1. The effect of A1-adenosine receptor antagonism via 8-cyclopentyl-1,3-dipropyl-xanthine (CPDPX) on the stimulation of skeletal muscle glucose uptake by contractions and hypoxia was investigated in isolated perfused rat hindquarters. The standard perfusate contained either no insulin or a submaximal insulin concentration at 100 microU ml-1. 2. Muscles were stimulated to contract for 45 min by intermittent tetanic stimulation of the sciatic nerve. Hypoxia was induced by reducing perfusate haematocrit from 30% to 10% on the one hand, and by switching the gassing of the perfusate from a 35% to a 0% O2 mixture for 60 min on the other hand. The effect of contractions and hypoxia alone, or in combination, was investigated. 3. Hypoxia-induced muscle glucose uptake was not altered by CPDPX in the absence or presence of insulin. In contrast, contraction-induced glucose uptake was reduced by approximately 25 % (P < 0.05) by exposure of muscles to CPDPX. CPDPX did not affect hindlimb glucose uptake either before or after contractions. 4. The increment of muscle glucose uptake during hypoxia combined with contractions was greater (P < 0.05) than the effect of hypoxia alone. 5. The current findings provide evidence that the mechanism by which hypoxia stimulates muscle glucose uptake is, at least in part, different from the mechanism of glucose uptake stimulation by contractions, because (i) A1-adenosine receptors regulate insulin-mediated glucose uptake in muscle during contractions but not during hypoxia and (ii) submaximal hypoxia and contractions are additive stimuli to muscle glucose uptake.