On the mechanisms underlying digitalis toxicity in cardiac Purkinje fibers.

The different mechanisms by which digitalis enhances pacemaker automaticity in canine Purkinje fibers has been studied under different conditions. Transmembrane potentials of quiescent, spontaneously active, or electrically driven fibers were recorded in the presence and absence of strophanthidin (10(-5)-10(-7) M). In quiescent fibers, strophanthidin caused the membrane potential to depolarize and to develop oscillations of progressively larger magnitude which were followed by spontaneous activity. In spontaneously active preparations strophanthidin enhanced the slope of diastolic depolarization and therefore the rate of discharge. In both cases, there was no evidence of oscillations during diastolic depolarization. A steepening of diastolic depolarizations without superimposed oscillations (and eventually also followed by spontaneous activity) was observed in preparations driven electrically at very slow rates. However, in fibers driven at faster rates (30/min or more) in the presence of ouabain, oscillations developed during diastolic depolarization. These oscillations were frequency dependent in two respects: 1) at slower rates the oscillations remained constant during the drive, the actual magnitude being proportional to the driving rate; 2) at rate of 60/min or more, the oscillations increased in size with each successive beat. Fast rhythms were initiated by a progressive acceleration of the pacemaker potential or abruptly by an extrasystole. When spontaneous activity ceased, the membrane increased slowly toward the control value. We conclude that digitalis increases the frequency of discharge of Purkinje fibers 1) by enhancing diastolic depolarization when the rate of discharge is slow; 2) by developing a new current which modifies diastolic depolarization when diastole is sufficiently short; and 3) by means of the potassium plateau current when the rate of spontaneous discharge is fast. Whether one or more of these mechanisms are operational in affecting Purkinje fiber automaticity depends critically on the rate of discharge of the fibers.