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

Abstract

1 The effect of disopyramide on the maximum upstroke velocity (V,,,,) 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 V.. 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 2s 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 /LM. 4 Recovery of V.. 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 V.. 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.

Electrophysiological effects of diprafenone, a dimethyl congener of propafenone on guinea‐pig ventricular cells

“…In fact, like the present data for diprafenone, the extent of use-dependent block of ,.,< of INa with penticainide, disopyramide and flecainide was shown to be attenuated by hyperpolarization, while enhanced by depolarization of membrane potential within the range of -90 to -70 mV (Carmeliet, 1988;Gruber & Carmeliet, 1989;Anno & Hondeghem, 1990).…”

“…Under such conditions, hyperpolarization would enhance drug dissociation from channel receptors by increasing the resting fraction of drug-associated channels at the expense of their inactivated fraction (Hondeghem & Katzung, 1984;. The voltage-dependence of V,,<, recovery for diprafenone is opposite to these drugs, and similar to those reported for penticainide (Carmeliet, 1988) and disopyramide (Gruber & Carmeliet, 1989). They proposed the idea of 'activation trapping' to interpret the reverse voltage-dependence of , recovery.…”

Electrophysiological interactions between disopyramide and its major metabolite, mono-N-dealkyldisopyramide, in canine ventricular tissue

“…The recovery time constants of V max depression wi th propafenone and quinidine in vitro are simi1ar (Grant et al, 1982;Weld et al, 1982;Kohlhardt and Seifert, 1983), while that with procainamide i5 slight1y shorter (Courtney, 1980;Ehcing et al, 1988) and that with disopyramide is longer (Campbell, 1983a;Flemming and Sasyniuk, 1989;Gruber and Carmeliet, 1989). The recovery kinetics of al1 these agents, however, are so slow that there is minimal recovery of V max during clinica1 diastole.…”

“…At clinically relevant concentrations, however, the probability that two drug molecules interact simultaneously with the same receptor would be relatively small. ll5 1 Finally, since disopyramide has a greater affinity for activated channels (Kodama et al, 1986 andGruber and Carmeliet. 1989), shortening of action potential duration by MND would probably not affect depression of V max produced by the parent drug.…”

“…The parent compound a1so fails to shift the vmax-membrane potential relationship (Gruber and Carmeliet, 1989). Thus MND, like the parent compound, may also interact with the sodium channel during activation.…”