Endogenous Adenosine Increases Coronary Flow by Activation of Both A2A and A2B Receptors in Mice

Talukder, Milton; Morrison, R. Ray; Ledent, Catherine; Mustafa, S. Jamal

doi:10.1097/00005344-200304000-00008

Cited by 53 publications

(53 citation statements)

References 29 publications

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“…Currently, there are four known adenosine receptor (AR) subtypes namely, A 1 , A 2A , A 2B , and A 3 . 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].…”

Section: Introductionmentioning

confidence: 64%

“…Also, in the absence of nNOS, eNOS was able to somehow change its expression to compensate for the loss of nNOS [26]. Generally, in coronary circulation, A 2B AR was found to play a minor role, compared to A 2A AR, in regulating coronary blood flow and/or myocardial contraction [1,2,27]. In this study, we found that NECA (a non-specific adenosine agonist known to activate low affinity A 2B AR)-induced relaxation at high concentration in wire myograph experiments and the concentration-response relationship was shifted to the left in A2AKO ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

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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“…The presence of A3R in the rat coronary circulation has also been claimed [442]. A2AR and A2BR also mediate coronary vasodilation in mice [443,444] and up-regulation of A2BR in A2AR knockout mouse coronary artery has been reported [237,445]; an involvement of K ATP channels in this action was also demonstrated [445].…”

Section: Coronary Blood Vesselsmentioning

confidence: 94%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

120

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This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

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“…We [20,44] and others [10,11,45] previously demonstrated that adenosine also plays a physiological role in regulating coronary resting flow in human [11], swine [10], dogs [45], guinea pigs [46], and mice [20,44], while some other groups failed to observe an endogenous role of adenosine [3,47,48], which leaves this scientific topic controversial. This discrepancy may be due to different animal models, differences in species, and/or different agonists and antagonists applied in these studies [19].…”

Section: Adenosine-induced Increase In Coronary Flow Is Mediated In Pmentioning

confidence: 99%

“…This discrepancy may be due to different animal models, differences in species, and/or different agonists and antagonists applied in these studies [19]. However, the application of exogenous adenosine to increase coronary flow for the investigation of adenosine receptor-mediated signaling pathways has been well established [37,44]. Thus, in agreement with previous studies from our laboratory [37,44,49] and others [14], adenosine produced a large increase in coronary flow in isolated mouse hearts, supporting the overall effect of vasodilation by adenosine in the coronary circulation [14,15,37,50,51].…”

Section: Adenosine-induced Increase In Coronary Flow Is Mediated In Pmentioning

confidence: 99%

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Zhou

Rajamani

Labazi

et al. 2015

Purinergic Signalling

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Adenosine increases coronary flow mainly through the activation of A 2A and A 2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A 1 or A 3 ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A 2A but not A 2B ARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H 2 O 2 ) production was measured in isolated coronary arteries from WT, A 2A AR k n o c k o u t ( K O ) , a n d A 2 B A R K O m i c e u s i n g dichlorofluorescein immunofluorescence. Adenosineinduced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A 2B but not A 2A AR KO isolated hearts. Similarly, the A 2A AR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A 2B AR KO, while the A 2B AR selective agonist BAY 60-6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10 μM) increase in H 2 O 2 formation in both WT and A 2B AR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H 2 O 2 production in A 2A AR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H 2 O 2 , which critically depends upon the presence of A 2A AR.

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Endogenous Adenosine Increases Coronary Flow by Activation of Both A2A and A2B Receptors in Mice

Cited by 53 publications

References 29 publications

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

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

Cardiac purinergic signalling in health and disease

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

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