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Objective: The fate of an impulse arising from stimulation is determined by the ability of the wave front to recruit sufficient Na channels from adjacent cells. Previous numerical studies of mutant Na channels revealed both the velocity of a conditioning wave and the recruiting capacity of the front as determinants of the vulnerable period (VP), an interval within which excitation results in unidirectional conduction. Drugs that block excitatory Na channels in a voltage dependent manner, such as antiarrhythmics, abused substances and antidepressants, slow the restoration of Na conductance trailing an action potential and are associated with proarrhythmia and sudden cardiac death. We hypothesized that drug-induced slowing of Na conductance recovery would flatten the Na conductance restoration gradient thereby reducing the recruiting capacity of a front, extending the VP and increasing the probability of unidirectional propagation., Methods: In a cable of ventricular cells, we explored the sensitivity of the VP to voltage-dependent blockade. While varying the unbinding time constant from 100 ms to 5 s, we measured the Na conductance restoration gradient, the liminal length, the refractory period (RP) and the VP., Results: Reducing the rate of drug unbinding flattened the restoration gradient, diminished the recruiting capacity of a premature impulse and extended the liminal length, RP and the VP. The VP was linearly dependent on the drug unbinding time constant. Rapidly unbinding drugs (time constant <1 s) reduced the liminal length below that of a quiescent cable., Conclusions: Slowing the unbinding rate of voltage-dependent drug block of Na channels extended the RP and the VP. Drugs with unbinding time constants greater than 1 s dramatically increased the probability of unidirectional propagation, reflecting increases in both the RP and the VP. This study provides a new mechanism linking Na channel function, compromised by voltage-dependent Na channel drug block, with proarrhythmic conditions that can lead to sudden cardiac death following premature stimulation.

Objective: The objectives were (a) to evaluate the effects of WAY-123,398, a new class III antiarrhythmic agent, on the action potential of canine Purkinje fibres in comparison with dofetilide, E-4031, and dl-sotalol, and (b) to characterise the mechanism of the class III action by studying its effects on several ionic currents in isolated cat myocytes., Methods: Transmembrane potentials in Purkinje fibres were studied with standard microelectrodes filled with 3M KCl. Myocytes were isolated by enzymatic disaggregation with collagenase and current recordings were obtained by voltage clamp with either the nystatin perforated patch technique or the usual whole cell configuration., Results: WAY-123,398 prolonged action potential duration (APD) in Purkinje fibres and in cat ventricular myocytes without altering other variables of the action potential; in Purkinje fibres the concentration producing a 20% prolongation of APD-60 mV at a basic cycle length of 1000 ms was 0.2 microM. After depolarising voltage steps, the delayed rectifier (IK) peak tail currents in cat myocytes were blocked with IC50 = 0.1 microM. The block was unaffected by varying the duration (200 to 500 ms) or the frequency (0.4 to 2.5 Hz) of the depolarising steps. A much higher concentration of WAY-123,398 (10 microM) did not have effects on the L type Ca current (ICa-L), and on the inward rectifier (IK1) and transient outward (I(to)) K currents., Conclusions: The results indicate that WAY-123,398 is an effective and specific class III agent devoid of class I activity, and suggest that WAY-123,398 prolongs cardiac repolarisation by specifically blocking the delayed rectifier current (IK). The block was unchanged over a range of frequencies and duration of depolarisation, showing no evidence of "reverse use dependence" of block.

Objective: The aim was to compare the effects of the class Ic antiarrhythmic drugs flecainide, encainide, and recainam on the delayed rectifier current, IK., Methods: Membrane currents were studied using the single suction pipette voltage clamp technique in freshly dissociated cat ventricular myocytes bathed in HEPES buffered physiological saline at 32 degrees C., Results: Flecainide and encainide decreased IK with IC50 values of 2.1 microM and 6 microM, respectively. Recainam (100 microM) reduced IK by only 7 (SEM 3)% after 20-30 min exposure and by 19% after an 80 min exposure (IC50 > 400 microM). None of the compounds blocked the inward rectifier, IK1. Block of IK by flecainide and encainide increased with depolarisation following a voltage dependence similar to that describing channel activation. Flecainide and encainide also slowed the time course of the IK tail currents, consistent with drug dissociating from open channels., Conclusions: The observed voltage dependence for IK block by flecainide and encainide resembles the interaction reported between these agents and the excitatory sodium channel, ie, depolarisation enhances block while repolarisation leads to removal of block. The results further suggest that the electrophysiological profile of class Ic agents can have a markedly different ionic basis, ie, K+ channel block by flecainide and encainide is balanced by a potent block of sodium channels, while recainam appears to be a weak but relatively specific blocker of sodium channels only. These differences are not readily accommodated by the current Harrison-Vaughan-Williams classification scheme, and suggest the possibility that potentially important drug specific differences can exist within the same antiarrhythmic drug class.