABP or blood glucose. Microinjection of the ionotropic glutamate receptor antagonist kynurenic acid into the RVLM significantly reduced lumbar SNA and ABP. Selective blockade of NMDA but not non-NMDA glutamate receptors resulted in similar reductions of lumbar SNA. In marked contrast, microinjection of the angiotensin II type 1 receptor antagonist losartan or the melanocortin 3/4 antagonist SHU9119 had no effect on lumbar SNA or ABP. Western blot analysis showed that insulin receptor expression is significantly lower in the RVLM than the hypothalamus, and direct microinjection of insulin into the RVLM did not significantly increase lumbar SNA. These findings suggest that hyperinsulinemia increases lumbar SNA by activation of a glutamatergic NMDA-dependent projection to the RVLM.