Adenosine A2aReceptors Increase Arterial Endothelial Cell Nitric Oxide

Li, Jianming; Fenton, Richard A.; Wheeler, H. Brownell; Powell, Craig C.; Peyton, Brian D.; Cutler, Bruce S.; Dobson, James G.

doi:10.1006/jsre.1998.5439

Cited by 99 publications

(82 citation statements)

References 31 publications

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“…Some previous studies have shown blunting of Ado-induced skeletal muscle vasodilation by NOS inhibition (32,37), whereas other studies demonstrated no effect of NOS inhibition Ado-induced skeletal muscle vasodilation (3,18,19). In the present study, we demonstrate a statistically significant contribution of NO to Ado-mediated vasodilation in Ado responders only.…”

Section: Discussioncontrasting

confidence: 46%

“…Some studies have shown that inhibition of NO synthase (NOS) blunted exercise hyperemia (9, 11), whereas other demonstrated no effect of NOS inhibition on exercise hyperemia (6,32,36). Similarly, some studies have shown blunting of Ado-induced skeletal muscle vasodilation by NOS inhibition (32,37), whereas other studies demonstrated no effect of NOS inhibition on Ado-induced skeletal muscle vasodilation (3,18,19).With this information as background, the purpose of the present investigation was to test the hypothesis that subjects with robust forearm vasodilator responses to Ado would have robust vasodilator responses to exercise, and vice versa. We reasoned that if Ado were a key metabolite causing blood flow to increase during exercise in humans, vasodilator responsiveness during Ado infusion would be similar to increases in forearm blood flow (FBF) during handgrip exercise.…”

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Bimodal distribution of vasodilator responsiveness to adenosine due to difference in nitric oxide contribution: implications for exercise hyperemia

Martin

Nicholson²,

Eisenach³

et al. 2006

Journal of Applied Physiology

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distribution of vasodilator responsiveness to adenosine due to difference in nitric oxide contribution: implications for exercise hyperemia. J Appl Physiol 101: [492][493][494][495][496][497][498][499] 2006. First published April 13, 2006; doi:10.1152/japplphysiol.00684.2005.-To gain insight into the role of adenosine (Ado) in exercise hyperemia, we compared forearm vasodilation induced by intra-arterial infusion of three doses of Ado with vasodilation during three workloads of forearm handgrip exercise in 27 human subjects. We measured forearm blood flow (FBF) using Doppler ultrasound and mean arterial pressure (MAP) via brachial artery catheters and calculated forearm vascular conductance (FVC ϭ FBF/MAP) during each infusion dose or workload. We found that about half of the subjects demonstrated robust vasodilator responsiveness to both Ado infusion and exercise, and the other half demonstrated blunted vasodilator responsiveness to Ado infusion compared with exercise. In 15 subjects (identified as "Ado responders"), the change in FVC above baseline was 209 Ϯ 33, 419 Ϯ 57, and 603 Ϯ 75 ml ⅐ min Ϫ1 ⅐ 100 mmHg Ϫ1 for the low, medium, and high doses of Ado, respectively, and 221 Ϯ 35, 413 Ϯ 54, and 582 Ϯ 70 ml ⅐ min Ϫ1 ⅐ 100 mmHg Ϫ1 for the low, medium, and high exercise workloads, respectively. In the other 12 subjects (identified as "Ado nonresponders"), the change in FVC above baseline was 102 Ϯ 36, 113 Ϯ 42, and 151 Ϯ 54 ml ⅐ min Ϫ1 ⅐ 100 mmHg Ϫ1 for the low, medium, and high doses of Ado, respectively (P Ͻ 0.05 vs. Ado responders), whereas exercise hyperemia was not different from Ado responders (P Ͼ 0.05). Furthermore, infusion of N G -monomethyl-Larginine (L-NMMA) blunted vasodilator responses to Ado infusion only in Ado responders (P Ͻ 0.01 vs. post-L-NMMA) and had no effect on exercise in either group. We also found differences in vasodilator responses to isoproterenol at all doses, but acetylcholine only at one dose, between Ado responders and nonresponders. We conclude that vasodilator responsiveness to Ado exhibits a bimodal distribution among human subjects involving differences in the contribution of nitric oxide to Ado-mediated vasodilation. Finally, our data support the concept that neither Ado nor nitric oxide is obligatory for exercise hyperemia.skeletal muscle blood flow; isoproterenol; acetylcholine; reactive hyperemia; N G -monomethyl-L-arginine MUSCLE BLOOD FLOW INCREASES dramatically during dynamic exercise. However, the main vasodilators that contribute to exercise hyperemia and their interactions remain uncertain (16,33,35). Possible contributors include, among others, adenosine (Ado) and related compounds. Studies in animals have both supported and rejected a role of Ado in exercise hyperemia. Some studies have demonstrated an increase in Ado concentration in venous blood (7) and/or an increase in interstitial Ado concentration in skeletal muscle (1, 39) during muscle contraction. In contrast, other studies failed to show any increase in venous Ado concentration (1, 39) or skeletal muscl...

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Section: Discussioncontrasting

confidence: 46%

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confidence: 99%

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confidence: 99%

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Bimodal distribution of vasodilator responsiveness to adenosine due to difference in nitric oxide contribution: implications for exercise hyperemia

Martin

Nicholson²,

Eisenach³

et al. 2006

Journal of Applied Physiology

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“…Previous studies from our group demonstrated that both A 2A AR and A 2B AR mediated endogenous and exogenous adenosine-induced dilation in mouse coronary circulation [1,2]. Cell culture studies also demonstrated the involvement of A 2A AR and A 2B AR mediated NO release in porcine and human coronary endothelial cells [3,4]. However, there are very few functional studies demonstrating whether NO release is responsible for A 2A AR mediated coronary vasodilation.…”

Section: Introductionmentioning

confidence: 89%

“…The hearts from 8 A2AWT and 6 A2AKO mice were excised as described in Langendorff Experiments and placed in oxygenated (5% CO 2 and 95% O 2 ) modified Kreb-Henseleit buffer (in mM: NaCl 120, NaHCO 3 [22]. Each vascular ring was stretched to a resting tension (100 mg) that consisted mainly of passive tension and was allowed to equilibrate for at least 30 min.…”

Section: Coronary Wire Myograph Experimentsmentioning

confidence: 99%

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

Teng¹,

Ledent²,

Mustafa³

2008

Journal of Molecular and Cellular Cardiology

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In this study, we looked into possible compensatory changes of other adenosine receptors (AR) in A 2A genetic knockout mice (A2AKO) as well as the functional role of nitric oxide (NO) in A 2A ARmediated vasodilation. Gene expression of ARs from coronary arteries of A 2A AR wild type mice (A2AWT) and A2AKO were studied using real time-PCR. Functional studies were carried out in isolated heart and isolated coronary artery preparations. A 2B AR was found to be 4.5 fold higher in A2AKO than in A2AWT, while A 2A AR expression was absent in A2AKO. There was no difference in A 1 and A 3 ARs between WT and KO animals. The concentration-relaxation curve for adenosine-5′-N-ethylcarboxamide (NECA, non-selective AR agonist) in isolated coronary arterial rings in A2AKO was shifted to the left when compared to A2AWT. The concentration-response curve for A 2B selective agonist (Bay 60-6583) was also shifted to the left in A2AKO hearts. L-NAME, a nonspecific NO synthase inhibitor, did not affect baseline coronary flow (CF) until the concentration reached 10 µM in A 2A WT (76.32 ± 11.35% from baseline, n=5). In A 2A KO, the CF decreased significantly by L-NAME only at a higher concentration (100 µM, 93.32 ± 5.8% from baseline, n=5). L-NMA (1 µM, n=4), another non-specific NO synthase inhibitor, also demonstrated similar results in decreasing CF (59.66±3.23% from baseline in A2AWT, while 81.76±8.91% in A2AKO). It was further demonstrated that the increase in CF by 100 µM NECA was significantly blunted with 10 µM L-NAME (377.08 ± 25.23% to 305.41 ± 30.73%, n=9) in A 2A WT but not in A 2A KO (153.66 ± 22.7% to 143.88 ± 36.65%, n=5). Similar results were also found using 50 nM of CGS-21680 instead of NECA in A 2A WT (346±22.85 to 277±31.39, n=6). No change in CF to CGS-21680 was noted in A 2A AKO. Our data demonstrate, for the first time, that coronary A 2B AR was up-regulated in mice deficient in A 2A AR. We also provide direct evidence supporting a role for NO in A 2A AR-mediated coronary vasodilation. The data further support the role for A 2A AR in the regulation of basal coronary tone through the release of NO.

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Subcellular distributions of adenosine A1 and A2A receptors in the rat dorsomedial nucleus of the solitary tract at the level of the area postrema

Pickel

Chan

Linden

et al. 2006

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Adenosine A1 and A2A receptors mediate distinct cardiovascular components of defense reactions that are ascribed, in part, to opposing actions within the nucleus tractus solitarius. To assess the cellular sites of relevance to these actions, we examined the light and electron microscopic immunolabeling of adenosine A1 and A2A receptors in the rat dorsomedial nucleus of the solitary tract at the level of the area postrema (dmNTS-AP), a region crucial for cardiovascular regulation involving vagal baroreceptor afferents. Immunoreactivity for each receptor was independently localized to distinct segments of plasma membranes and endomembranes in somatodendritic, axonal, and glial profiles. The dendritic labeling for each receptor also was detected within and near asymmetric, excitatory-type synapses. Of all peroxidase labeled profiles exclusive of somata, approximately 58% were A1- and 39% were A2A-labeled dendrites. Dendrites and astrocytic glia were the profiles that most often expressed both subtypes of adenosine receptors. The axonal labeling for A2A receptors was seen mainly in unmyelinated axons, whereas the A1 receptors were prominently localized within axon terminals. These terminals often formed single or multisynaptic excitatory-type junctions or single symmetric synapses on dendrites, a few of which expressed A1 and A2A receptors. These results provide the first ultrastructural evidence that A1 and A2A receptors have distributions conductive to their dual involvement in modulating the output of single neurons and glial function in the dmNTS-AP, where the predominate presynaptic effects of adenosine are mediated through A1 receptors.

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Adenosine A2aReceptors Increase Arterial Endothelial Cell Nitric Oxide

Cited by 99 publications

References 31 publications

Bimodal distribution of vasodilator responsiveness to adenosine due to difference in nitric oxide contribution: implications for exercise hyperemia

Bimodal distribution of vasodilator responsiveness to adenosine due to difference in nitric oxide contribution: implications for exercise hyperemia

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

Subcellular distributions of adenosine A1 and A2A receptors in the rat dorsomedial nucleus of the solitary tract at the level of the area postrema

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