PKa Does Not Predict pH Potentiation of Sodium Channel Blockade by Lidocaine and W621 1 in Guinea Pig Ventricular

During diastole, tertiary amine local anesthetic molecules may exit cardiac sodium channels quickly through the membrane if they are neutral, or more slowly through the aqueous channel pore if they are charged. Extracellular acidosis potentiates so-dium channel bkckade by these drugs, and drug pK. should be a potent predictor of the degree of response of drug dissociation kinetics to changes in extracellular pH. To test this hypothesis, we measured kinetics of recovery from drug-induced channel blockade in guinea pig papillary muscle exposed to lidocaine (pl 7.86) and to W621 1 (pK. 6.29) using V as a measure of peak sodium current. Both compounds, which are physicochem-ically very similar in respects other than pK.,, delayed V recovery in a pH-dependent fashion. As pH was lowered from 7.9 to 6.5, the recovery time constant rose from 86 to 230 msec for lidocaine and from 53 to 154 msec for W621 1. We revised an earlier kinetic scheme of drug-channel interaction to incorpo-rate newer concepts of drug trapping and ionization within the channel, and the resulting anelytic expressions fit the data well. Important implications of the new scheme are that the pK. of the drug-receptor complex may differ from the drug p1<., and that deprotonation of channel-bound charged drug molecules may be a rate-limiting process. Extracellular acidosis slows the dissociation oftertiary amine local anesthetics from Na channels of nerve (Khodorov et at., 1977), skeletal muscle (Schwarz et at., 1977) and heart (Betan-court and Dresel, 1979; Grant et at., 1980). These compounds enter and leave the channel during the upstroke and plateau of the action potential under the control of voltage-sensitive gat