1. A form of skeletal muscle fatigue was examined with isolated animal and human muscle preparations. The possibility that methylxanthines could overcome this was investigated.
2. Prolonged contractile activity resulted in a long-lasting impairment of force generation at low frequencies of stimulation at times when the force at higher frequencies had substantially recovered. This was seen with both fast-twitch and slow-twitch animal muscles and with samples of isolated human muscle.
3. The decrease in low-frequency force was due to a decrease in twitch amplitude, suggesting damage to the processes involved in excitation-contraction coupling.
4. Caffeine and theophylline at concentrations of 1 mmol/l rapidly and completely reversed the effects of this form of fatigue in both animal and human muscle preparations.
5. Agents that potentiate muscle force production could be an effective means of counteracting the effects of an important form of skeletal muscle fatigue, but a clinically useful compound would need to be more potent than the methylxanthines currently in use.