The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres.

1. The effect of disopyramide on the maximum upstroke velocity (Vmax) and the sodium current of rabbit cardiac Purkinje fibres was studied with the two-microelectrode voltage-clamp technique. 2. In the absence of stimulation the drug did not cause block at membrane potentials ranging from -100 to -65 mV. Use-dependent block of Vmax was most pronounced at -75 mV. At hyperpolarized membrane potentials development of use-dependent block was faster than at depolarized membrane potentials. The time course of development of use-dependent block was not significantly influenced by the duration of the depolarizing pulse. These results strongly suggest that disopyramide predominantly blocks activated sodium channels. 3. The relative decrease of the sodium current at the beginning of a 2 s depolarizing clamp to -45 mV was almost the same as at the end, implying a rapid blockade of activated sodium channels. The Hill plots were linear with slopes ranging from 0.978 to 1.08 indicating a first order reaction; the dissociation constant for activated channels was 70 microM. 4. Recovery of Vmax from use-dependent block during rest was strongly voltage-dependent, the time constant of recovery increasing upon hyperpolarization. When the fraction of charged molecules was reduced by changing the pH of the external solution, the voltage-dependence of recovery was decreased. In contrast, recovery of Vmax for a change in holding potential from -80 to -95 mV was very fast during repetitive stimulation. 5. It is concluded that disopyramide blocks the sodium channel during activation and is trapped in the channel when the activation gate closes.