The effects of caffeine on tension development and intracellular calcium transients in rat ventricular muscle.

The effects of caffeine on tension and intracellular [Ca2+] were investigated in rat ventricular muscle using the Ca2+-sensitive photoprotein, aequorin. Contracture was induced by rapid application of 0.5-10 mM-caffeine solution at 20 degrees C. In normal Tyrode solution at 8 degrees C, or in Na+-deficient solution in which Na+ was isotonically replaced by sucrose, peak tension of caffeine contracture was potentiated and relaxation was prolonged. Caffeine contracture could not be induced immediately after a prior contracture. Repriming time was 10 min in Tyrode solution, and was much shorter in Na+-deficient solution or in high-K+ solution containing 105.9 mM-K+. Caffeine prolonged the plateau of action potential dose dependently. At low temperature, prolongation of the plateau phase by caffeine was more marked. Twitch tension showed a triphasic change after application of caffeine; peak tension transiently increased in a potentiating phase (P phase), and then decreased below control level in an inhibitory phase (I phase) followed by gradual recovery in a recovery phase (R phase). The effects of caffeine on the Ca2+ transients during a twitch were also complex, depending on time after application and dose of caffeine. In low caffeine concentration (below 0.5 mM) the peak of the Ca2+ transient was potentiated in the I phase, although the peak tension was suppressed. At high concentration (above 3 mM) the peaks of both the Ca2+ transient and twitch tension were suppressed. In every concentration of caffeine tested (0.1-5 mM), time to the Ca2+ transient and twitch tension peaks was prolonged, and the falling phases of both were delayed. Caffeine might release Ca2+ from intracellular store(s) and enhance the slow inward current. The Ca2+ transient obtained in this study clearly indicate that the prolonged time to peak tension in the presence of caffeine is due to the slow rise of intracellular [Ca2+] and prolonged time to peak of the Ca2+ transient. It is also quite possible that caffeine modulates the Ca2+ sensitivity of a contractile system in dose- and time-dependent manners.