The Effects of Ketamine and Propofol on Neuronal Nicotinic Acetylcholine Receptors and P2x Purinoceptors in PC12 Cells

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Abstract
We studied the effects of ketamine and propofol on two ligand-gated ion channels mediating fast synaptic transmission through sympathetic ganglia, neuronal nicotinic acetylcholine receptors (nAchRs), and P2X purinoceptors in a rat pheochromocytoma cell line PC12 using whole cell voltage clamp recording. Ketamine and propofol similarly inhibited the nicotine-induced inward current reversibly and dose-dependently at the membrane potential of -60 mV but had no effects on the adenosine triphosphate-induced current. Both anesthetics accelerated the current decay during agonist application, resulting in greater inhibition on the steady current than the peak current. The 50% inhibition concentration values for the steady current were lower than the clinically relevant concentrations for ketamine (2.8+/-0.6 microM) and higher than those for propofol (5.4+/-0.6 microM). Both anesthetics induced an addition of the fast component to the decay phase and an acceleration of the slow component, which suggests an open channel blockade or an enhancement of desensitization as a mechanism. The effects on closed channels seemed to be small because preincubation with the anesthetics did not significantly augment the block. Inhibition was voltage-independent at membrane potentials between -20 and -70 mV and was consistent with a noncompetitive block. Inhibition of the neuronal nAchR-mediated current may lead to the suppression of synaptic transmission in sympathetic ganglia by ketamine, but not by propofol, at the clinically relevant concentrations. However, these results are not consistent with changes in sympathetic nerve activities reported for animals or humans anesthetized with ketamine or propofol, which suggests effects from other systems, such as the central nervous system in vivo. Ketamine (at smaller than clinically relevant concentrations) and propofol (at larger than clinically relevant concentrations) inhibited neuronal nicotinic acetylcholine receptor-mediated current in PC12 cells, which possess the receptors that resemble those in postganglionic sympathetic neurons. These findings are not consistent with in vivo experiments, which suggests that effects from other systems, such as the central nervous system, are of importance.