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ANESTHETIC PHARMACOLOGY

Sensitivity of the 7 Nicotinic Acetylcholine Receptor to Isoflurane May Depend on Receptor Inactivation

Department of Anesthesiology, Columbia University, New York

Address correspondence to Pamela Flood, MD, Department of Anesthesiology, Columbia University, 630 West 168th St., New York, NY 10032. Address e-mail to pdf3{at}columbia.edu

In previous studies, we demonstrated that nicotinic acetylcholine receptors (nAChRs) composed of the 7 subunit are unaffected by the co-application of isoflurane with agonists at concentrations up to 640 µM (two times the minimum alveolar anesthetic concentration). Modulation of 7-nAChR activity by isoflurane might have important behavioral ramifications because these receptors are expressed diffusely in the central and peripheral nervous systems and play pre- and postsynaptic roles in synaptic transmission. Here we have demonstrated that under some potentially physiologically relevant circumstances, the activation of 7 nAChRs may be inhibited by clinically relevant concentrations of isoflurane. We evaluated isoflurane inhibition of 7 nAChRs from chicks and humans expressed in Xenopus oocytes using two-electrode voltage clamp methodology. We determined the influence of time of preperfusion of isoflurane, agonist concentration, and membrane potential on inhibition by isoflurane. Both activation by a large concentration of agonist and isoflurane preperfusion increased inhibition. The half-maximal inhibitory concentration for isoflurane inhibition of chick 7 nAChR with isoflurane preperfusion and activation by 100 µM of acetylcholine was 938 ± 26, and when activated by 1 mM of acetylcholine, it was 408 ± 51 µM. The increase in inhibition with isoflurane preexposure and large agonist concentration raises the possibility that isoflurane interacts preferentially with a closed or closed-desensitized state of the channel.

IMPLICATIONS: Nicotinic receptors expressed in the brain have been considered a possible target for the actions of isoflurane. We studied the effect of isoflurane on 7 type nicotinic receptors expressed in Xenopus oocytes. We find that when activated by large concentrations of acetylcholine, 7 nicotinic receptors are inhibited by isoflurane at concentrations near MAC.

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