Calcium displacement by local anesthetics. Dependence on pH and anesthetic charge

P. S. Low, D. H. Lloyd, T. M. Stein, J. A. Rogers

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107 Scopus citations


Ca2+ and local anesthetics act either antagonistically or agonistically on an extraordinary variety of both neuronal and non-neuronal processes. In order to evaluate the molecular basis of these relationships, an examination of the effect of local anesthetics on 45Ca2+ binding to the cytoplasmic surface of the erythrocyte membrane was conducted. It was found that all anesthetics, regardless of charge or molecular geometry, depleted the red cell membrane to the same level of residual 45Ca2+ Thus, the same number of 45Ca2+ binding sites are accessible to such diverse compounds as lidocaine (+), t-butyl alcohol (O), and sodium pentobarbital (-). The concentration of each anesthetic required for 45Ca2+ displacement was found to correlate with the concentration of anesthetic observed to perturb several biological processes. The function describing the relationship between 45Ca2+ displacement and anesthetic concentration was shown to depend on the charge and degree of substitution of the anesthetic. Cationic anesthetics were found to displace 45Ca2+ with a hyperbolic dependence on anesthetic concentration, while uncharged anesthetics displaced 45Ca2+ invariably in a cooperative manner. Furthermore, tertiary amine anesthetics converted from largely hyperbolic to sigmoidal behavior as the solution pH was increased. A peculiar rise in membrane-bound 45Ca2+ was observed in the presence of low concentrations of straight chain alcohols, but this increase converted to the usual 45Ca2+ displacement at higher alcohol concentrations. The tendency to enhance 45Ca2+ binding at low alcohol concentration decreased as the degree of substitution of the carbinol carbon increased. The above observations are all predicted in a model of calcium displacement which ascribes the capacity of an anesthetic to displace calcium to its ability to insert between a two-point calcium attachment site on the membrane surface and to increase the Ca2+-ligand bond distance beyond the optimal bond length of 9.6Å.

Original languageEnglish (US)
Pages (from-to)4119-4125
Number of pages7
JournalJournal of Biological Chemistry
Issue number10
StatePublished - 1979

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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