The effects of theophylline and caffeine on the isolated rat diaphragm

It is a well known fact that theophylline enhances the force of diaphragmatic contraction and delays fatigue. The action of caffeine which is a methylxanthine analogue on skeletal muscle are complex. It was claimed in few studies that the caffeine was more effective on the diaphragmatic contractility than the theophylline. The aim of this study is to compare the effects of theophylline and caffeine on the tension generated by fresh and fatigued diaphragmatic muscle. Studies were performed in vitro on diaphragmatic muscle strips of rats activated by electrical stimuli applied via the phrenic nerve. Isometric twitch characteristics (twitch tension, contraction and 1/2 relaxation time) were measured. Force-frequency responses were generated using twitches and tetanic contractions produced by stimulating the phrenic nerve with 0.2 ms pulses at 10, 20, 50 and 100 Hz for 1 s with 30 s intervals. Moderate fatigue was then induced by repeated submaximal contractions (25 Hz, 160 ms, at the rate of 1/s for 45 contractions). In fresh muscle 1 mM theophylline and 1 mM caffeine increased diaphragmatic tension 40.98 +/- 8.50% and 82.30 +/- 12.21% of the initial value respectively. Theophylline did not alter contraction time but prolonged 1/2 relaxation time, whereas caffeine had no effect on any one. Theophylline induced force production in all frequencies. Caffeine caused an increase in force only in < 20 Hz, but a decrease in 50 and 100 Hz. In brief submaximal fatigue, both 1 mM theophylline and 1 mM caffeine partly prevented fatigue (effect of caffeine was more potent). This study suggests that caffeine has a greater effect than theophylline on the muscle. Possible mechanism(s) of action of theophylline and caffeine on diaphragmatic contractility and fatigue were discussed. It may well be the fact that they might have different mechanisms of action on the isolated rat diaphragm.