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Experiments were performed under Saffan anaesthesia on normoxic (N) rats and on chronically hypoxic rats exposed to 12% O 2 for 1, 3 or 7 days (1, 3 or 7CH rats): N rats routinely breathed 21% O 2 and CH rats 12% O 2 . The 1, 3 and 7CH rats showed resting hyperventilation relative to N rats, but baseline heart rate (HR) was unchanged and arterial blood pressure (ABP) was lowered. Femoral vascular conductance (FVC) was increased in 1 and 3CH rats, but not 7CH rats. When 1-7CH rats were acutely switched to breathing 21% O 2 for 5 min, ABP increased and FVC decreased, consistent with removal of a hypoxic dilator stimulus that is waning in 7CH rats. We propose that this is because the increase in haematocrit and vascular remodelling in skeletal muscle help restore the O 2 supply. The increases in FVC evoked by acute hypoxia (8% O 2 for 5 min) and by infusion for 5 min of α-calcitonin gene-related peptide (α-CGRP), which are NO-dependent, were particularly accentuated in 1CH, relative to N rats. The NO synthesis inhibitor L-NAME increased ABP, decreased HR and greatly reduced FVC, and attenuated increases in FVC evoked by acute hypoxia and α-CGRP, such that baselines and responses were similar in N and 1-7CH rats. We propose that in the first few days of chronic hypoxia there is tonic NO-dependent vasodilatation in skeletal muscle that is associated with accentuated dilator responsiveness to acute hypoxia and dilator substances that are NO -dependent.

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Experiments were performed on anaesthetized normoxic (N) rats and chronically hypoxic rats that had been exposed to 12% O 2 for 1, 3 or 7 days (1, 3 or 7CH rats). The adenosine A 1 receptor antagonist DPCPX did not affect the resting hyperventilation of 1-7CH rats breathing 12% O 2 and increased resting heart rate (HR) in 1CH rats only. DPCPX partially restored the decreased baseline arterial pressure (ABP) and increased femoral vascular conductance (FVC) of 1 and 3CH rats, but had no effect in N or 7CH rats. DPCPX also attenuated the decrease in arterial blood pressure (ABP) and increase in FVC evoked by acute hypoxia in N and 1-7CH rats. The non-selective adenosine receptor antagonist 8-SPT had no further effect on baselines or cardiovascular responses to acute hypoxia, but attenuated the hypoxia-evoked increase in respiratory frequency in 1-7CH rats. In N, and 1 and 3CH rats, the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine had no effect on baselines or increases in FVC evoked by acetylcholine. We propose: (i) that tonically released adenosine acting on A 1 receptors reduces HR in 1CH rats and stimulates endothelial NOS in 1 and 3CH rats to decrease ABP and increase FVC, the remaining NO-dependent tonic vasodilatation being independent of iNOS activity; (ii) that in 7CH rats, tonic adenosine release has waned; (iii) that in 1-7CH rats, adenosine released by acute hypoxia stimulates A 1 but not A 2 receptors to produce muscle vasodilatation, and stimulates carotid body A 2 receptors to increase respiration. Adenosine makes a major contribution to the cardiovascular and ventilatory responses evoked by acute systemic hypoxia. In human subjects and the rat, a major part of the vasodilatation evoked in hindlimb muscle (increase in femoral vascular conductance, FVC) is mediated by adenosine acting on A 1 receptors (Neylon & Marshall, 1991;Bryan & Marshall, 1999a;Leuenberger et al. 1999). Further, adenosine contributes to the secondary fall in tidal volume (V T ) and heart rate (HR) that occur during extended periods of acute hypoxia (Millhorn et al. 1984;. This accords with evidence that adenosine can decrease HR by acting on cardiac A 1 receptors (Evans et al. 1982;Belardinelli et al. 1989) and decrease V T and respiratory frequency (R F ) by acting on central neural A 1 receptors (Eldridge et al. 1985;Wessberg et al. 1985;Schmidt et al. 1995). Adenosine also stimulates A 2 receptors in the carotid body and so may contribute to the increase in R F of acute hypoxia (Monteiro & Ribeiro, 1987;Kobayashi et al. 2000).The adaptations that occur in ventilation and haematocrit (Hct) from the onset of chronic hypoxia have been extensively investigated (e.g. Olson & Dempsey, 1978;Dempsey & Forster, 1982;Ou et al. 1992). By contrast, relatively little is known of the cardiovascular adaptations. We have now confirmed (accompanying paper Walsh & Marshall, 2006) that resting hyperventilation is already present in rats exposed to chronic hypoxia (12% O 2 ) for 1, 3 and 7 days (1, 3 and 7CH rats), while an incr...

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