Interaction of lidocaine and benzocaine in depressing Vmax of ventricular action potentials.

This paper reports the interactions between lidocaine and benzocaine with cardiac sodium channels. The magnitude of the maximum upstroke velocity (Vmax) of the guinea-pig papillary muscle action potential was taken as an indirect measurement of the sodium current. The hypothesis that both the charged and neutral forms of local anaesthetics share a common receptor was tested. In preparations stimulated at a frequency of 0.1 Hz, a mixture of equieffective concentrations of benzocaine and lidocaine produced a decrease in Vmax similar to that obtained with each of the drugs alone. Therefore, the tonic blockade produced with this mixture of anaesthetics was comparable with the theoretical values predicted by equilibrium binding equations, which is indicative of a common receptor for both drugs. Although benzocaine did not produce frequency-dependent effects, it did attenuate those produced by lidocaine when both anaesthetics were applied. During repeated action potentials, using short diastolic intervals, the frequency-dependent effects of lidocaine were due to the accumulation of blocked sodium channels. The binding of lidocaine to both open and inactivated channels during a conditioning action potential was determined by the zero-time intercept of the slow component of the recovery of Vmax induced by the drug. Under these conditions, benzocaine decreased the fraction of channels blocked by lidocaine. Hence, the parallel shift produced by benzocaine on the dose-response (fraction of blocked Vmax) curves of lidocaine, strongly suggests that both drugs competed for the same receptor site. Furthermore, this receptor, mediating the blockade of cardiac sodium channels, seems to be responsible for both the tonic and frequency-dependent effect of lidocaine on the heart.