1. The two‐microelectrode method of voltage clamp was used in single myocytes isolated from guinea‐pig ventricles to investigate the mechanism underlying the arrhythmogenic interaction between low external K+ and digitalis. 2. We investigated the effects of ouabain (10(‐6) M) with 4 mM‐K+ or 2 mM‐K+ on the peak magnitude of the inward component of oscillatory current (Iti) recorded upon repolarization to the resting potential after depolarizing clamps to ‐5 mV, and on the characteristics of the steady‐state current‐voltage relationship. 3. Whereas ouabain with 4 mM‐K+ did not alter the current‐voltage relationship from its control shape, ouabain with 2 mM‐K+ caused marked changes in the curve: the zero‐current intercept was shifted in a negative direction, the region of low slope conductance was extended to more negative potentials, and the curve was shifted downward relative to the control current‐voltage relationship. The changes in the current‐voltage relationship induced by ouabain with 2 mM‐K+ were very similar to those induced by 2 mM‐K+ alone. 4. The functional consequence of the changes in the current‐voltage relationship induced by ouabain with 2 mM‐K+ was a highly significant reduction in the amount of outward current (Ith) needed to reach the threshold for excitation; Ith was reduced from 1.6 +/‐ 0.4 nA (n = 6) in ouabain with 4 mM‐K+ to 0.8 +/‐ 0.3 nA (n = 5) in ouabain with 2 mM‐K+. 5. The mean value for Iti was larger in ouabain with 2 mM‐K+ (0.58 +/‐ 0.41 nA, mean +/‐ S.D., n = 4) than in ouabain with 4 mM‐K+ (0.42 +/‐ 0.38 nA, n = 5). Although the increase in Iti was not statistically significant because of the large variability of the measurement, it is possible that the increase might be physiologically significant. 6. Our results suggest that the arrhythmogenic interaction between digitalis and low K+ is due to the combined effects of low K+ on the current‐voltage relationship and on the size of the peak inward current induced by ouabain. Whereas the effect of low K+ and ouabain on the inward current was highly variable, the effects on the current‐voltage curve were far more consistent, pointing to an important role for alterations in the current‐voltage relationship in the arrhythmogenic interaction between low K+ and ouabain.
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