Ouabain-induced Wenckebach conduction block in canine Purkinje fibers: The role of cycle length and time dependent changes in membrane potential

The purpose of this study was to determine the mechanism for digitalis-induced Wenckebach conduction block. Canine Purkinje cells were exposed to ouabain (2.0 × 10^?7 M) and studied with conventional microelectrode techniques. When trains of stimuli were interrupted by a 5 second pause, restoration of stimuli resulted in successive action potentials showing an increasing slope of phase 4 depolarization which was expressed after the last beat as a delayed afterdepolarization. For any given state of ouabain toxicity, a beat-to-beat reduction in maximal diastolic potential could be induced by shortening the basic cycle length. If basic cycle length remained constant, continued exposure to ouabain would increase the net voltage reduction in membrane potential occurring during the train of ten beats. During the 5 second pause, an increase in membrane potential was observed and this hyperpolarization was of the same magnitude as the depolarization occurring during stimulation. With successive beats as membrane potential was reduced, action potential amplitude and $\text{dV}\text{dt}$ were concomitantly reduced and conduction slowed. Intracellular current threshold measurements showed that the reduction in membrane potential initially was associated with decreased current threshold requirements, but later in toxicity current threshold was markedly increased for beats occurring late in the train. These data suggest that (1) the beat-to-beat reduction in membrane potential is due to both an increase in the height of the delayed afterdepolarization and a reduction in maximal diastolic potential; (2) trains of beats are associated with progressive prolongation of activation time with concomitant reduction in $\text{dV}\text{dt}$ and membrane potential; and (3) failure of conduction is probably related to Purkinje segments showing decreased excitability.