Nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine?

Belle, H. Van

doi:10.1093/cvr/27.1.68

Cited by 122 publications

(62 citation statements)

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“…26 In this sense, recent studies have reported that adenosine transport inhibitors, such as propentofylline, exert a protective effect in rat cerebral ischemia by inhibiting the transport of adenosine into cells, resulting in increased extracellular concentrations of endogenous adenosine and enhanced stimulation of adenosine receptors. 6,27 As shown in Fig. 5, the administration of an adenosine A 2 receptor antagonist (DMPX) at a dose 0.1 mg/kg to preconditioned rats did not modify the protective effect of preconditioning.…”

Section: Discussionmentioning

confidence: 88%

The Protective Role of Adenosine in Inducing Nitric Oxide Synthesis in Rat Liver Ischemia Preconditioning Is Mediated by Activation of Adenosine A2 Receptors

et al. 1999

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This study aims to determine if the protective role of adenosine in liver ischemic preconditioning is mediated by the activation of adenosine receptors and to ascertain which of these receptors is implicated in the process. Administration of adenosine A 1 and A 2 receptor antagonists to preconditioned animals indicates that hepatic preconditioning is mediated by the activation of adenosine A 2 receptors. Propentofylline (an inhibitor of adenosine transport into cells) in the preconditioned group, subjected to previous administration of an adenosine A 2 receptor antagonist, prevented the negative effect of the latter on the protection offered by preconditioning. An increase of NO production was detected just immediately after hepatic preconditioning, and the administration of an adenosine A 2 receptor antagonist to the preconditioning group prevented this increase, thus abolishing the protective effect of preconditioning. However, the administration of a NO donor to the preconditioned group subjected to previous administration of the adenosine A 2 receptor antagonist was able to maintain the preconditioning effects. In conclusion, these results indicate that, in preconditioning, the protective effect of adenosine could be a result of an increase in extracellular adenosine. This in turn would induce the activation of adenosine A 2 receptors, which, by eliciting an increase in NO generation, would protect against the injury associated with hepatic ischemia-reperfusion. (HEPATOLOGY 1999;29: 126-132.)Ischemic preconditioning, first shown in the myocardium has become a phenomenon described in the intestine, 1 brain, 2 and liver. 3 We have previously shown that ischemic preconditioning, induced by brief ischemia and reperfusion periods, renders the liver more tolerant to subsequent sustained ischemia-reperfusion. 4 We have also shown that the administration of adenosine mimics the effect of preconditioning in ischemic livers, and that the metabolization of endogenous adenosine by adenosine deaminase abolished the protective effect of preconditioning. We have further shown the beneficial effect of adenosine in inducing NO synthesis in ischemic tissue, 4 although the exact mechanism by which adenosine offered protection was not determined in that study. Recent work in heart preconditioning has shown that preconditioning-induced protection may require the activation of adenosine receptors. Thus, an adenosine receptor agonist can simulate the preconditioning whereas an adenosine receptor antagonist blocks its beneficial effect. 5 Also, recent studies in cerebral ischemia, have obtained evidence that the response to adenosine persists or is enhanced by nucleoside transport inhibitors such as propentofylline. Inhibition of adenosine uptake would increase its concentration in the extracellular space and hence potentiate its effects, particularly if adenosine binds to a specific receptor site on the external surface of the membrane. 6 Adenosine receptors have been divided into three major subclasses: A 1 , A 2 , and A 3 , 5,7 ...

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Section: Discussionmentioning

confidence: 88%

The Protective Role of Adenosine in Inducing Nitric Oxide Synthesis in Rat Liver Ischemia Preconditioning Is Mediated by Activation of Adenosine A2 Receptors

et al. 1999

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“…The Ado uptake inhibitor, midazolam, depresses excitatory synaptic transmissions in the hippocampus [220]. In addition, Ado uptake inhibitors have less severe adverse effects compared to Ado receptor agonists [221,222]. Some controversial results were described in relation to nucleoside transporter inhibition, e.g., papaverine may have pro-and anticonvulsant effects in different models [134,213,217,[223][224][225].…”

Section: Inhibition Of Nucleoside Transportersmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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“…These include enhancement of the target selectivity and effectiveness of cytotoxic nucleoside analogues used in anti-cancer and anti-viral therapy [1,2], as well as manipulation of the biological activities of adenosine to enhance its neuroprotective [3][4][5][6][7] and cardioprotective [8][9][10][11][12] actions. Many of these protocols involve inhibition of the cellular uptake or release of nucleosides.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and functional characterization of inhibitor-sensitive (mENT1) and inhibitor-resistant (mENT2) equilibrative nucleoside transporters from mouse brain

Kiss

Farah

Kim

et al. 2000

Biochemical Journal

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Mammalian cells express at least two subtypes of equilibrative nucleoside transporters, i.e. ENT1 and ENT2, which can be distinguished functionally by their sensitivity and resistance respectively to inhibition by nitrobenzylthioinosine. The ENT1 transporters exhibit distinctive species differences in their sensitivities to inhibition by dipyridamole, dilazep and draflazine (human mouse rat). A comparison of the ENT1 structures in the three species would facilitate the identification of the regions involved in the actions of these cardioprotective agents. We now report the molecular cloning and functional expression of the murine (m)ENT1 and mENT2 transporters. mENT1 and mENT2 encode proteins containing 458 and 456 residues respectively, with a predicted 11-transmembrane-domain topology. mENT1 has 88 % and 78 % amino acid identity with rat ENT1 and human ENT1 respectively ; mENT2 is more highly conserved, with 94 % and 88 % identity with rat ENT2 and human ENT2 respectively. We have also isolated two additional distinct cDNAs that encode proteins similar to mENT1 ; these probably represent distinct mENT1 isoforms or alternative splicing products. One cDNA encodes a protein with two additional amino acids

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Nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine?

Cited by 122 publications

References 0 publications

The Protective Role of Adenosine in Inducing Nitric Oxide Synthesis in Rat Liver Ischemia Preconditioning Is Mediated by Activation of Adenosine A2 Receptors

The Protective Role of Adenosine in Inducing Nitric Oxide Synthesis in Rat Liver Ischemia Preconditioning Is Mediated by Activation of Adenosine A2 Receptors

The Antiepileptic Potential of Nucleosides

Molecular cloning and functional characterization of inhibitor-sensitive (mENT1) and inhibitor-resistant (mENT2) equilibrative nucleoside transporters from mouse brain

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