The influence of pH on th electrophysiological effects of lidocaine in guinea pig ventricular myocardium.

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Abstract
Lidocaine is more depressant in ischemic than normal myocardium. To determine the influence of pH on the electrophysiological effects of lidocaine, transmembrane potential and dV/dtmax [1st derivative of left ventricular pressure] were recorded from guinea pig papillary muscles mounted in a single sucrose gap. Recovery kinetics of dV/dtmax were studied by introducing progressively early premature responses during phase 4 at a drive rate of 0.5 Hz. In Krebs-Henseleit solution (HCO3- = 25 mM, CO2 = 5%, pH 7.4), lidocaine (1.5 .times. 10-5 M) did not significantly change action potential characteristics. The recovery time constant (.tau.) of dV/dtmax was increased from 10 .+-. 4 (mean .+-. SD) to 91 .+-. 12 ms. In the presence of lidocaine, .tau. increased from 91 .+-. 12 to 212 .+-. 5 ms when the extracellular pH (pHo) was lowered by increasing the [CO2] to 20% (HCO3- = 25 mM, pHo = 6.95). When pHo was lowered by decreasing [HCO3-] (HCO3- = 7.5 mM, CO2 = 5% pHo = 6.95), .tau. increased from 96 .+-. 11 to 185 .+-. 41 ms. If the [CO2] was increased to 20% while the pHo was maintained at 7.4 [HCO3- = 85], .tau. was unchanged compared to a [CO2] of 5%. Drug-free solutions of pHo = 6.95 (CO2 = 5% or 20%; HCO3- = 7.5 or 25 mM) did not increase .tau.. The increase in .tau. with a decrease in pHo was greater than that predicted by a change in distribution of the drug across the membrane. Local anesthetics bind to a receptor in the Na channel, thereby inactivating it. The process of recovery from inactivation during the resting state occurs by exit of uncharged drug through the membrane. The degree of protonation of receptor-bound drug is increased by extracellular acidosis. This decreases the proportion of drug that may leave the receptor via the membrane and hence causes a slowing of the recovery from inactivation.