The diaphragm is the primary muscle for inspiration and fatigue in this tissue will obviously contribute to breathlessness and limit exercise performance. The diaphragm can also contribute to ‘locomotion’ by enhancing the force applied on the water during the sculling stroke in rowers. The cellular mechanisms associated with fatigue in the diaphragm remain elusive due to our poor understanding of excitation-contraction coupling in respiratory muscle. The diaphragm, like the heart (but not locomotor muscle), is dependent upon extracellular calcium for its normal activation. Consequently, any change in plasma calcium concentration (e.g. due to dehydration, hypervolaemia or diuresis) could alter the force generating capacity of diaphragm.We investigated the influence of changes in extracellular calcium concentration on force generation in isolated rabbit hemidiaphragm preparations killed by a lethal anaesthetic overdose (200 mg sodium penotbarbital). The preparations were subjected to direct tetanic stimulation (40 Hz, 0.5 s duration) for 10 min at three different duty cycles (i.e. the duration between successive tetani was 20, 10 and 5 secs) and at three different calcium concentrations (5, 2 and 0.5 mM).The muscle was allowed to recover fully between each calcium concentration. The different calcium concentrations were applied in random order.The figure shows that the greatest cumulative reduction in force (an index of fatigue) was observed at the lowest extracellular calcium concentration, while high calcium concentration delayed the onset of fatigue.These data demonstrate that the force generating capacity of the diaphragm is influenced by changes in extracellular calcium concentration. A decrease in plasma calcium concentration will increase the susceptibility of respiratory muscle to fatigue and may contribute to the symptom of breathlessness.