Inotropic effects of digitoxin in isolated guinea-pig heart under conditions which alter contraction

In order to examine which calcium pool(s) might contribute to the therapeutic action of digitalis, the positive inotropic effect of digitoxin was quantified under conditions in which different calcium pools were either predominant or suppressed. Isolated left atrial muscle of guinea-pig heart was stimulated at 0.5 Hz at 30 degrees C. After a brief rest period, the first contraction (post-rest contraction) observed when electrical stimulation was resumed was markedly greater than the contraction observed under 0.5 Hz stimulation. Post-rest contraction was apparently dependent on the rest period and related to a ryanodine-sensitive, verapamil-insensitive calcium pool. Post-rest contraction was moderately enhanced by 0.2 microM digitoxin, either in the absence or presence of verapamil. A step-wise increase in the frequency of stimulation following the rest period caused a typical staircase phenomenon, which was markedly suppressed by verapamil but not by ryanodine. Digitoxin markedly augmented the staircase in the absence or presence of ryanodine. Paired-pulse stimulation markedly increased the developed tension, which was slightly reduced by verapamil but not by ryanodine. Digitoxin substantially increased the developed tension evoked by paired-pulse stimulation. In left atrial preparations of rat heart, an increase in stimulation frequency decreased the force of contraction; however, paired-pulse stimulation increased the force, indicating that the enhancement of developed tension by an increase in stimulation frequency and that by paired-pulse stimulation have different mechanisms. Thus, the positive inotropic action of digitoxin does not appear to be restricted to a specific calcium pool; however, the inotropic effect was greater under the conditions in which superficial calcium pool plays a predominant role.