To the Editor: Campagna et al. (May 22 issue)1 provide a comprehensivereview of the mechanisms of actions of inhaled anesthetics.I was surprised, however, by some of the information they providein Table 2 of their article. First, the authors suggest thatthe channels coupled to ionotropic glutamate receptors are permeableto calcium and magnesium. However, these channels are permeableonly to calcium and monovalent cations, especially in the caseof N-methyl-D-aspartate (NMDA) receptors. Magnesium actuallyblocks NMDA channels in a voltage-dependent manner,2 a characteristicthat is the basis for its use as a noncompetitive NMDA antagonistin some clinical situations (e.g., excessive nociception). Second,there is no general agreement that serotonin type 3 receptors"[inhibit] resting potassium-leak currents." These channelsare permeable to monovalent cations and, in some cases, calciumand are directly excitatory.3
Table 3 might have been more positive about data concerningthe opening of some background, two-pore–domain potassiumchannels by halogenated alkanes and ethers. This effect hasbeen demonstrated with several agents (chloroform, halothane,isoflurane, and sevoflurane) by at least two groups4,5 in differentpreparations.
Vincent M. Seutin, M.D., Ph.D. University of Liège B-4000 Liège, Belgium v.seutin{at}ulg.ac.be
References
Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003;348:2110-2124. [Free Full Text]
Amino acid transmitters. In: Rang HP, Dale MM, Ritter JM, Gardner P. Pharmacology. 4th ed. New York: Churchill Livingstone, 2001:470-82.
Sanders-Bush E, Mayer SE. 5-Hydroxytryptamine (serotonin): receptor agonists and antagonists. In: Hardman JG, Limbird LE, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001:269-90.
Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 1999;2:422-426. [CrossRef][Web of Science][Medline]
Sirois JE, Lei Q, Talley EM, Lynch C III, Bayliss DA. The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. J Neurosci 2000;20:6347-6354. [Free Full Text]
The authors reply: We appreciate Dr. Seutin's close readingof our review. We agree that the physiologic roles of 5-hydroxytryptaminetype 3 channels remain unclear. Adding to the complexity inthis area, recent data indicate that, depending on the agent,inhaled anesthetics can enhance or inhibit the function of 5-hydroxytryptaminetype 3A receptors.1 The effects of inhaled anesthetics on channelsthat conduct background potassium-leak currents are also fascinating,complex, and difficult to summarize briefly. The findings ofPatel et al.2 and others do not suggest that the various backgroundpotassium channels have a common role in anesthetic actions.A reasonable inference is that they may influence the side-effectprofiles of different agents. In revising and condensing Table2, we truncated the entry for NMDA-sensitive glutamate channels,which should read, "Cation conductance for calcium and magnesiuminhibition." The entry for -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate should read, "Cation conductancefor calcium," which is subunit-dependent.3
It has been brought to our attention that the structure of sevofluraneshown in Figure 1 is erroneous. The formula for the correctstructure is CH(CF3)2-O-CH2F. To our embarrassment, the structuresfor methoxyflurane (CH3-O-CF2-CHCl2) and enflurane (CHF2-O-CF2-CHFCl)are also incorrect. Regarding nitrous oxide, some sources suggestthat the oxygen atom is bound to both nitrogen atoms in a cyclictriangle, but in fact the arrangement is linear. The structureis best represented as a resonant hybrid of NN+–O–and N–=N+=O.
Jason A. Campagna, M.D., Ph.D. Keith W. Miller, D.Phil. Stuart A. Forman, M.D., Ph.D. Massachusetts General Hospital Boston, MA 02114 saforman{at}partners.org
References
Suzuki T, Koyama H, Sugimoto M, Uchida I, Mashimo T. The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydroxytryptamine3 receptors expressed in Xenopus oocytes. Anesthesiology 2002;96:699-704. [CrossRef][Web of Science][Medline]
Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 1999;2:422-426. [CrossRef][Web of Science][Medline]
Kohler M, Burnashev N, Sakmann B, Seeburg PH. Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing. Neuron 1993;10:491-500. [CrossRef][Web of Science][Medline]
Correction
to
Campagna et al., 
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and kainate should read, "Cation conductance for calcium," which is subunit-dependent.3 
N+–O– and N–=N+=O. 
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