Inhaled Anesthetics Do Not Combine to Produce Synergistic Effects Regarding Minimum Alveolar Anesthetic Concentration in Rats Edmond I Eger II, MD* Michael Tang* Mark Liao, BS* Michael J. Laster, DVM* Ken Solt, MD†‡ Pamela Flood, MD§ Andrew Jenkins, PhD Douglas Raines, MD†‡ Jan F. Hendrickx, MD¶ Steven L. Shafer, MD¶** Tanifuji Yasumasa, MD†† James M. Sonner, MD* 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 synergisti- cally, 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 -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. (Anesth Analg 2008;107:479 –85) A present consensus holds that ligand-gated and/or voltage-gated ion channels mediate the actions of in- haled anesthetics, including the capacity of these anes- thetics to produce immobility. Plausible candidates include  amino butyric acid (GABA A ), glycine, serotonin, nicotinic acetylcholine, various glutamate [e.g., NMDA (N-methyl-d-aspartic acid) and AMPA- kainate (AMPA is -amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid)], adrenergic, and opioid receptors, and potassium and sodium channels. We previously examined the relevance of most of these to mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation (i.e., their relevance to MAC, the minimum alveolar concentration of inhaled anesthetic that produces im- mobility in 50% of subjects given a noxious stimula- tion). 1 Each channel appeared to have, at most, a modest relevance as a mediator of immobility. 1 Thus, if such channels explain anesthesia, they must act in concert and probably must produce more than simply an additive effect. Synergy is required because the modest anesthetic effects on individual channels seem insufficient to produce immobility through an addi- tive summation of effects. And yet, as noted in a From the *Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; †Department of Anesthesia and Critical Care, Massachusetts General Hospital, and ‡Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts; §Department of Anesthesiology, Columbia Univer- sity, New York City, New York; Department of Anesthesiology, Emory University, Atlanta, Georgia; ¶Department of Anesthesia, Stanford University, Stanford, California; **Department of Biopharma- ceutical Science, UCSF, San Francisco, California; and ††Department of Anesthesiology, Jekei University School of Medicine, Tokyo, Japan. Supported by NIH grant 1PO1GM47818 (UCSF). Dr. Eger is a paid consultant to Baxter Healthcare Corp. Baxter Healthcare Corp. donated the desflurane and isoflurane used in these studies. Dr. Steven L. Shafer, Editor-in-Chief, was recused from all editorial decision related to this manuscript. Dr. Flood is the wife of Dr. Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by James Bovill, former Section Editor of Anesthetic Pharmacology, and Dr. Shafer was not involved in any way with the editorial process or decision. Address correspondence and reprint requests to Dr. Edmond I Eger II, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to egere@anesthesia. ucsf.edu. Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/01.ane.0000295805.70887.65 Vol. 107, No. 2, August 2008 479