• Anesthesiology · Aug 1992

    Stereoselective inhibition of neuronal sodium channels by local anesthetics. Evidence for two sites of action?

    • S Lee-Son, G K Wang, A Concus, E Crill, and G Strichartz.
    • Anesthesia Research Laboratories, Brigham and Women's Hospital, Boston, Massachusetts 02115.
    • Anesthesiology. 1992 Aug 1;77(2):324-35.

    AbstractThe objective of this study was to determine if the "tonic," resting inhibition of Na+ channels by local anesthetics results from binding at a site different from that for "phasic," use-dependent inhibition. Stereoselective actions of four local anesthetics were examined in isolated frog peripheral nerve and single Na+ channels. Using the sucrose-gap method on desheathed nerves, four actions of local anesthetics were assayed: 1) tonic depression of compound action potentials at low stimulation frequency (one per minute); 2) phasic depression of the compound action potential during trains of stimulation at 5, 10, and 20 Hz; 3) competitive antagonism of the reversible Na+ channel activator veratridine assayed through the depolarization of the compound resting membrane potential; and 4) depression of the depolarization of the compound resting membrane potential initially induced by the irreversible channel activator batrachotoxin. For assays 1, 2, and 3, all local anesthetics showed a stereoselectivity, where rectus, or (+), enantiomers were more potent than sinister, or (-), enantiomers. In contrast, for the noncompetitive antagonism of veratridine's action and the depression of batrachotoxin-induced depolarization, also a noncompetitive interaction between anesthetic and activator, the (-) enantiomer was more potent than the corresponding (+) enantiomer. Blockade of single Na+ channels activated by batrachotoxin in planar lipid bilayers was also stereoselective for the (-) enantiomer. These findings, along with previously reported voltage-clamp results, can be applied to infer properties of a local anesthetic binding site in activator-free channels. Local anesthetic molecules with more sharply angled shapes have stronger stereoselectivities than less angled, more planar drugs. The inversion of the stereopotency induced by the activators can be explained by either of two mechanisms. There may be two binding sites for local anesthetics, one of high and one of low affinity and of opposite stereoselectivity; activators may change the conformation at the high affinity site, reducing its local anesthetic affinity below that of the usual low affinity site and thereby revealing the pharmacology of the weaker site. Alternatively, only a single binding site may exist and be conformationally altered by activators such that both anesthetic affinity and stereopotency are modified. In activator-free channels, however, a single, high-affinity binding site with a constant stereoselectivity can account for both tonic and phasic inhibition by local anesthetics.

      Pubmed     Full text   Copy Citation     Plaintext  

      Add institutional full text...

    Notes

     
    Knowledge, pearl, summary or comment to share?
    300 characters remaining
    help        
    You can also include formatting, links, images and footnotes in your notes
    • Simple formatting can be added to notes, such as *italics*, _underline_ or **bold**.
    • Superscript can be denoted by <sup>text</sup> and subscript <sub>text</sub>.
    • Numbered or bulleted lists can be created using either numbered lines 1. 2. 3., hyphens - or asterisks *.
    • Links can be included with: [my link to pubmed](http://pubmed.com)
    • Images can be included with: ![alt text](https://bestmedicaljournal.com/study_graph.jpg "Image Title Text")
    • For footnotes use [^1](This is a footnote.) inline.
    • Or use an inline reference [^1] to refer to a longer footnote elseweher in the document [^1]: This is a long footnote..

    hide…

What will the 'Medical Journal of You' look like?

Start your free 21 day trial now.

We guarantee your privacy. Your email address will not be shared.