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

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Abstract
Current theories envision recovery from local anesthetic block of Na 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. The effects of 3 related compounds with similar pKa on the time course of .ovrhdot.Vmax [maximum velocity] reactivation were compared in guinea pig papillary muscle at pHo 7.4 and 6.95. The compounds were lidocaine and its 2 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 .mu.M and pHo 7.4, the potency order for .ovrhdot.Vmax depression at 0 diastolic interval was lidocaine (53 .+-. 6%), monoethylglycinexylidide (17 .+-. 3%), and then glycinexylidide (7.8 .+-. 1.9%). The decay of .ovrhdot.Vmax block appeared monoexponential, and the time constant of recovery was dose independent. There were significant differences in the .tau.r [time constant for decay in total Vmax block] .tau. increase with extracellular pH reduction (P < 0.05; Scheffe contrasts). The increase was greatest with lidocaine [73 .+-. 28% (mean .+-. SD)], less with monoethylglycinexylidide (42 .+-. 15%), and least with glycinexylidide (13 .+-. 17%). 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 MW.

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