title: Cardiovascular stability and unchanged muscle sympathetic activity during xenon anaesthesia: role of norepinephrine uptake inhibition.
abstract: BACKGROUND
  Intraoperative hypotension is associated with increased risk of perioperative complications. The N-methyl-d-aspartate (NMDA) receptor (NMDA-R) antagonist xenon (Xe) induces general anaesthesia without impairment of cardiac output and vascular resistance. Mechanisms involved in cardiovascular stability have not been identified.
  
  
  METHODS
  Muscle sympathetic activity (MSA) (microneurography), sympathetic baroreflex gain, norepinephrine (NE) plasma concentration (high-performance liquid chromatography), anaesthetic depth (Narcotrend(®) EEG monitoring), and vital parameters were analysed in vivo during Xe mono-anaesthesia in human volunteers (n=8). In vitro, NE transporter (NET) expressing HEK293 cells and SH-SY5Y neuroblastoma cells were pre-treated with ketamine, MK-801, NMDA/glycine, or vehicle. Subsequently, cells were incubated with or without Xe (65%). NE uptake was measured by using a fluorescent NET substrate (n=4) or [(3)H]NE (n=6).
  
  
  RESULTS
  In vivo, Xe anaesthesia increased mean (standard deviation) arterial pressure from 93 (4) to 107 (6) mm Hg and NE plasma concentration from 156 (55) to 292 (106) pg ml(-1), P<0.01. MSA and baroreflex gain were unaltered. In vitro, ketamine decreased NET activity (P<0.01) in NET-expressing HEK293 cells, while Xe, MK-801, and NMDA/glycine did not. Xe reduced uptake in SH-SY5Y cells expressing NET and NMDA-Rs (P<0.01). MK-801 (P<0.01) and ketamine (P<0.01) also reduced NET activity, but NMDA/glycine blocked the effect of Xe on [(3)H]NE uptake.
  
  
  CONCLUSIONS
  In vivo, Xe anaesthesia does not alter sympathetic activity and baroreflex gain, despite increased mean arterial pressure. In vitro, Xe decreases the uptake of NE in neuronal cells by the inhibition of NET. This inhibition might be related to NMDA-R antagonism and explain increased NE concentrations at the synaptic cleft and in plasma, contributing to cardiovascular stability during Xe anaesthesia.
authors.affiliation: Department of Anaesthesiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Neukirchen
authors.forename: J
authors.initials: J
authors.lastname: Hipp
authors.forename: M S
authors.initials: MS
authors.lastname: Schaefer
authors.forename: T
authors.initials: T
authors.lastname: Brandenburger
authors.forename: I
authors.initials: I
authors.lastname: Bauer
authors.forename: M
authors.initials: M
authors.lastname: Winterhalter
authors.forename: P
authors.initials: P
authors.lastname: Kienbaum
authors.forename: R
authors.initials: R
authors.lastname: Werdehausen
mesh_terms: D000328:Adult; D018685:Anesthetics, Inhalation / Q000097:blood / Q000494:pharmacology*; D017704:Baroreflex / Q000187:drug effects; D001784:Blood Gas Analysis / Q000379:methods; D001794:Blood Pressure / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects*; D009638:Norepinephrine / Q000097:blood; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000097:blood / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014978:Xenon / Q000097:blood / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; D050484:Norepinephrine Plasma Membrane Transport Proteins; D014978:Xenon; D009638:Norepinephrine