Possible Agonistic Interaction of Defibrotide, A DNA Derivative, with Adenosine Receptors “In Vitro”

Bianchi, Giorgio; Mantovani, M; Prino, G; Salvetti, Laura; Barone, Domenico

doi:10.1080/07328319108047258

Cited by 3 publications

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“…This antagonism appeared to be competitive, being reversed by increasing the concentration of the drug; it also paralleled receptor binding and in vitro studies in which defibrotide was shown to stimulate adenosine receptors in a concentration range comparable to ours. 11 This finding provides a novel insight as to the possibility of adenosine interacting with the cyclooxygenase pathway. However, lack of information on adenosine itself in preventing cyclooxygenase desensitization and the fact that we did not provide direct evidence that this autacoid behaves comparably to defibrotide in our study prevent us from drawing definitive conclusions.…”

Section: Discussionmentioning

confidence: 88%

“…10 Further studies have demonstrated that this interaction with the adenosine receptors is functionally agonistic and can be antagonized by a known theophylline-like antagonist. 11 Aim of the present work was to investigate whether affinity (likely to be agonistic) of defibrotide for adenosine receptors may help to explain its interaction with the eicosanoid pathway. We focused on the enhancement of prostanoid neosynthesis from exogenously added arachidonic acid (AA) in the vascular tissue.…”

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confidence: 99%

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Enhancement by Defibrotide of Prostanoid Neosynthesis from Arachidonic Acid: An Adenosine Receptor-Mediated Effect?

Bianchi¹,

Calvani²,

Mantovani³

et al. 1991

Semin Thromb Hemost

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The antithrombotic and anti-ischemic drug defibrotide is known to enhance PGI2 and prostaglandin E2 release and to interact competitively and agonistically with adenosine A1 and A2 receptors. To elucidate a possible molecular mechanism of action of this drug, we measured prostanoid neosynthesis from exogenous AA in isolated, intraluminally perfused RbA (5 to 10 preparations/group). Defibrotide (30 micrograms/ml) almost doubled the conversion rate of AA (15 micrograms) into PGI2-la (quantitated by a bioassay system): 56.8 +/- 5.3 versus 32.9 +/- 7.8 ng, compared with controls. The adenosine receptor antagonist 8-PT, at concentrations of 0.625, 1, and 1.6 micrograms/ml, dose-dependently and up to 100% inhibited the effect of defibrotide; however, a higher concentration of this latter (100 micrograms/ml) shifted to the right the 8-PT inhibition curve. A second AA bolus given into RbA caused homologous desensitization: 43 and 62% reduction of AA conversion after two versus one bolus was observed in controls receiving 15 and 30 micrograms AA. This phenomenon was inhibited by 30 micrograms/ml defibrotide (32% reduction only at two boluses, instead of 62% displayed by comparable controls), but this effect was abolished by 1.6 micrograms/ml 8-PT; once again, 100 micrograms/ml defibrotide overcame the antagonism by 8-PT. We conclude that defibrotide enhances prostanoid neosynthesis from AA and reduces homologous desensitization of the cyclooxygenase pathway through a mechanism possibly linked to stimulation of adenosine receptors.

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%