Positive and negative chronotropic effects of caffeine in spontaneously beating rabbit sino-atrial node cells.

1. Effects of caffeine on the automaticity in spontaneously beating rabbit sino-atrial node cells were examined. 2. Caffeine (0.5-2 mM) caused only a positive chronotropic effect. At over 5 mM, caffeine caused an initial positive and subsequently a negative chronotropic effect. Both were not modified by pindolol (1 microM) and atropine (1 microM). 3. At 10 mM, a dysrhythmia occurred in all 9 preparations. The effects were reversible, and dysrhythmia also disappeared after washout. 4. When extracellular K+ was increased from 2.7 to 8 mM, the dysrhythmia induced by caffeine (10 mM) was abolished, and the sinus rate was increased. 5. Addition of tetrodotoxin (TTX) (10(-7) M) in the presence of caffeine (10 mM) also abolished the dysrhythmia and increased the sinus rate. 6. In addition, a decrease in extracellular Ca2+ ([Ca]o) to 0.5 mM abolished the dysrhythmia and increased the sinus rate, whereas increasing [Ca]o to 7.4 mM potentiated the negative chronotropic effect and failed to inhibit the dysrhythmia. 7. These results indicate that the positive chronotropic effect is due to the stimulatory effect of caffeine, and the negative effect is directly and indirectly due to development of cellular calcium overload.