Previous in vitro and in vivo studies have provided evidence implicating cocaine block of cardiac sodium channels as a putative mechanism for cocaine-induced arrhythmias and sudden death. Cocaine also has been shown to cause seizures which can result in respiratory and/or metabolic acidosis. In this study we investigated how changes in both internal pH (pHi) and external pH (pHo) over the range of 6.6 to 9.2 modify the sodium channel blocking properties of cocaine in isolated guinea pig ventricular myocytes by using the whole-cell variant of the patch clamp technique. Use-dependent block produced by a train of 1-sec pulses to -20 mV was not affected by changes in pHi, but both the amplitude and time constant for approaching steady-state block were significantly affected by changes in pHo. Characterization of the time course of cocaine binding during a depolarizing pulse indicated that the kinetics of drug interaction with inactivated channels were independent of pHi, but were significantly affected by changes in pHo. The rate of recovery from channel block at a holding potential of -140 mV also was independent of pHi, but strongly dependent on pHo, with the unblocking time constant decreasing exponentially as pHo was increased. The results of this study indicate that cocaine's effect on cardiac sodium channels can be modulated significantly by changes in pHo, and provide further support for previously poorly tested assumptions of the modulated receptor hypothesis.