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

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 A2A 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.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 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%.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.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.These results indicate that both A1 and A2A receptors are present in hindlimb muscle and can mediate vasodilatation and that A1 and A2A 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+ (KATP) channels so promoting K+ efflux, our results allow the proposal that KATP channels may be coupled to both A1 and to A2A 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

Oxygen delivery and oxygen consumption in rat hindlimb during systemic hypoxia: role of adenosine

In anaesthetised rats, the increase in femoral vascular conductance (FVC) evoked by moderate systemic hypoxia is mediated by adenosine acting on A1 receptors. It is also nitric oxide (NO) dependent: it is attenuated by NO synthase (NOS) inhibition, but restored when baseline FVC is restored by sodium nitroprusside (SNP), a NO donor. However, under these conditions there was in increase in the critical O2 delivery (DO2,crit) at which hindlimb O2 consumption (V̇O2) becomes directly dependent upon O2 delivery (DO2), indicating that V̇O2 is regulated by newly synthesised NO.In the present study, after NOS inhibition, when baseline FVC was restored with SNP infusion, the increases in FVC evoked by breathing 12 and 8 % O2 were reduced by the A1 receptor antagonist DPCPX, by 60 and 40 %, respectively (n = 8). The A2A receptor antagonist ZM241385 reduced the FVC increase evoked by 12 % O2 (by 45 %, n = 8), but did not alter that evoked by 8 % O2.DPCPX also reduced the increases in FVC evoked by graded systemic hypoxia, breathing 14–6 % O2 and increased DO2,crit, from 0.64 ± 0.06 to 0.95 ± 0.07 ml O2 min−1 kg−1 (control vs. DPCPX). However, ZM241385 (n = 8) had no effect on the FVC increases or on DO2,crit (0.70 ± 0.02 ml O2 min−1 kg−1, n = 8).Thus, the increases in FVC evoked by mild to severe systemic hypoxia are mediated by A1 receptors. These responses, which are attributable to proximal arteriolar dilatation, help maintain DO2. Even after NOS inhibition, adenosine still increases FVC via A2A (moderate hypoxia only) and A1 receptors, providing baseline levels of NO are present. Furthermore, adenosine, acting via A1 receptors, is important in determining DO2,crit and therefore in maintaining V̇O2. We propose that this is achieved by A1-evoked dilatation of terminal arterioles and is mediated by increased synthesis of NO