Sodium channels and the synaptic mechanisms of inhaled anaesthetics

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Sodium channels and the synaptic mechanisms of inhaled anaesthetics H.C. Hemmings British Journal of Anaesthesia Volume 103, Issue 1, Pages 61-69 (July 2009) DOI: 10.1093/bja/aep144 Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 1 Steps in the process of synaptic transmission. The action potential invades the presynaptic bouton (1) leading to depolarization mediated by voltage-gated Na+ channels. This can be mimicked in isolated nerve terminals by the chemical secretogogue 4-aminopyridine. The depolarization activates voltage-gated Ca2+ channels closely coupled to docked and releasable synaptic vesicles. (2) Increased extracellular K+ can depolarize the membrane potential independent of Na+ channel involvement to an extent sufficient to activate Ca2+ channels and transmitter release. The local elevations in intracellular Ca2+ concentration bind to the SNARE vesicle fusion complex, leading to exocytosis of transmitter. (3) The transmitter enters the synaptic cleft where it diffuses to the postsynaptic cell, activates synaptic and extrasynaptic receptors, and thereby modifies the excitability of the postsynaptic cell. (4) Anaesthetics can potentially disrupt this process at multiple points. Considerable evidence implicates inhibition of presynaptic voltage-gated Na+ channels as a probable site of inhaled anaesthetic action, particularly at excitatory glutamatergic synapses. British Journal of Anaesthesia 2009 103, 61-69DOI: (10.1093/bja/aep144) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

Fig 2 Selective inhibition of Na+ channel-dependent glutamate release by isoflurane. Nerve terminals isolated from rat cerebral cortex were pre-labelled with radio-labelled glutamate and GABA, and release was measured following stimulation with either 4-aminopyridine (4AP) or elevated extracellular K+ as described in Figure 1.95 Na+ channel-dependent release of both glutamate (IC50=0.44 mM) and GABA (IC50=0.58 mM) evoked by 4AP was more sensitive to inhibition by isoflurane than release of glutamate (IC50=2.6 mM) or GABA (IC50=1.9 mM) evoked by elevated K+, consistent with a greater sensitivity of presynaptic Na+ channels than Ca2+ channels or other downstream processes. Moreover, 4AP-evoked release of the excitatory transmitter glutamate was inhibited at significantly lower concentrations than release of the inhibitory transmitter GABA within the clinical concentration range (0.5–2 MAC, or minimum alveolar concentration, which corresponds to the mean effective dose) indicated by gray shading. IC50, concentration for 50% inhibition. Unpublished data from H.C.H. and R.I. Westphalen. British Journal of Anaesthesia 2009 103, 61-69DOI: (10.1093/bja/aep144) Copyright © 2009 British Journal of Anaesthesia Terms and Conditions