Correspondence

Correction

Mechanisms of Actions of Inhaled Anesthetics

N Engl J Med 2003; 349:909-910August 28, 2003

Article

To the Editor:

Campagna et al. (May 22 issue)1 provide a comprehensive review of the mechanisms of actions of inhaled anesthetics. I was surprised, however, by some of the information they provide in Table 2 of their article. First, the authors suggest that the channels coupled to ionotropic glutamate receptors are permeable to calcium and magnesium. However, these channels are permeable only to calcium and monovalent cations, especially in the case of N-methyl-D-aspartate (NMDA) receptors. Magnesium actually blocks NMDA channels in a voltage-dependent manner,2 a characteristic that is the basis for its use as a noncompetitive NMDA antagonist in some clinical situations (e.g., excessive nociception). Second, there is no general agreement that serotonin type 3 receptors “[inhibit] resting potassium-leak currents.” These channels are permeable to monovalent cations and, in some cases, calcium and are directly excitatory.3

Table 3 might have been more positive about data concerning the opening of some background, two-pore–domain potassium channels by halogenated alkanes and ethers. This effect has been demonstrated with several agents (chloroform, halothane, isoflurane, and sevoflurane) by at least two groups4,5 in different preparations.

Vincent M. Seutin, M.D., Ph.D.
University of Liège, B-4000 Liège, Belgium
v.seutin@ulg.ac.be

5 References

1. 1

   Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003;348:2110-2124
   Full Text | Web of Science | Medline

2. 2

   Amino acid transmitters. In: Rang HP, Dale MM, Ritter JM, Gardner P. Pharmacology. 4th ed. New York: Churchill Livingstone, 2001:470-82.
   

3. 3

   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.
   

4. 4

   Patel AJ, Honore 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

5. 5

   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
   Web of Science | Medline

Author/Editor Response

We appreciate Dr. Seutin's close reading of our review. We agree that the physiologic roles of 5-hydroxytryptamine type 3 channels remain unclear. Adding to the complexity in this area, recent data indicate that, depending on the agent, inhaled anesthetics can enhance or inhibit the function of 5-hydroxytryptamine type 3A receptors.1 The effects of inhaled anesthetics on channels that conduct background potassium-leak currents are also fascinating, complex, and difficult to summarize briefly. The findings of Patel et al.2 and others do not suggest that the various background potassium channels have a common role in anesthetic actions. A reasonable inference is that they may influence the side-effect profiles of different agents. In revising and condensing Table 2, we truncated the entry for NMDA-sensitive glutamate channels, which should read, “Cation conductance for calcium and magnesium inhibition.” The entry for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and kainate should read, “Cation conductance for calcium,” which is subunit-dependent.3

It has been brought to our attention that the structure of sevoflurane shown in Figure 1 is erroneous. The formula for the correct structure is CH(CF₃)₂-O-CH₂F. To our embarrassment, the structures for methoxyflurane (CH₃-O-CF₂-CHCl₂) and enflurane (CHF₂-O-CF₂-CHFCl) are also incorrect. Regarding nitrous oxide, some sources suggest that the oxygen atom is bound to both nitrogen atoms in a cyclic triangle, but in fact the arrangement is linear. The structure is best represented as a resonant hybrid of N≡N⁺–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@partners.org

3 References

1. 1

   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

2. 2

   Patel AJ, Honore 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

3. 3

   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