Charlesworth, Paul; (1992) Anaesthetic modulation of ion channel kinetics in bovine chromaffin cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The thesis describes a patch clamp study of the action of anaesthetics on the ion channels primarily responsible for initiating secretion in bovine chromaffin cells. The adrenal chromaffin cell is homologous with sympathetic post-ganglionic neurones and was chosen as a model for studying excitatory neuronal synapses. Pre- and post- synaptic events are modelled by effects on the voltage-gated calcium channels and nicotinic acetylcholine receptor channel respectively. The overall aim has been to describe anaesthetic depression of excitatory synaptic transmission at the ion channel level. Results of experiments with a representative range of anaesthetic agents are shown. Modulation of the nicotinic receptor channel has been studied at the level of whole cell currents and single ion channels. Whole cell macroscopic currents were subjected to spectral analysis to derive kinetic parameters of channel gating. These parameters were also calculated from single channel studies and the results used to derive models explaining the modulation of nicotinic acetylcholine receptor channels by anaesthetics. It is shown that while there are common features in the action of different agents, the detailed mechanism by which they inhibit nicotinic gated ion channels varies. Prior to investigating the action of anaesthetics on calcium channel currents, a study was made using a variety of voltage pulse protocols and selective channel blockers to characterise the macroscopic current and asses the contribution of the various calcium channel sub-types. It is shown that calcium currents in chromaffin cells have two components, probably carried by L and N type channels as described by other workers. Of the anaesthetics studied, all but procaine reduced whole cell calcium channel currents within a relevant concentration range. A major component of the reduction in ion flux was due to an enhanced rate at which currents decayed after being activated by depolarising voltage pulses. This was observed with all effective agents, though the magnitude of the effect varied and it was not possible to ascribe it to a selective action on either channel type.

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