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Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium.

Publication ,  Journal Article
Broughton, A; Grant, AO; Starmer, CF; Klinger, JK; Stambler, BS; Strauss, HC
Published in: Circ Res
October 1984

Current theories envision recovery from local anesthetic block of sodium channels via slow hydrophilic and fast hydrophobic paths. Extracellular pH reduction which increases cationic/neutral anesthetic form should especially prolong recovery kinetics of highly lipid soluble compounds that could readily exit via the hydrophobic pathway at normal extracellular pH. To test this hypothesis, we compared the effects of three related compounds with similar pKa on the time course of Vmax reactivation in guinea pig papillary muscle at pHo 7.4 and 6.95. The compounds were lidocaine and its two desethylation products, monoethylglycinexylidide and glycinexylidide. Judged from the octanol:water partition coefficient, lidocaine was the most lipid soluble (log partition coefficient 2.39 +/- 0.10), followed by monoethylglycinexylidide (log partition coefficient 1.32 +/- 0.09) and glycinexylidide was the least lipid soluble (log partition coefficient 0.41 +/- 0.09). At 30 microM and pHo 7.4, the potency order for Vmax depression at zero diastolic interval was lidocaine (53 +/- 6%), monoethylglycinexylidide (17 +/- 3%), and then glycinexylidide (7.8 +/- 1.9%). The decay of Vmax block appeared monoexponential, and the time constant of recovery was dose independent. Most important is the fact that there were significant differences in the tau r increase with extracellular pH reduction (P less than 0.05; Scheffé contrasts). The increase was greatest with lidocaine [73 +/- 28% (mean +/- SD)], less with monoethylglycinexylidide (42 +/- 15%), and least with glycinexylidide (13 +/- 17%). The simplest interpretation of the differences in extracellular pH-dependence of recovery kinetics was that recovery from block due to the neutral form of these ionizable local anesthetics depended on lipid solubility, whereas recovery from block due to the protonated form depended on molecular weight.

Duke Scholars

Published In

Circ Res

DOI

ISSN

0009-7330

Publication Date

October 1984

Volume

55

Issue

4

Start / End Page

513 / 523

Location

United States

Related Subject Headings

  • Water
  • Solubility
  • Octanols
  • Membrane Potentials
  • Lipids
  • Lidocaine
  • Kinetics
  • Hydrogen-Ion Concentration
  • Heart
  • Guinea Pigs
 

Citation

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Broughton, A., Grant, A. O., Starmer, C. F., Klinger, J. K., Stambler, B. S., & Strauss, H. C. (1984). Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium. Circ Res, 55(4), 513–523. https://doi.org/10.1161/01.res.55.4.513
Broughton, A., A. O. Grant, C. F. Starmer, J. K. Klinger, B. S. Stambler, and H. C. Strauss. “Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium.Circ Res 55, no. 4 (October 1984): 513–23. https://doi.org/10.1161/01.res.55.4.513.
Broughton A, Grant AO, Starmer CF, Klinger JK, Stambler BS, Strauss HC. Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium. Circ Res. 1984 Oct;55(4):513–23.
Broughton, A., et al. “Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium.Circ Res, vol. 55, no. 4, Oct. 1984, pp. 513–23. Pubmed, doi:10.1161/01.res.55.4.513.
Broughton A, Grant AO, Starmer CF, Klinger JK, Stambler BS, Strauss HC. Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium. Circ Res. 1984 Oct;55(4):513–523.

Published In

Circ Res

DOI

ISSN

0009-7330

Publication Date

October 1984

Volume

55

Issue

4

Start / End Page

513 / 523

Location

United States

Related Subject Headings

  • Water
  • Solubility
  • Octanols
  • Membrane Potentials
  • Lipids
  • Lidocaine
  • Kinetics
  • Hydrogen-Ion Concentration
  • Heart
  • Guinea Pigs