Inhaled Anesthetics Do Not Combine to Produce Synergistic Effects Regarding Minimum Alveolar Anesthetic Concentration in Rats

In Brief BACKGROUND: We hypothesized that pairs of inhaled anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By “divergently,” we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and γ-aminobutyric acid type A, glycine, N-methyl-d-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-d-aspartic acid blocker MK-801 had divergent effects on the MACs of these anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that inhaled anesthetics act on a single site to produce immobility in the face of noxious stimulation. IMPLICATIONS: The divergent potencies of many inhaled anesthetics on ion channels suggest the possibility that combinations of such anesthetics might be superadditive (synergistic). However, we found that combinations of inhaled anesthetics do not produce synergistic interactions as regards MAC. Fifteen of 16 combinations produced additivity and one produced infraadditivity (antagonism), a result consistent with a common site of anesthetic action.