AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

Liu, Yanping; Yang, Xiangdong; Yang, Xi‐Ming; Walker, Sheree; Förster, Karina; Cohen, Michael V.; Krieg, Thomas; Downey, James M.

doi:10.1007/s00395-009-0056-9

Cited by 15 publications

(12 citation statements)

References 30 publications

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“…However, it was not possible to duplicate the protection of AMP-579 with CGS-21680 alone (18). Recently, AMP-579 has been shown to be a potent A 2b AR agonist as well (11), making its pharmacological properties very similar to those of NECA. There is one report in which an A 2a AR-selective agonist alone could limit infarct size (21), but in that study infarct size was measured after a prolonged reperfusion time during which postinfarct inflammation may have further extended the infarct.…”

Section: Resultsmentioning

confidence: 99%

Both A_2a and A_2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Methner

Schmidt

Cohen

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Pre- and postconditioning depend on the activation of adenosine receptors (ARs) at the end of the index ischemia. The aim of this study was to determine which receptor subtypes must be activated. In situ mouse hearts underwent 30 min of regional ischemia, followed by 2 h of reperfusion. As expected, either ischemic postconditioning (6 cycles of 10 s of reperfusion and 10 s of coronary occlusion) or infusion of the selective A(2b) adenosine receptor (A(2b)AR) agonist BAY60-6583 (BAY60) for 60 min, starting 5 min before reperfusion reduced infarct size in wild-type C57Bl/6N mice. Protection from either was abolished by the selective A(2b)AR antagonist MRS-1754, confirming a role for A(2b)AR. Additionally, the coadministration of ischemic postconditioning and a selective A(2a)AR antagonist led to the loss of protection as well. 5'-Ectonucleotidase (CD73) is thought to be necessary for the production of adenosine during ischemia. As predicted, ischemic postconditioning did not protect CD73 knockout mice. Selective agonists of either A(2b)AR (BAY60) or A(2a)AR (CGS-21680), as well as the coadministration of ischemic postconditioning and BAY60, also failed to protect hearts of the CD73 knockout mice. But the nonselective A(1)/A(2)AR agonist 5'-(N-ethylcarboxamido)adenosine (NECA) was protective, suggesting that the activation of multiple AR subtypes might be required. The coadministration of CGS-21680 and BAY60 also elicited profound protection, indicating that two AR subtypes, A(2a) and A(2b), must be simultaneously activated for protection to occur.

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Section: Resultsmentioning

confidence: 99%

Both A_2a and A_2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Methner

Schmidt

Cohen

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…AMP579 limits myocardial infarction in in vivo rabbit heart 46 and reduces ischemic contracture and infarct size in isolated rabbit heart when administered during reperfusion. 47,48 Recently, Downey and colleagues reinterpreted the cardioprotective effects of AMP579 to be the result of A 2B agonism, because they were blocked by A 2B selective antagonists MRS1754 and PSB1115. 48 Our data raise the possibility that these authors may have actually interfered with A 1 /A 2 receptor synergy and that AMP579 is likely to activate A 1 and A 2 receptors as part of its protective mechanism.…”

Section: Discussionmentioning

confidence: 97%

Cooperative Cardioprotection Through Adenosine A1 and A2A Receptor Agonism in Ischemia-Reperfused Isolated Mouse Heart

Urmaliya¹,

Pouton²,

Ledent³

et al. 2010

Journal of Cardiovascular Pharmacology

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Recent reports have shown that adenosine A1 receptor-mediated cardioprotection requires concomitant A2 receptor activation, but no study thus far has shown that this phenomenon occurs using A1 agonists at reperfusion. Thus, we compared adenosine A2A receptor knockout (A2AKO) and wild-type mouse hearts (n = 9-11) subjected to global ischemia (30 minutes) and reperfusion (60 minutes) in the presence and absence of the A1 agonist N-cyclopentlyadenosine (CPA). We also determined the effects of selective antagonists at A2A and A2B receptors on CPA-induced protection. In wild-type hearts, CPA (100 nM) significantly (P < 0.05) improved contractility (52.7 ± 6.2% versus 23.9 ± 4.9% of preischemia), left ventricular developed pressure, end diastolic pressure; reduced infarct size (7.9 ± 1.7% versus 23.9 ± 6.6% area at risk); decreased lactate dehydrogenase efflux; and increased ERK1/2 phosphorylation at 60 minutes of reperfusion. Adenosine A2A (ZM241385, 50 nM) and A2B (MRS1754, 100 nM) receptor antagonists abolished CPA-mediated cardioprotection in wild-type groups as did the A1 receptor antagonist DPCPX (P < 0.05). In A2AKO hearts, CPA did not improve functional parameters and protective signaling with the exception of end diastolic pressure. In this model, using a clinically relevant mode of pharmacologic intervention, pERK 1/2-dependent A1-mediated cardioprotection requires a cooperative activation of A2 receptors, presumably through endogenous adenosine.

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“…22,23 Unfortunately, AMP-579 is an unspecific Adora1, Adora2a, and Adora2b agonist, which makes it difficult to draw conclusions about the adenosine receptor subtype involved. 24,25 Studies in gene targeted mice suggest that primarily signaling through Adora2b is responsible for this effect on PMNs. 13 …”

Section: Discussionmentioning

confidence: 99%

Adora2b Signaling on Bone Marrow Derived Cells Dampens Myocardial Ischemia-Reperfusion Injury

et al. 2012

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Background Cardiac ischemia-reperfusion injury (I/R) represents a major cause of cardiac tissue injury. Adenosine signaling dampens inflammation during cardiac I/R. Here, we investigated the role of the adenosine A2b-receptor (Adora2b) on inflammatory cells during cardiac I/R. Methods To study Adora2b signaling on inflammatory cells, we transplanted wild-type (WT) bone marrow (BM) into Adora2b−/− mice or Adora2b−/− BM into WT mice. To study the role of polymorphonuclear leukocytes (PMNs), neutrophil-depleted WT mice were treated with an Adora2b agonist. Following treatments, mice were exposed to 60 min of myocardial ischemia and 120 min of reperfusion. Infarct sizes and Troponin-I levels were determined by triphenyltetrazolium chloride staining and ELISA, respectively. Results Transplantation of WT-BM into Adora2b−/− mice decreased infarct sizes by 19 ± 4% and Troponin-I by 87.5 ± 25.3 ng/ml (mean ± SD, n = 6). Transplantation of Adora2b−/− BM into WT mice increased infarct sizes by 20 ±3% and Troponin-I levels by 69.7 ± 17.9 ng/ml (mean ± SD, n = 6). Studies on the reperfused myocardium revealed PMNs as dominant cell type. PMN-depletion or Adora2b agonist treatment reduced infarct sizes by 30 ± 11% or 26 ± 13% (mean ± SD, n = 4), however the combination of both did not reveal further cardioprotection. Cytokine profiling showed significantly higher cardiac tumor-necrosis-factor-α levels in Adora2b−/− compared to WT mice (39.3 ± 5.3 vs. 7.5 ± 1.0 pg/mg protein, mean ± SD, n = 4). Pharmacological studies on human activated PMNs revealed an Adora2b dependent tumor-necrosis-factor-α release. Conclusion Adora2b signaling on BM-derived cells such as PMNs represents an endogenous cardioprotective mechanism during cardiac I/R. Our findings suggest that Adora2b agonist treatment during cardiac I/R reduces tumor-necrosis-factor-α release of PMNs, thereby dampening tissue injury.

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AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

Cited by 15 publications

References 30 publications

Both A_2a and A_2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Both A_2a and A_2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Cooperative Cardioprotection Through Adenosine A1 and A2A Receptor Agonism in Ischemia-Reperfused Isolated Mouse Heart

Adora2b Signaling on Bone Marrow Derived Cells Dampens Myocardial Ischemia-Reperfusion Injury

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AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

Cited by 15 publications

References 30 publications

Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Cooperative Cardioprotection Through Adenosine A1 and A2A Receptor Agonism in Ischemia-Reperfused Isolated Mouse Heart

Adora2b Signaling on Bone Marrow Derived Cells Dampens Myocardial Ischemia-Reperfusion Injury

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Both A_2a and A_2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Both A_2a and A_2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts