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Cells of the coronary sinus of the canine heart can exhibit triggered activity which each action potential arises from a depolarizing after-potential that follows the previous action potential; an early after-hyperpolarization commonly precedes the delayed after-depolarization and both are increased in amplitude by the addition of noradrenaline. The delayed after-depolarization is thought to be caused by an inward current activated by a rise in intracellular Ca2+ that is, in turn, caused by Ca2+-induced release of Ca2+ from the sarcoplasmic reticulum (s.r.). The effects of caffeine and of ryanodine on the electrical activity of the coronary sinus were investigated because each of those agents is thought to affect the handling of intracellular Ca2+ by the s.r. The steady-state effect of exposure to 5 mM-caffeine is to cause the delayed after-depolarization to move much earlier in the cycle, and become too small to give rise to an action potential so that preparations cannot show triggered activity; moreover, if a burst of activity is in progress it is terminated by exposure to 5 mM-caffeine. Exposure to 0.5 mM-caffeine causes the delayed after-depolarization to move earlier in the cycle but to become larger so that triggered activity is more easily induced and longer lasting than in the absence of caffeine. Shortly after the addition (or wash-out) of 5 mM-caffeine the after-depolarization transiently resembles that seen in the presence of 0.5 mM-caffeine so that bursts of triggered activity may occur just after the addition or removal of 5 mM-caffeine. Exposure to 5 mM-caffeine abolishes early rapid repolarization (phase 1), shifts the plateau to a more positive level and retards the completion of repolarization. The effect on phase 1 is mimicked by exposure to solutions low in Cl-; the effect on the plateau is mimicked by exposure to 20 mM-tetraethylammonium (TEA); fibres exposed to solutions containing 20 mM-TEA and 21 mM-Cl- show action potentials very like those of fibres exposed to 5 mM-caffeine. If a fibre already exposed to a low Cl-, TEA-containing solution is then exposed to 5 mM-caffeine, no further change occurs in the action potential but the characteristic effects of caffeine on the after-depolarization appear. Exposure to ryanodine prevents the appearance of the delayed after-depolarization but leads to the appearance of an exceptionally long depolarizing after-potential that begins very early in diastole and, though waning, persists almost throughout diastole.(ABSTRACT TRUNCATED AT 400 WORDS)

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.