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

Abstract

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...

Glucose-induced islet blood flow increase in rats: interaction between nervous and metabolic mediators

“…Previous studies on the influence of adenosine on the splanchnic circulation, including the pancreas, have unequivocally demonstrated that the vasodilating effects are mediated by A 2 receptors (18,24). However, a vasodilator response mediated by A 1 receptors exists in other vascular beds, e.g., the diaphragm (14) and other skeletal muscle (8,9,38).…”

Long-Term Stimulation of Adenosine A2b Receptors Begun After Myocardial Infarction Prevents Cardiac Remodeling in Rats

“…Because 4 subtypes of adenosine receptors have been cloned in the rat, 9,10 we used specific antagonists for subtypes of adenosine receptors: DPCPX for A1 adenosine receptors, A2a for SCH58161, A2b for MRS1754, and A3 for MRS1523. 20,[22][23][24][25]35 We found that the improvement in cardiac performance by long-term stimulation by CADO was blunted by MRS1754 but not by the antagonist of other subtypes of adenosine receptors. To the best of our knowledge, this study was the first to demonstrate the involvement of adenosine A2b receptor in cardiac remodeling.…”

Skeletal muscle contraction-induced vasodilator complement production is dependent on stimulus and contraction frequency

“…Both cell types have been reported to possess A1, A2 A , and A2 B membrane receptor subtypes (37). ADO receptors have been shown to cause vasodilation through NO-dependent processes and K ATP channels (8,23,33), although the exact location of the K ATP channels (endothelial cells or smooth muscle cells) is unknown. ADO receptors on smooth muscle cells have been shown to facilitate vasodilation through cAMP/protein kinase A-dependent mechanisms, resulting in the opening of K ATP channels, presumably on smooth muscle cells, and the resulting hyperpolarization will cause vasodilation (for review, see Ref.…”

“…Vascular cell NOS is involved in the dilatory pathways for other vasodilators implicated in muscle contraction such as ACh and ADO (8,23), and L-NAME application may, therefore, also be blunting the dilatory response imposed by these dilators during contraction. Although we did not test the contribution of ACh in this study, we did test the contribution of ADO.…”