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 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. 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 FVC induced by hypoxia and that induced by adenosine; the control responses to these stimuli were comparable in magnitude and both were reduced by approximately 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-ethylcarboxamidoadeno sin e hydrochloride; i.a. infusion for 5 min). ZM 241385 also reduced the increase in FVC induced by adenosine by approximately 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 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.
Bryan
P T
PT
Department of Physiology, The Medical School, Birmingham B15 2TT,, UK.
Marshall
J M
JM
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001784:Blood Gas Analysis; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000737:chemistry*; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D012119:Respiration; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D000959:Antihypertensive Agents; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014665:Vasodilator Agents; D014970:Xanthines; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C058394:2-chloro-N(6)cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine