The regulation of cyclic GMP during anaesthesia
The glutamate-NO-cyclic GMP pathway has previously been identified as a potential major target for general anaesthetic agents. An animal model of type I NOS gene disrupted mice was employed to investigate in vivo effects of the general anaesthetic agents isoflurane, ketamine, pentobarbital, and propofol on cyclic GMP in the presence or absence of the isoform specific NOS inhibitor, 7-nitroindazole. G protein function was studied ex vivo in whole brains. Primary neuronal cell cultures were employed to investigate the effects of anaesthetic agents on glutamate stimulated cyclic GMP production. The influence of anaesthetic agents on the metabolism of cyclic GMP via phosphodiesterases was studied in vitro. The effects of anaesthetic agents on the regulation of cyclic GMP in humans are unknown. Cyclic GMP was measured in human oral mucosal transudate in volunteers and patients undergoing short general anaesthesia. A prospective double-blind placebo controlled crossover trial was conducted assessing the effects of selective PDE5 inhibition on propofol sedation requirements in healthy volunteers. Both studies indicate a potential role of cyclic GMP mediating consciousness in humans. The work presented in this thesis indicates substantial effects of anaesthetic agents on the regulation of cyclic GMP in in vivo, ex vivo, in vitro and human studies and provides new insights into the mechanisms involved in modulating general anaesthesia. However, a great deal of further work remains before the complex processes underlying general anaesthesia are fully elucidated.