MULTIPLE EFFECTS OF CAFFEINE ON CALCIUM CURRENT IN RAT VENTRICULAR MYOCYTES

Caffeine exerts a number of different effects on L-type calcium current in rat ventricular myocytes. These include: (1) a slowing of inactivation that is comparable to, but not additive to, that produced by prior treatment of the cells with ryanodine (a selective sarcoplasmic reticulum Ca2+ releaser) or high concentrations of intracellular 1,2-bis[2-aminophenoxy]ethane-N,N,N',N'-tetraacetic acid (BAPTA) (a fast Ca2+ chelator), (2) a stimulation of peak I(Ca) that is comparable to, but not additive to that produced by prior treatment with isobutylmethylxanthine (a selective phosphodiesterase inhibitor), and (3) a dose-dependent decrease of peak I(Ca) that is not prevented by pretreatment with any of these agents. None of the caffeine actions could be mimicked or prevented by administration of 8-phenyltheophylline, a specific adenosine receptor antagonist. We conclude that only the slowing of I(Ca) inactivation is due to caffeine's ability to deplete the sarcoplasmic reticulum of calcium. The stimulatory effect of caffeine on peak I(Ca) is probably due to phosphodiesterase inhibition, while caffeine's inhibitory effect on I(Ca) is independent of these processes and could be a direct effect on the channel. The multiplicity of caffeine actions independent of its effects on the sarcoplasmic reticulum lead to the conclusion that ryanodine, though slower acting and essentially irreversible, is a more selective agent than caffeine for probing sarcoplasmic reticulum function and its effects on other processes.