P Flood1, J Ramirez-Latorre, L Role. 1. Columbia University, Department of Anesthesiology, New York, New York 10032, USA. PDF3@Columbia.edu
Abstract
BACKGROUND: The mechanisms of action of general anesthetics are not completely understood. Many general anesthetics are reported to potentiate gamma-aminobutyric acid (GABAA) and glycine receptors in the central nervous system (CNS) and to inhibit the muscle-type nicotinic acetylcholine receptor (nAChR). The effects of general anesthetics on another family of ligand-gated ion channel in the CNS, the nAChRs, have not been defined. METHODS: Two types of CNS acetylcholine receptor, the alpha 4 beta 2 receptor or the alpha 7 homomeric receptor, were expressed heterologously in Xenopus laevis oocytes. Using the standard two-microelectrode voltage-clamp technique, peak acetylcholinegated current was measured before and after coapplication of isoflurane or propofol. RESULTS: Coapplication of either isoflurane or propofol with acetylcholine resulted in potent, dose-dependent inhibition of the alpha 4 beta 2 receptor current with median inhibitory concentrations of 85 and 19 microM, respectively. The inhibition of the alpha 4 beta 2 receptor by both isoflurane and propofol appears to be competitive with respect to acetylcholine. The alpha 7 receptor current was not effected by either anesthetic. CONCLUSIONS: The CNS-type nAChRs are differentially affected by isoflurane and propofol. The alpha 4 beta 2 receptor is affected by isoflurane more potently than the most sensitive GABAA or glycine receptor that has been reported, whereas the alpha 7 homomeric receptor is not affected by either anesthetic. Inhibition of specific subtypes of nAChRs in the CNS, along with potentiation of GABAA and glycine receptors, may contribute to the effects and side effects of general anesthetics.
BACKGROUND: The mechanisms of action of general anesthetics are not completely understood. Many general anesthetics are reported to potentiate gamma-aminobutyric acid (GABAA) and glycine receptors in the central nervous system (CNS) and to inhibit the muscle-type nicotinic acetylcholine receptor (nAChR). The effects of general anesthetics on another family of ligand-gated ion channel in the CNS, the nAChRs, have not been defined. METHODS: Two types of CNS acetylcholine receptor, the alpha 4 beta 2 receptor or the alpha 7 homomeric receptor, were expressed heterologously in Xenopus laevis oocytes. Using the standard two-microelectrode voltage-clamp technique, peak acetylcholinegated current was measured before and after coapplication of isoflurane or propofol. RESULTS: Coapplication of either isoflurane or propofol with acetylcholine resulted in potent, dose-dependent inhibition of the alpha 4 beta 2 receptor current with median inhibitory concentrations of 85 and 19 microM, respectively. The inhibition of the alpha 4 beta 2 receptor by both isoflurane and propofol appears to be competitive with respect to acetylcholine. The alpha 7 receptor current was not effected by either anesthetic. CONCLUSIONS: The CNS-type nAChRs are differentially affected by isoflurane and propofol. The alpha 4 beta 2 receptor is affected by isoflurane more potently than the most sensitive GABAA or glycine receptor that has been reported, whereas the alpha 7 homomeric receptor is not affected by either anesthetic. Inhibition of specific subtypes of nAChRs in the CNS, along with potentiation of GABAA and glycine receptors, may contribute to the effects and side effects of general anesthetics.