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

Summary The effects of the homologous series of carboxylic esters, methyl propionate to methyl decanoate, on the steadystate inactivation of the sodium current in squid axons have been studied. The esters moved the relationship between the inactivation parameter,h, 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 ofh 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 hydrocarbonsn-butane ton-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.Differences between the effects of the ester series on steady-state inactivation and on the reduction of the peak sodium current suggest that, in the unclamped squid axon, excitability is influenced by at least two distinct mechanisms in which at least two sites of action are involved.