THE EFFECTS OF CAFFEINE ON INTRACELLULAR CALCIUM, FORCE AND THE RATE OF RELAXATION OF MOUSE SKELETAL-MUSCLE

1. Intracellular calcium concentration ([Ca2+](i)) and force were measured from isolated single fibres of mouse skeletal muscle. The effects of 5 mM caffeine on muscle fibres at rest and during short tetani were examined. 2. Caffeine increased tetanic tension and slowed the rate of relaxation. [Ca2+](i) was increased in the presence of caffeine both in the resting muscle and during tetani. The time course of decline of [Ca2+](i) after a tetanus is complex with a large, early, rapid phase followed by a smaller and slower phase. Caffeine accelerated the early phase but slowed the later phase. 3. The sensitivity of the myofibrillar proteins to Ca2+ measured in the intact fibre was increased in the presence of caffeine, confirming earlier findings on skinned muscle fibres. 4. Analysis of the late phase of the decline of [Ca2+](i) after a tetanus provides information about the properties of the sarcoplasmic reticulum (SR) Ca2+ pump. Caffeine slowed the pump to 60-70% of the control value at a given [Ca2+](i) but had no effect on the Ca2+ leak from the SR. 5. Analysis of relaxation made use of the Ca2+-derived force in which the [Ca2+](i) during relaxation was converted to the Ca2+-derived force by means of the steady-state relation between [Ca2+](i) and force. The Ca2+-derived force fell more slowly in the presence of caffeine but the lag between Ca2+-derived force and measured force was unaffected. Thus, the slowed relaxation was caused by changes in Ca2+ handling and not by slowed cross-bridge kinetics. 6. A model of the Ca2+ movements and force production of muscle was used to examine independently the effects of increased Ca2+ sensitivity, slowing of the SR Ca2+ pump and increased SR Ca2+ permeability. The effects of caffeine on [Ca2+](i), tetanic force and relaxation could be explained by a combination of these three effects.