In rats, acute systemic hypoxia (5 min) evokes skeletal muscle vasodilatation (increase in femoral vascular conductance, FVC) that is partly mediated by adenosine acting at A₁-, but not A_2A-receptors (Bryan & Marshall, 1999). Further, a tonic increase in FVC is present in rats exposed to chronic systemic hypoxia (CH) for 1 and 3 days, which is partially reversed by the A₁-receptor antagonist, DPCPX (Walsh & Marshall, 2000). A₁-receptors have been shown to redistribute from cell surface to cytoplasm during continued exposure to adenosine (Saura et al. 1998). Thus, we have tested whether the vasodilator role of adenosine changes over the first 6 h of CH. In male Wistar rats anaesthetized with Saffan (4-8 mg kg^-1 h^-1 I.V.), cardiovascular variables were recorded during 6 h of either normoxia (N; n=7) after vehicle or CH (breathing 12% O₂), either after vehicle (n=7), DPCPX (0.1 mg kg^-1 I.V.; n=7) or 8-PT (10 mg kg^-1 I.V., an adenosine receptor antagonist which is non-selective between sub-types; n=7). At the end of the experiment animals were killed. Variables were analysed at 0, 5 and 10 min and at 10 min intervals for the first hour and then hourly. All variables remained steady during N. CH induced a maintained fall in P_aO₂ (from 87±2 to 44±2 mmHg, mean ± S.E.M). At 5 min of CH, mean arterial pressure (MAP) had fallen from 123±2 to 72±5 mmHg (P<0.001, ANOVA and Fishers post hoc), but returned to 103±6 mmHg at 1 h of CH and was maintained until 6 h. Concomitantly, FVC was increased at 5 min CH (0.013±0.0016 to 0.024±0.003 ml min^-1 mmHg^-1; P<0.01), gradually waned back to baseline levels at 2-3 h, but increased again to 0.018±0.002 ml min^-1 mmHg^-1 by 4 h where it remained until 6 h of CH (P<0.05). Neither DPCPX nor 8-PT affected baselines. However, both antagonists attenuated the initial fall in MAP and increase in FVC (to ~90-100 mmHg and ~0.012-0.020 ml min^-1 mmHg^-1, respectively, P<0.05) at 5 min of CH, but had no significant effect from 1-6 h of CH. Thus, 6 h of CH induces muscle vasodilatation that wanes by 2-3 h and partially recovers by 4-6 h. We suggest that the muscle vasodilatation of the first hour is dependent on adenosine acting on A₁-receptors but not on the lower affinity A_2A-receptors that are blocked by 8-PT (see Bryan & Marshall, 1999). Other dilator mechanisms become important after 2-3 h of CH, while A₁-receptors may be recycling to the cell surface to become operational by 1-3 days CH (see Walsh & Marshall, 2000).