Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus.
Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus.
复制标题
DOI：
10.1161/hypertensionaha.110.160671
复制
发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Stocker SD
中科院分区：
文献类型：
--
作者：
Ward KR;Bardgett JF;Wolfgang L;Stocker SD
高胰岛素血症增加交感神经活动，并导致肥胖和糖尿病患者的心血管功能障碍。下丘脑室旁核的神经元通过与脊髓中的节前神经元的单突触和多突触连接来调节交感神经活动。本研究的目的是确定下丘脑室旁核神经元是否介导胰岛素的交感反应。在α-氯醛糖麻醉的雄性Sprague-Dawley大鼠（280-420 g）中，通过输注胰岛素（3.75 mU/kg/min）和50%葡萄糖（0.75-2.0 ml/h）120 min进行高胰岛素-正常血糖钳夹。在90 min时，胰岛素显著增加腰交感神经活动，而肾交感神经活动、心率或血糖水平无任何变化。双侧注射GABAA受体激动剂蝇蕈醇抑制下丘脑室旁核完全逆转了交感兴奋反应。然而，直接注射胰岛素到下丘脑室旁核没有改变腰交感神经活动，从而表明胰岛素激活下丘脑室旁核上游的神经元。有趣的是，下丘脑室旁核注射黑皮质素3/4受体拮抗剂SHU 9119可消除对胰岛素的交感神经反应，但不受血管紧张素II 1型受体拮抗剂氯沙坦的影响。最后一组实验表明，在高胰岛素血症期间，下丘脑室旁核神经元的激活增加了对延髓头端腹外侧的多巴胺能驱动。总的来说，这些研究结果表明，胰岛素激活黑皮质素依赖性途径下丘脑室旁核，增加延髓头端腹外侧区的多巴胺能驱动，并改变心血管功能。
Hyperinsulinemia increases sympathetic nerve activity and contributes to cardiovascular dysfunction in obesity and diabetes. Neurons of the hypothalamic paraventricular nucleus regulate sympathetic nerve activity through mono- and poly-synaptic connections to preganglionic neurons in the spinal cord. The purpose of the present study was to determine whether hypothalamic paraventricular nucleus neurons mediate the sympathetic response to insulin. Hyperinsulinemic-euglycemic clamps were performed in α-chloralose-anesthetized, male Sprague-Dawley rats (280–420 g) by an infusion of insulin (3.75 mU/kg/min) and 50% dextrose (0.75–2.0 ml/h) for 120 min. At 90 min, insulin significantly increased lumbar sympathetic nerve activity without any change in renal sympathetic nerve activity, heart rate, or blood glucose levels. Inhibition of the hypothalamic paraventricular nucleus with bilateral injection of the GABAA receptor agonist muscimol completely reversed the sympathoexcitatory response. However, direct injection of insulin into the hypothalamic paraventricular nucleus did not alter lumbar sympathetic nerve activity and thereby suggests insulin activates neurons upstream of the hypothalamic paraventricular nucleus. Interestingly, the sympathetic response to insulin was eliminated by hypothalamic paraventricular nucleus injection of the melancortin 3/4 receptor antagonist SHU9119 but unaffected by the angiotensin II type 1 receptor antagonist losartan. A final set of experiments suggests activation of hypothalamic paraventricular nucleus neurons during hyperinsulinemia increases glutamatergic drive to the rostral ventrolateral medulla. Collectively, these findings indicate insulin activates a melanocortin-dependent pathway to the hypothalamic paraventricular nucleus that increases glutamatergic drive to the rostral ventrolateral medulla and alter cardiovascular function.