Adenosine receptor subtypes and vasodilatation in rat skeletal muscle during systemic hypoxia: A role for A₁ receptors

1. In anaesthetized rats we tested responses evoked by systemic hypoxia (breathing 8% O₂ for 5 min) and adenosine (I.A. infusion for 5 min) before and after administration of a selective adenosine A₁ receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), or a selective adenosine A(2A) receptor antagonist ZM 241385. Arterial blood pressure, (ABP), heart rate (HR), femoral blood flow (FBF) and femoral vascular conductance (FVC: FBF/ABP) 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 A₁ agonist CCPA (2-chloro-N⁶-cyclopentyladenosine; I.A. infusion for 5 min). DPCPX also reduced both the increase in PVC 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 A(2A) agonist CGS 21680 (2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamido-adenosine 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 hypoxia-induced K⁺ uptake, or a reduction in K⁺ efflux. 5. These results indicate that both A₁ and A(2A) receptors are present in hindlimb muscle and can mediate vasodilatation and that A₁ and A(2A) receptors contribute equally to dilatation induced by infused adenosine. However, they suggest that endogenous adenosine released during systemic hypoxia induces dilatation only by acting on A₁ receptors. Given previous evidence that adenosine can stimulate receptors on skeletal muscle fibres that are coupled to ATP-sensitive K⁺ (K(ATP)) channels so promoting K⁺ efflux, our results allow the proposal that K(ATP) channels may be coupled to both A₁ and to A(2A) receptors and may be stimulated to open by adenosine released during hypoxia, but indicate that, during systemic hypoxia, K⁺ efflux caused by either receptor subtype makes a very minor contribution to the muscle vasodilatation.