Kim Seung Jae, Pilowsky Paul M, Farnham Melissa M J
Department of Physiology, Sydney Medical School, University of Sydney, and Heart Research Institute, Sydney, New South Wales, Australia.
Department of Physiology, Sydney Medical School, University of Sydney, and Heart Research Institute, Sydney, New South Wales, Australia
J Pharmacol Exp Ther. 2016 Sep;358(3):492-501. doi: 10.1124/jpet.116.234443. Epub 2016 Jul 6.
Intermittent hypoxia causes a persistent increase in sympathetic nerve activity (SNA), which progresses to hypertension in conditions such as obstructive sleep apnea. Orexins (A and B) are hypothalamic neurotransmitters with arousal-promoting and sympathoexcitatory effects. We investigated whether the sustained elevation of SNA, termed sympathetic long-term facilitation, after acute intermittent hypoxia (AIH) is caused by endogenous orexin acting on spinal sympathetic preganglionic neurons. The role of orexin in the increased SNA response to AIH was investigated in urethane-anesthetized, vagotomized, and artificially ventilated Sprague-Dawley rats (n = 58). A spinally infused subthreshold dose of orexin-A (intermittent; 0.1 nmol × 10) produced long-term enhancement in SNA (41.4% ± 6.9%) from baseline. This phenomenon was not produced by the same dose of orexin-A administered as a bolus intrathecal infusion (1 nmol; 7.3% ± 2.3%). The dual orexin receptor blocker, Almorexant, attenuated the effect of sympathetic long-term facilitation generated by intermittent orexin-A (20.7% ± 4.5% for Almorexant at 30 mg∙kg(-1) and 18.5% ± 1.2% for 75 mg∙kg(-1)), but not in AIH. The peripheral chemoreflex sympathoexcitatory response to hypoxia was greatly enhanced by intermittent orexin-A and AIH. In both cases, the sympathetic chemoreflex sensitization was reduced by Almorexant. Taken together, spinally acting orexin-A is mechanistically sufficient to evoke sympathetic long-term facilitation. However, AIH-induced sympathetic long-term facilitation appears to rely on mechanisms that are independent of orexin neurotransmission. Our findings further reveal that the activation of spinal orexin receptors is critical to enhance peripheral chemoreceptor responses to hypoxia after AIH.
间歇性低氧会导致交感神经活动（SNA）持续增加，在诸如阻塞性睡眠呼吸暂停等情况下会发展为高血压。食欲素（A和B）是具有促觉醒和交感兴奋作用的下丘脑神经递质。我们研究了急性间歇性低氧（AIH）后SNA的持续升高（称为交感神经长期易化）是否由内源性食欲素作用于脊髓交感神经节前神经元所致。在经乌拉坦麻醉、迷走神经切断并人工通气的Sprague-Dawley大鼠（n = 58）中研究了食欲素在AIH引起的SNA增加反应中的作用。脊髓内注入阈下剂量的食欲素A（间歇性；0.1 nmol×10）使SNA从基线水平产生长期增强（41.4%±6.9%）。同样剂量的食欲素A作为鞘内推注给药（1 nmol）则未产生此现象（7.3%±2.3%）。双重食欲素受体阻断剂阿莫瑞林减弱了间歇性食欲素A产生的交感神经长期易化作用（阿莫瑞林30 mg∙kg(-1)时为20.7%±4.5%，75 mg∙kg(-1)时为18.5%±1.2%），但对AIH无此作用。间歇性食欲素A和AIH极大地增强了外周化学反射对低氧的交感兴奋反应。在这两种情况下，阿莫瑞林均可降低交感化学反射敏感性。综上所述，脊髓作用的食欲素A在机制上足以引发交感神经长期易化。然而，AIH诱导的交感神经长期易化似乎依赖于独立于食欲素神经传递的机制。我们的研究结果进一步表明，脊髓食欲素受体的激活对于增强AIH后外周化学感受器对低氧的反应至关重要。
