title: Anesthesia with sevoflurane in neonatal rats: Developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl(-) importer antagonists.
abstract: BACKGROUND
  1.5 million children under 12 months of age are exposed to general anesthesia annually in the United States alone. Human and especially animal studies provide evidence that exposure to general anesthesia during the early postnatal period may lead to long-term neurocognitive abnormalities via poorly understood mechanisms. We investigated whether an immature stress response system and γ-aminobutyric acid (GABA) type A receptor activities are involved in mediating these abnormalities.
  
  
  METHODS
  Sprague-Dawley rats at postnatal days 4, 5 or 6 were anesthetized with 2.1% sevoflurane for 6h; maternally separated and house reared rats served as controls.
  
  
  RESULTS
  Sevoflurane anesthesia markedly increased corticosterone levels in rat pups of both genders. In adulthood, these rats responded to stress with heightened secretion of corticosterone and a greater increase in corticosterone levels in males versus females. Only male rats, previously exposed to neonatal sevoflurane, had a higher frequency of miniature inhibitory postsynaptic currents in CA1 neurons, spent a shorter time in open arms of the elevated plus maze (EPM) and exhibited impaired prepulse inhibition (PPI) of startle. Pretreatment of male rats prior to sevoflurane with the Na(+)-K(+)-2Cl(-) cotransporter inhibitor, bumetanide, or the mineralocorticoid receptor antagonist, RU28318, normalized endocrine responses to stress and the EPM behavior in adulthood, while only those pretreated with bumetanide exhibited normalized PPI of startle responses. Neither bumetanide nor RU28318 altered the effect of sevoflurane on synaptic activity.
  
  
  CONCLUSIONS
  Sevoflurane-enhanced neuronal excitation and elevated corticosteroid levels at the time of anesthesia contribute to the mechanisms initiating neonatal sevoflurane-induced long-term endocrine and neurobehavioral abnormalities.
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Sijie
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; Department of Anesthesiology, People's Hospital of Zhengzhou University, Zhengzhou, P.R.China.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Christoph N
authors.initials: CN
authors.lastname: Seubert
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gravenstein
authors.affiliation: The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA; Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Terrie
authors.initials: T
authors.lastname: Vasilopoulos
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA. Electronic address: amartynyuk@anest.ufl.edu.
authors.forename: Anatoly E
authors.initials: AE
authors.lastname: Martynyuk
mesh_terms: D000769:Anesthesia, Inhalation / Q000009:adverse effects*; D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000523:psychology; D002034:Bumetanide / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D003345:Corticosterone / Q000097:blood*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D008297:Male; D008426:Maternal Deprivation; D008738:Methyl Ethers / Q000009:adverse effects*; D009490:Neurosecretory Systems / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D000077149:Sevoflurane; D012727:Sex Characteristics; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D018118:Chloride Channels; D008738:Methyl Ethers; D011963:Receptors, GABA-A; D002034:Bumetanide; D013148:Spironolactone; D000077149:Sevoflurane; C041006:RU 28318; D003345:Corticosterone
keywords: Brain; Corticosterone; Endocrine; GABA; Neonatal; Sevoflurane