COMPARISON OF THE EFFECTS OF CAFFEINE AND OTHER METHYLXANTHINES ON [CA2+](I) IN RAT VENTRICULAR MYOCYTES

1 The effects of caffeine and other methylxanthines were investigated on intracellular calcium concentration ([Ca2+](i)) and contraction in rat isolated ventricular myocytes. The use of the fluorescent indicator, Indo-1, allowed simultaneous measurement of [Ca2+](i) and the intracellular concentration of the methylxanthines. 2 Rapid application of caffeine (10 mM) produced a transient rise of [Ca2+](i) which decayed to resting levels. This was accompanied by a transient contraction which decayed to a level above baseline. The addition of theophylline also produced a transient increase of [Ca2+](i). However, following the initial transient, contraction decayed before redeveloping to a maintained level. 3 Direct measurements showed that [caffeine](i) rose more quickly than did [theophylline](i). The slower rise of [theophylline](i) was associated with a delay in the increase of [Ca2+](i). At lower concentrations of the methylxanthines, theophylline was less effective than caffeine at initiating Ca release. The rate of entry of theobromine was similar to that of theophylline. 4 Isocaffeine did not produce a rise of [Ca2+](i). The rate of rise of [isocaffeine](i) was much slower than that of either caffeine or theophylline. 5 Measurements of the oil:water partition coefficient showed that the order of relative partitioning into oil was: caffeine > theophylline > theobromine > isocaffeine. This is similar to the order of rate of entry into the cell. 6 We conclude that many of the differences in the effects of these methylxanthines can be attributed to differences in membrane permeability due to differences in oil:water partition.