title: Caveolae and propofol effects on airway smooth muscle.
abstract: BACKGROUND
  The i.v. anaesthetic propofol produces bronchodilatation. Airway relaxation involves reduced intracellular Ca(2+) ([Ca(2+)](i)) in airway smooth muscle (ASM) and lipid rafts (caveolae), and constitutional caveolin proteins regulate [Ca(2+)](i). We postulated that propofol-induced bronchodilatation involves caveolar disruption.
  
  
  METHODS
  Caveolar fractions of human ASM cells were tested for propofol content. [Ca(2+)](i) responses of ASM cells loaded with fura-2 were performed in the presence of 10 µM histamine with and without clinically relevant concentrations of propofol (10 and 30 μM and intralipid control). Effects on sarcoplasmic reticulum (SR) Ca(2+) release were evaluated in zero extracellular Ca(2+) using the blockers Xestospongin C and ryanodine. Store-operated Ca(2+) entry (SOCE) after SR depletion was evaluated using established techniques. The role of caveolin-1 in the effect of propofol was tested using small interference RNA (siRNA) suppression. Changes in intracellular signalling cascades relevant to [Ca(2+)](i) and force regulation were also evaluated.
  
  
  RESULTS
  Propofol was present in ASM caveolar fractions in substantial concentrations. Exposure to 10 or 30 µM propofol form decreased [Ca(2+)](i) peak (but not plateau) responses to histamine by ~40%, an effect persistent in zero extracellular Ca(2+). Propofol effects were absent in caveolin-1 siRNA-transfected cells. Inhibition of ryanodine receptors prevented propofol effects on [Ca(2+)](i), while propofol blunted [Ca(2+)](i) responses to caffeine. Propofol reduced SOCE, an effect also prevented by caveolin-1 siRNA. Propofol effects were associated with decreased caveolin-1 expression and extracellular signal-regulated kinase phosphorylation.
  
  
  CONCLUSIONS
  These novel data suggest a role for caveolae (specifically caveolin-1) in propofol-induced bronchodilatation. Due to its lipid nature, propofol may transiently disrupt caveolar regulation, thus altering ASM [Ca(2+)](i).
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Grim
authors.forename: A J
authors.initials: AJ
authors.lastname: Abcejo
authors.forename: A
authors.initials: A
authors.lastname: Barnes
authors.forename: V
authors.initials: V
authors.lastname: Sathish
authors.forename: D F
authors.initials: DF
authors.lastname: Smelter
authors.forename: G C
authors.initials: GC
authors.lastname: Ford
authors.forename: M A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.forename: C M
authors.initials: CM
authors.lastname: Pabelick
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D021941:Caveolae / Q000502:physiology*; D051242:Caveolin 1 / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D015742:Propofol / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D018686:Anesthetics, Intravenous; C495540:CAV1 protein, human; D051242:Caveolin 1; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D006632:Histamine; D002118:Calcium; D015742:Propofol