Evidence that the adenosine A3 receptor may mediate the protection afforded by preconditioning in the isolated rabbit heart

Liu, Guang S.; Richards, Steven C.; Olsson, Ray A.; Mullane, Kevin; Walsh, Robert S.; Downey, James M.

doi:10.1093/cvr/28.7.1057

Cited by 253 publications

(167 citation statements)

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“…Protection against MI was mediated by A1R and also probably A3R in the rabbit heart [515,623]. Activation of A2AR at reperfusion was shown to reduce infarct size in dog heart [519].…”

Section: Myocardial Infarctionmentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

119

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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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“…Protection against MI was mediated by A1R and also probably A3R in the rabbit heart [515,623]. Activation of A2AR at reperfusion was shown to reduce infarct size in dog heart [519].…”

Section: Myocardial Infarctionmentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

119

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“…The combined extracts were dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified with preparative thin layer chromatography (PTLC, silica gel) with the mobile phase consisting of mixtures of methanol (3% for 21 or 5% for 44, by volume) and chloroform.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…Acting through the A 2A adenosine receptor (AR), it suppresses prolonged inflammation [2] and causes vasodilation and inhibits platelet aggregation, thus increasing the amount of oxygen available to an organ under stress. Adenosine agonists selective for the A 3 AR are of interest as cerebroprotective [3], cardioprotective [4,5], and anticancer [6] agents.…”

Section: Introductionmentioning

confidence: 99%

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Gao

Mamedova

Chen

et al. 2004

Biochemical Pharmacology

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The affinity and efficacy at four subtypes (A 1 , A 2A , A 2B and A 3 ) of human adenosine receptors (ARs) of a wide range of 2-substituted adenosine derivatives were evaluated using radioligand binding assays and a cyclic AMP functional assay in intact CHO cells stably expressing these receptors. Similar to previous studies of the N 6 -position, several 2-substituents were found to be critical structural determinants for the A 3 AR activation. The following adenosine 2-ethers were moderately potent partial agonists (K i , nM): benzyl (117), 3-chlorobenzyl (72), 2-(3-chlorophenyl)ethyl (41), and 2-(2-naphthyl)ethyl (130). The following adenosine 2-ethers were A 3 AR antagonists: 2,2-diphenylethyl, 2-(2-norbornan)ethyl, R-and S-2-phenylbutyl, and 2-(2-chlorophenyl)ethyl. 2-(S-2-Phenylbutyloxy)a-denosine as an A 3 AR antagonist right-shifted the concentration-response curve for the inhibition by NECA of cyclic AMP accumulation with a K B value of 212 nM, which is similar to its binding affinity (K i = 175 nM). These 2-substituted adenosine derivatives were generally less potent at the A 1 AR in comparison to the A 3 AR, but fully efficacious, with binding K i values over 100 nM. The 2-phenylethyl moiety resulted in higher A 3 AR affinity (K i in nM) when linked to the 2-position of adenosine through an ether group (54), than when linked through an amine (310) or thioether (1960). 2-[2-(lNaphthyl)ethyloxy]adenosine (K i = 3.8 nM) was found to be the most potent and selective (>50-fold) A 2A agonist in this series. Mixed A 2A /A 3 AR agonists have been identified. Interestingly, although most of these compounds were extremely weak at the A 2B AR, 2-[2-(2-naphthyl)ethyloxy]adenosine (EC 50 = 1.4 µM) and 2-[2-(2-thienyl)-ethyloxy]adenosine (EC 50 = 1.8 (M) were found to be relatively potent A 2B agonists, although less potent than NECA (EC 50 = 140 nM).

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“…The chemoprotective feature of the A3AR agonists is associated with other cytoprotective characteristics of these compounds. A3AR activation by low agonist concentration has been found to mediate functions, such as cerebroprotective activity following chronic administration of IB-MECA to gerbils with cerebral ischaemia (von Lubitz et al, 1994), cardioprotective activity during prolonged stimulated ischaemia by rescuing injured myocytes (Liu et al, 1994), and an anti-inflammatory effect (Bowlin et al, 1997).…”

Section: A3 Adenosine Receptor Agonists Inhibit Colon Carcinoma G Ohamentioning

confidence: 99%

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

et al. 2003

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Adenosine is a purine nucleoside that acts as a regulatory molecule by binding to specific G-protein-coupled A1, A 2A , A 2B , and A3 cell surface receptors. We have recently demonstrated that adenosine inhibits tumour cell growth and concomitantly stimulates bone marrow cell proliferation via activation of the A3 adenosine receptor (A3AR). In the present study, we show that a synthetic agonist to the A3AR, CF101, at the low nanomolar concentration range, inhibits HCT-116 human colon carcinoma cell growth. This effect was reversed by the selective A3AR antagonist MRS1523, demonstrating the specificity of the response. CF101 (given orally) was efficacious in inhibiting the development of primary tumours in xenograft and syngeneic models in which mice were inoculated subcutaneously with human HCT-116 or murine CT-26 colon carcinoma cells, respectively. Moreover, CF101 suppressed (50%, Po0.01) colon cancer liver metastases in syngeneic mice inoculated to the spleen with CT-26 cells. The mechanism of action entailed upregulation of interleukin-12 production in the CF101-treated groups and potentiation of NK cell activity. In the HCT-116 xenograft model in which a combined therapy of CF101 and 5-fluorouracyl (5-FU) was examined, an additive antitumour effect was demonstrated. Moreover, CF101 prevented the 5-FU-induced myelotoxicity, resulting in normal values of white blood cell and neutrophil counts. We conclude that the A3AR agonist CF101, a small orally bioavailable molecule, exerts systemic anticancer, antimetastatic, and myeloprotective effects in colon carcinoma-bearing mice, and may serve as an adjuvant treatment to enhance the chemotherapeutic index and prevent myelotoxicity.

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Evidence that the adenosine A3 receptor may mediate the protection afforded by preconditioning in the isolated rabbit heart

Cited by 253 publications

References 0 publications

Cardiac purinergic signalling in health and disease

Cardiac purinergic signalling in health and disease

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

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