Etomidate is a potent intravenous general anesthetic that has minimal effects on the cardiovascular and respiratory systems. It is a carboxylated imidazole compound that contains a single asymmetric carbon atom and thus exists in two mirror-image enantiomeric forms, with R(+)-etomidate being approximately 15 times more potent as an anesthetic than S(—)-etomidate (Tomlin et al. 1998). It turns out that there are relatively few molecular targets that show any significant sensitivity to R(+)-etomi-date, with one notable exception: the GABAa receptor. This important inhibitory neuro-transmitter-gated receptor channel is markedly potentiated by etomidate at clinically relevant concentrations and, importantly, it displays a stereoselectivity toward etomidate comparable with that found for anesthetic potencies in animals (Tomlin et al. 1998). (Incidentally, according to Tomlin et al. , etomidate shows no stereoselectivity when interacting with lipid bilayers.) It has recently been found that GABAA receptors which contain either the or P3 subunits show a particularly high sensitivity to etomidate (Belelli et al. 1997). It is highly likely that etomidate acts very selectively and exerts its major effects by potentiating the activities of GABAA receptor channels, with little involvement of other CNS targets.
Ketamine is another intravenous anaesthetic that may exert its effects largely at a single molecular target, although not the GABAA receptor. (In fact, ketamine is one of the very few anesthetics that do not potentiate the GABAA receptor [Franks and Lieb 1994; Brockmeyer et al. 1995]. It appears to act by blocking the aqueous pore of the NMDA receptor channel [MacDonald et al. 1987]). This conclusion has been drawn not only on grounds of sensitivity (Anis et al. 1983) but also because the NMDA receptor displays a stereoselectivity for ketamine very similar to that found for general anesthesia in animals, with the S(+) enantiomer being approximately three times more potent than the R(—) enantiomer (Lodge 1982; Zeilhofer et al. 1992; White et al. 1985; Ryder et al. 1978).
Although it is certainly possible that other molecular targets will be found which are im portant in the anesthetic states induced by these agents (particularly ketamine), it seems safe to conclude that, at the very least, these anesthetics cause loss of consciousness by directly binding to and affecting very different molecular targets: Etomidate potentiates the inhibitory GABAa receptor channel, while ketamine inhibits the excitatory NMDA receptor channel. How does this bear on the NMDA hypothesis?
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