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.