Modulation of presynaptic cholinergic mechanisms by volatile anaesthetic agents.

The effects of volatile anaesthetic agents on three aspects of presynaptic acetylcholine (ACh) metabolism were investigated in vitro. Choline uptake and choline acetyltransferase (ChAT) activity were studied using rat cortical synaptosomes and ACh release was investigated employing rat cortical slices. The effect of volatile anaesthetic agents on neurotransmitter systems and the importance of ACh as a central neurotransmitter involved in the regulation of the conscious state is discussed. The evidence suggesting that central ACh function may be altered by anaesthesia is reviewed. Total choline uptake was inhibited non-competitively by all three volatile anaesthetic agents studied and the IC50 was 1.38 % for halothane, which is close to the ED50 for unconsciousness (minimum alveolar concentration, MAC). If present in vivo this may contribute to the process of anaesthesia. The Michaelis constant (Km) of ChAT was reduced significantly by enflurane but was unaffected by halothane and isoflurane. If present in vivo, an enflurane-induced reduction in Km of ChAT could lead to facilitation of ACh synthesis and contribute to the convulsant properties of enflurane, ACh release was measured using a modified chemiluminescent assay. ACh release was inhibited by halothane with an IC50 of 0.38 %, approximately one third of MAC. This is the most potent anaesthetic effect on neurotransmitter release reported in vitro to date. The results of this study demonstrate the in vitro sensitivity of presynaptic cholinergic metabolism to clinically relevant doses of anaesthetic agents and suggests that the cholinergic system may be a target for their action.