Lidocaine has been reported to be more depressant in ischemic than normal myocardium. To determine the influence of pH on the electrophysiological effects of lidocaine, we recorded trans-membrane potential and dV/dtmulfrom guinea pig papillary muscles mounted in a single sucrose gap. Recovery kinetics of dV/dtma, 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 x 10−5M) did not significantly change action potential characteristics. The recovery time constant (T) of dV/dtmaxwas increased from 10 ± 4 (mean ± SD) to 91 ± 12 msec. In the presence of lidocaine, T increased from 91 ± 12 to 212 ± 5 msec when the extracellular pH (pHo) was lowered by increasing the [CO2] to 20% (HCO3− = 25 mM, pHo= 6.95). Similarly, when pHowas lowered by decreasing [HCO3−] (HCO3− = 7.5 mM, CO2= 5%, pHo= 6.95), T increased from 96 ± 11 to 185 ± 41 msec. However, if the [CO2] was increased to 20% while the pHowas maintained at 7.4 [HCO3− = 85], T was unchanged compared to a [CO2] of 5%. Drug-free solutions of pHo= 6.95 (CO2= 5% or 20%; HCOr = 7.5 or 25 mM) did not increase T. The increase in T with a decrease in pHowas greater than that predicted by a change in distribution of the drug across the membrane. These data are consistent with the view that local anesthetics bind to a receptor in the sodium 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.Circ Res 47: 542-550, 1980