BACKGROUND: Halothane inhibits airway smooth muscle contraction in part by inhibiting the functional coupling between muscarinic receptors and one of its cognate heterotrimeric G proteins, Galphaq. Based on previous studies indicating a more potent effect of halothane and sevoflurane on airway smooth muscle contraction compared with isoflurane, the current study hypothesized that at anesthetic concentrations of 2 minimum alveolar concentration (MAC) or less, halothane and sevoflurane but not isoflurane inhibit acetylcholine-promoted Galphaq guanosine nucleotide exchange. METHODS: Galphaq guanosine nucleotide exchange was measured in crude membranes prepared from COS-7 cells transiently coexpressing the human M3 muscarinic receptor and human Galphaq. A radioactive, nonhydrolyzable analog of guanosine-5'-triphosphate, [35S]GTPgammaS, was used as a reporter for nucleotide exchange at Galphaq. RESULTS: Acetylcholine caused a concentration-dependent increase in Galphaq [35S]GTPgammaS-GDP exchange. Neither anesthetic affected constitutive Galphaq [35S]GTPgammaS-GDP exchange in the absence of acetylcholine. Conversely, each anesthetic caused a concentration-dependent and reversible inhibition of Galphaq [35S]GTPgammaS-GDP exchange when promoted by acetylcholine. At concentrations of 3 MAC or less, the effect of halothane and sevoflurane were significantly greater than that of isoflurane, with only a minimal inhibition by isoflurane observed at 2 MAC. CONCLUSION: The differential effects of volatile anesthetics on acetylcholine-promoted guanosine nucleotide exchange at Galphaq are consistent with the apparent more potent direct effect of halothane and sevoflurane compared with isoflurane on muscarinic receptor-mediated contraction of isolated airway smooth muscle. These differential effects also suggest a mode of anesthetic action that could be due to anesthetic-protein interactions and not simply anesthetic accumulation in the lipid membrane.
BACKGROUND:Halothane inhibits airway smooth muscle contraction in part by inhibiting the functional coupling between muscarinic receptors and one of its cognate heterotrimeric G proteins, Galphaq. Based on previous studies indicating a more potent effect of halothane and sevoflurane on airway smooth muscle contraction compared with isoflurane, the current study hypothesized that at anesthetic concentrations of 2 minimum alveolar concentration (MAC) or less, halothane and sevoflurane but not isoflurane inhibit acetylcholine-promoted Galphaqguanosine nucleotide exchange. METHODS:Galphaqguanosine nucleotide exchange was measured in crude membranes prepared from COS-7 cells transiently coexpressing the humanM3 muscarinic receptor and humanGalphaq. A radioactive, nonhydrolyzable analog of guanosine-5'-triphosphate, [35S]GTPgammaS, was used as a reporter for nucleotide exchange at Galphaq. RESULTS:Acetylcholine caused a concentration-dependent increase in Galphaq [35S]GTPgammaS-GDP exchange. Neither anesthetic affected constitutive Galphaq [35S]GTPgammaS-GDP exchange in the absence of acetylcholine. Conversely, each anesthetic caused a concentration-dependent and reversible inhibition of Galphaq [35S]GTPgammaS-GDP exchange when promoted by acetylcholine. At concentrations of 3 MAC or less, the effect of halothane and sevoflurane were significantly greater than that of isoflurane, with only a minimal inhibition by isoflurane observed at 2 MAC. CONCLUSION: The differential effects of volatile anesthetics on acetylcholine-promoted guanosine nucleotide exchange at Galphaq are consistent with the apparent more potent direct effect of halothane and sevoflurane compared with isoflurane on muscarinic receptor-mediated contraction of isolated airway smooth muscle. These differential effects also suggest a mode of anesthetic action that could be due to anesthetic-protein interactions and not simply anesthetic accumulation in the lipid membrane.
Authors: Eduardo E Icaza; Xinyan Huang; Ying Fu; Richard R Neubig; Helen A Baghdoyan; Ralph Lydic Journal: Anesth Analg Date: 2009-11 Impact factor: 5.108
Authors: George Gallos; Neil R Gleason; Laszlo Virag; Yi Zhang; Kentaro Mizuta; Robert A Whittington; Charles W Emala Journal: Anesthesiology Date: 2009-04 Impact factor: 7.892
Authors: Heinrich Gompf; Jingqiu Chen; Yi Sun; Masashi Yanagisawa; Gary Aston-Jones; Max B Kelz Journal: Anesthesiology Date: 2009-11 Impact factor: 7.892