It is widely accepted that adenosine is released within tissues under hypoxic conditions. Accordingly, several studies in which adenosine receptor antagonists or adenosine deaminase have been used indicate that locally released adenosine makes important contributions to the respiratory and cardiovascular responses that are induced by systemic hypoxia. For example, adenosine has been shown to contribute to the central respiratory depression of systemic hypoxia, by actions within the brain, and to play a part in the bradycardia and myocardial depression by local actions on the sino-atrial node and ventricular muscle (see Neylon & Marshall, 1991; and references therein). In these ways the actions of adenosine tend to counteract the hyperventilation and tachycardia that are the reflex, neurally mediated responses to systemic hypoxia (Marshall, 1994). In addition, experiments on the rat have indicated that locally released adenosine is responsible for at least 50% of the vasodilatation that occurs in skeletal muscle during systemic hypoxia and which overcomes the reflex vasoconstriction evoked by sympathetic nerve activation 1. In anaesthetized rats we tested responses evoked by systemic hypoxia (breathing 8% Oµ for 5 min) and adenosine (i.a. infusion for 5 min) before and after administration of a selective adenosine AÔ receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), or a selective adenosine A2A receptor antagonist ZM 241385. Arterial blood pressure, (ABP), heart rate (HR), femoral blood flow (FBF) and femoral vascular conductance (FVC: FBFÏABP) were recorded together with the K¤ concentration in arterial blood ([K¤]a) and in venous blood of hindlimb muscle ([K¤]v) before and at the 5th minute of hypoxia or agonist infusion. 2. In 12 rats, DPCPX reversed the fall in ABP and HR and the increase in FVC evoked by the selective AÔ agonist CCPA (2-chloro-N É-cyclopentyladenosine; i.a. infusion for 5 min). DPCPX also reduced both the increase in FVC induced by hypoxia and that induced by adenosine; the control responses to these stimuli were comparable in magnitude and both were reduced by •50%. 3. In 11 rats, ZM 241385 reversed the fall in ABP and increase in FVC evoked by the selective A2A agonist CGS 21680 (2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride; i.a. infusion for 5 min). ZM 241385 also reduced the increase in FVC induced by adenosine by •50%, but had no effect on the increase in FVC induced by hypoxia. 4. In these same studies, before administration of DPCPX, or ZM 241385, hypoxia had no effect on the venous-arterial difference for K¤ ([K¤]v-a), whereas after administration of either antagonist, hypoxia significantly reduced [K¤]v-a suggesting an increase in hypoxiainduced K¤ uptake, or a reduction in K¤ efflux. 5. These results indicate that both AÔ and A2A receptors are present in hindlimb muscle and can mediate vasodilatation and that AÔ and A2A receptors contribute equally to dilatation induced by infused adenosine. However, they suggest that endogenous ade...

In previous studies we have provided evidence, by using adenosine receptor antagonists, that a major part of the vasodilatation induced in skeletal muscle of the rat during systemic hypoxia is mediated by adenosine (Neylon & Marshall, 1991). From the effects of glibenclamide, which inhibits ATP-sensitive K¤ (KATP) channels, we argued that a part of the hypoxia-induced muscle vasodilatation, particularly the early part, is dependent on the opening of KATP channels (Marshall et al. 1993). On the other hand, since ¬_NAME (nitro-¬_arginine methyl ester), which blocks the synthesis of nitric oxide (NO), greatly reduced both the hypoxia-induced muscle vasodilatation and that evoked by Journal of Physiology (1999) 1. In anaesthetized rats, we recorded arterial blood pressure (ABP), heart rate (HR), femoral blood flow (FBF) and femoral vascular conductance (FVC). We tested the effects of the nitric oxide (NO) synthesis inhibitor ¬_NAME (nitro-¬_arginine methyl ester), or the ATP-sensitive K¤ (KATP) channel inhibitor glibenclamide, on responses evoked by systemic hypoxia (breathing 8% Oµ for 5 min) or i.a. infusion for 5 min of adenosine, the NO donor sodium nitroprusside (SNP), the adenosine A1 receptor agonist CCPA (2-chloro-N É-cyclopentyladenosine) or the adenosine A2A receptor agonist CGS 21680 (2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride). 2. ¬_NAME (10 mg kg¢ i.v.) greatly reduced the increase in FVC induced by hypoxia or adenosine, as we have shown before, but had no effect on the increase in FVC evoked by SNP. In addition, ¬_NAME abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that muscle vasodilatation induced by systemic hypoxia and infused adenosine are largely NO dependent. They also indicate that muscle dilatation induced by A1 receptor stimulation is entirely NO dependent while that induced by A2A receptors is largely NO dependent; dilatation may also be induced by direct stimulation of A2A receptors on the vascular smooth muscle. 3. Glibenclamide (10 or 20 mg kg¢ i.v.) reduced the increase in FVC induced by hypoxia, preferentially affecting the early part (< 1 min). In addition, glibenclamide greatly reduced the increase in FVC induced by adenosine, but it had no effect on that evoked by SNP. Further, glibenclamide abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that hypoxia-induced muscle vasodilatation is initiated by KATP channel opening. They also indicate that NO does not induce muscle vasodilatation by opening KATP channels on the vascular smooth muscle, but indicate that the dilatation induced by adenosine and by A2A receptor stimulation is largely dependent on KATP channel opening, while that induced by A1 receptor stimulation is wholly dependent on KATP channel opening. 4. These results, together with previous evidence that hypoxia-induced vasodilatation in skeletal muscle is largely mediated by adenosine...

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