title: Isoflurane pretreatment preserves adenosine triphosphate-sensitive K(+) channel function in the human artery exposed to oxidative stress caused by high glucose levels.
abstract: BACKGROUND
  Adenosine triphosphate (ATP)-sensitive K(+) channels contribute to significant regulatory mechanisms related to organ blood flow in both physiological and pathological conditions. High glucose impairs arterial ATP-sensitive K(+) channel activity via superoxide production. However, the effects of anesthetics on this pathological process have not been evaluated in humans. In the present study, we investigated whether pretreatment with the volatile anesthetic isoflurane preserves ATP-sensitive K(+) channel activity in the human artery exposed to oxidative stress caused by high glucose.
  
  
  METHODS
  All experiments were performed using human omental arteries without endothelium in the presence of d-glucose (5.5 mmol/L). Some arteries were treated with isoflurane (1.15% or 2.3%) in combination with d- or l-glucose (20 mmol/L) for 60 minutes, and then only isoflurane was discontinued. Relaxation and hyperpolarization of arterial segments in response to an ATP-sensitive K(+) channel opener levcromakalim were evaluated using the isometric force recording or electrophysiological study, respectively. Superoxide production was determined by dihydroethidium fluorescence. Immunohistochemical analysis for a subunit of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47phox was performed. Data were evaluated using repeated-measures analysis of variance or a factorial analysis of variance as appropriate, followed by Scheffé test.
  
  
  RESULTS
  The ATP-sensitive K(+) channel antagonist glibenclamide (10(-6) mol/L) abolished relaxation induced by cumulative addition of levcromakalim (10(-8) to 10(-5) mol/L) in arteries treated with l-glucose (20 mmol/L). Incubation with d-glucose (20 mmol/L) impaired the vasorelaxation induced by levcromakalim. The selective NADPH oxidase NOX2 inhibitor gp91ds-tat (10(-6) mol/L) and pretreatment with isoflurane (1.15% and 2.3%) restored relaxation in response to levcromakalim in arteries treated with d-glucose (20 mmol/L). Isoflurane (2.3%), gp91ds-tat (10(-6) mol/L), and their combination similarly restored hyperpolarization in response to levcromakalim (3 × 10(-6) mol/L) in arteries treated with d-glucose (20 mmol/L). Along with these results, isoflurane (2.3%) reduced superoxide production and the intracellular mobilization of the cytosolic NOX2 subunit p47phox toward smooth muscle cell membrane in arteries treated with d-glucose (20 mmol/L).
  
  
  CONCLUSIONS
  We have demonstrated for the first time a beneficial effect from the pretreatment with isoflurane on the isolated human artery. Pretreatment with isoflurane preserves ATP-sensitive K(+) channel activity in the human omental artery exposed to oxidative stress induced by high glucose, whereas the effect seems to be mediated by NADPH oxidase inhibition. Volatile anesthetics may protect human visceral arteries from malfunction caused by oxidative stress.
authors.affiliation: Department of Anesthesiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan. hkinoshi@wakayama-med.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iranami
authors.forename: Koji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Noboru
authors.initials: N
authors.lastname: Hatakeyama
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Azma
authors.forename: Shinji
authors.initials: S
authors.lastname: Kawahito
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Yamazaki
mesh_terms: D000368:Aged; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007530:Isoflurane / Q000494:pharmacology*; D054086:KATP Channels / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009213:Myography; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009852:Omentum / Q000098:blood supply*; D018384:Oxidative Stress / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D054086:KATP Channels; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; D019806:Cromakalim; D013481:Superoxides; D007530:Isoflurane; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D005947:Glucose