Local anesthetic action of carboxylic esters: Evidence for the significance of molecular volume and for the number of sites involved

Abstract

The effects of the homologous series of carboxylic esters, methyl propionate to methyl decanoate, on the steady-state inactivation of the sodium current in squid axons have been studied. The esters moved the relationship between the inactivation parameter, h infinity, and the membrane potential in the hyperpolarizing direction, thus reducing the number of sodium channels available at the resting potential. The concentration dependence of the shift at the mid-point of the curve of h infinity against potential has been measured for all esters except decanoate, which was almost inactive. Two aspects of these concentration dependences suggest that molecular volume is an important determinant of the effectiveness of each ester. Firstly, there is a sharp decline in activity above methyl hexanoate. This cut-off in activity resembles that for hydrocarbons where it has been suggested [e.g., Haydon, D.A., Urban, B.W. 1983, J. Physiol. (London) 341:411-427] to a result from a decrease in uptake with increasing molecular volume. (Further data for the hydrocarbons n-butane to n-heptane are reported here.) Secondly, the smallest compounds, methyl propionate and methyl butyrate, are less effective than would be predicted if equal membrane concentrations of each ester produced the same shift. The aqueous concentration dependences for these esters indicate that below methyl hexanoate, as the series is descended, progressively higher membrane concentrations are required to produce a given shift. This would be expected if the volume of ester in the membrane, rather than the number of molecules, is important.(ABSTRACT TRUNCATED AT 250 WORDS)

Four Applications of the Anesthetic Cut-off Effect

“…This conclusion has far-reaching consequences on the analyses of effects of anesthetics on the Hodgkin-Huxley characteristics. These were attributed to a solute effect on membrane thickness, which in turn affect the internal electric field in the membrane (Elliott et al, 1987). The suggested evidence in support was the 'parallel' effect of these solutes on membrane thickness.…”

“…Variations on the Hodgkin-Huxley equation still underlie the vast majority of contemporary biophysical models of neurons (Arbib, 1995). Shifts in the Hodgkin-Huxley inactivation h ∞ parameter, due to hyperpolarizing potentials, yield a typical curve when measured as a function of chain length of n-alkane agents (Elliott et al, 1987) (Fig. 1).…”

“…(c) The effect of alcohol size on bilayer thickness [data from McIntosh et al (1980)]. (d) Action of homologous paraffins on Na channels in squid giant axon [data from Elliott et al (1987)]. (e) Action of homologous ethyl esters on Na channels in squid giant axon [data from Elliott et al (1987)].…”

“…The same agents affect the Hodgkin-Huxley parameters of the squid giant axon. They yield a typical curve in which the Hodgkin-Huxley parameters vary continuously with the chain length of n-aliphatic agents (Elliott et al, 1987) (Fig. 1).…”

“…(d) Action of homologous paraffins on Na channels in squid giant axon [data from Elliott et al (1987)]. (e) Action of homologous ethyl esters on Na channels in squid giant axon [data from Elliott et al (1987)]. Ordinate values are given in each case as percentages of the maximal perturbation.…”