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

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Abstract
1 The effect of disopyramide on the maximum upstroke velocity () 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 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 0.98 to 1.08 indicating a first order reaction; the dissociation constant for activated channels was 70 μm. 4 Recovery of 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 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.