title: K channel impairment determines sex and age differences in epinephrine-mediated outcomes after brain injury.
abstract: Traumatic brain injury (TBI) is the leading cause of injury-related death in children, with boys and children under 4 years having particularly poor outcomes. Activation of ATP- and calcium-sensitive (KATPand KCa) channels produces cerebrovasodilation and contributes to autoregulation, both of which are impaired after TBI, contributing to poor outcomes. Upregulation of the c-Jun-terminal kinase (JNK) isoform of mitogen-activated protein kinase produces K channel function impairment after CNS injury. Vasoactive agents can be used to normalize cerebral perfusion pressure. Epinephrine (EPI) prevents impairment of cerebral autoregulation and hippocampal neuronal cell necrosis after TBI in female and male newborn and female juvenile but not male juvenile pigs via differential modulation of JNK. The present study used anesthetized pigs equipped with a closed cranial window to address the hypothesis that differential K channel impairment contributes to age and sex differences in EPI-mediated outcomes after brain injury. Results show that pial artery dilation in response to the KATPand KCachannel agonists cromakalim and NS 1619 was impaired after TBI and that such impairment was prevented by EPI in female and male newborn and female juvenile but not male juvenile pigs. Using vasodilation as an index of function, these data indicate that EPI protects cerebral autoregulation and limits histopathology after TBI through protection of K channel function via blockade of JNK in an age- and sex-dependent manner. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia.|Department of Pharmacology, University of Pennsylvania, Philadelphia.
authors.forename: William M
authors.identifier: 0000-0002-3241-801X
authors.initials: WM
authors.lastname: Armstead
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia.
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.affiliation: Department of Anesthesiology, Pediatrics, and Neurological Surgery, and Harborview Injury Prevention and Research Center, University of Washington, Seattle.
authors.forename: Monica S
authors.identifier: 0000-0002-4210-8066
authors.initials: MS
authors.lastname: Vavilala
mesh_terms: D000367:Age Factors; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D008297:Male; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D012727:Sex Characteristics; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D015221:Potassium Channels; D014665:Vasodilator Agents; D004837:Epinephrine
keywords: KATP, KCa channels; autoregulation; pressor support; traumatic brain injury