title: Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats.
abstract: 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.
authors.affiliation: Department of Physiology, Sydney Medical School, University of Sydney, and Heart Research Institute, Sydney, New South Wales, Australia.
authors.forename: Seung Jae
authors.identifier: 0000-0003-0268-6029
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, Sydney Medical School, University of Sydney, and Heart Research Institute, Sydney, New South Wales, Australia paul.pilowsky@hri.org.au.
authors.forename: Paul M
authors.identifier: 0000-0003-3500-467X
authors.initials: PM
authors.lastname: Pilowsky
authors.affiliation: Department of Physiology, Sydney Medical School, University of Sydney, and Heart Research Institute, Sydney, New South Wales, Australia.
authors.forename: Melissa M J
authors.identifier: 0000-0002-7612-1015
authors.initials: MM
authors.lastname: Farnham
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002628:Chemoreceptor Cells / Q000166:cytology* / Q000187:drug effects*; D007278:Injections, Spinal; D017774:Long-Term Potentiation / Q000187:drug effects*; D000068797:Orexins / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology*; D013997:Time Factors
chemical_list: D000068797:Orexins