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 indicato r, Indo-1, allowed simultaneous measurement of [Ca2+](i) and the intra cellular 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 whi ch decayed to a level above baseline. The addition of theophylline als o produced a transient increase of [Ca2+](i). However, following the i nitial transient, contraction decayed before redeveloping to a maintai ned level. 3 Direct measurements showed that [caffeine](i) rose more q uickly than did [theophylline](i). The slower rise of [theophylline](i ) was associated with a delay in the increase of [Ca2+](i). At lower c oncentrations of the methylxanthines, theophylline was less effective than caffeine at initiating Ca release. The rate of entry of theobromi ne 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 slo wer than that of either caffeine or theophylline. 5 Measurements of th e oil:water partition coefficient showed that the order of relative pa rtitioning into oil was: caffeine > theophylline > theobromine > isoca ffeine. 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 meth ylxanthines can be attributed to differences in membrane permeability due to differences in oil:water partition.