MECHANISM OF AUGMENTED PREMATURE RESPONSES IN CANINE VENTRICULAR MUSCLE

In an effort to determine the mechanism inducing paradoxical augmentation of the very premature action potential (AP), the authors performed the following experiments. Premature stimuli (S2) were applied to isolated canine ventricular muscle at variable intervals after every 10th to 15th driving stimulus (S1) at 0.5-1 Hz. Action potentials (R1 and R2) elicited by S1 and S2 of equal strength and duration were recorded by conventional microelectrode methods. Measurements were made of the amplitude (Amp), duration (ADP), plateau area (PA), and maximum rising velocity (V(max)) of each AP and the proximity (P), the interval from 90% repolarization point of R1 to S2. In normal K+ solution, R2 had a greater plateau area (PA2) than R1 at P less than 300 msec. Moreover, PA2 increased progressively with decreasing P at [Ca2+]o of 0.4, 1.6, and 6.4 mM and reached its maximum at P of 40-90 msec. The maximum ΔPA [(PA2-PA1)/PA1 x 100) was estimated at 15 ± 9, 28 ± 6, and 61 ± 11% at each [Ca2+]o, which showed that ΔPA increased significantly (P<0.01) as the [Ca2+]o was increased. Verapamil (10-5M) suppressed completely this augmentation in the plateau of the premature AP. In addition, experiments in high K+ (21 mM)-high Ca2+ (6.4-10 mM) solutions revealed that the Amp, APD, and V(max) of R2 were greater than those of R1. They progressively increased with a reduction of the S1-S2-interval, just as did the plateau of the premature AP at normal [K+]o. These findings suggest that augmented Ca2+ may be triggered by a very premature depolarization in canine ventricular muscle, in contrast to the prevailing concept that recovery from inactivation of the Ca2+ current is delayed in mammalian heart muscle.