Background. The i.v. anaesthetic propofol produces bronchodilatation. Airway relaxation involves reduced intracellular Ca2+ ([Ca 2+]i) in airway smooth muscle (ASM) and lipid rafts (caveolae), and constitutional caveolin proteins regulate [Ca2+]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 M histamine with and without clinically relevant concentrations of propofol (10 and 30 μM and intralipid control). Effects on sarcoplasmic reticulum (SR) Ca2+ release were evaluated in zero extracellular Ca2+ using the blockers Xestospongin C and ryanodine. Store-operated Ca2+ 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 [Ca2+]i and force regulation were also evaluated. Results. Propofol was present in ASM caveolar fractions in substantial concentrations. Exposure to 10 or 30 M propofol form decreased [Ca2+]i peak (but not plateau) responses to histamine by ∼40, an effect persistent in zero extracellular Ca2. Propofol effects were absent in caveolin-1 siRNA-transfected cells. Inhibition of ryanodine receptors prevented propofol effects on [Ca2+]i, while propofol blunted [Ca2+]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.
- bronchial smooth muscle
- calcium regulation
- intravenous anaesthetic
ASJC Scopus subject areas
- Anesthesiology and Pain Medicine