The effects of caffeine and ryanodine on the electrical activity of the canine coronary sinus.

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Abstract
1. Cells of the coronary sinus of the canine heart can exhibit triggered activity in 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. 2. 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. 3. 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. 4. 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. 5. 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); fibers exposed to solutions containing 20 mM-TEA and 21 mM-Cl- show action potentials very like those of fibres exposed to 5 mM-caffeine. 6. If the 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. 7. 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. 8. Many of our findings can be interpreted in terms of generally accepted effects of caffeine on the handling of intracellular Ca2+ by the s.r. and by the effects of intracellular Ca2+ on the ''cation channel''; however, several additional assumptions are required to interpret all of the effects, which are numerous, complex and concentration dependent.