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(Investigative Ophthalmology and Visual Science. 2001;42:3320-3324.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Adenosine Receptor Antagonists and Retinal Neovascularization in Vivo

Robert P. Mino1,2, Polyxenie E. Spoerri2, Sergio Caballero2, Denifield Player3, Luiz Belardinelli4, Italo Biaggioni5 and Maria B. Grant2

1 From the Departments of Molecular Biology and Genetics, 2 Pharmacology and Therapeutics, and 3 Anatomy and Cell Biology, University of Florida, Gainesville; 4 CV Therapeutics, Palo Alto, California; and the 5 Department of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee.

PURPOSE. The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was examined in a mouse pup model of oxygen-induced retinopathy.

METHODS. A previously described model of oxygen-induced retinal neovascularization in newborn mouse pups was used to examine the effect of various AdoR antagonists on neovascularization. The nonselective AdoR antagonist xanthine amine congener (XAC), the A2A-selective antagonist ZM241385, the A2B-selective antagonists 3-N-propylxanthine (enprofylline) and 3-isobutyl-8-pyrrolidinoxanthine (IPDX), and the A1-selective antagonist cyclopentyl-1,3-dipropylxanthine (CPX) were used. After the hyperoxia exposure the animals received daily intraperitoneal injections of pharmacologically relevant doses of AdoR antagonists for 5 days. Control animals received vehicle (0.1% dimethyl sulfoxide [DMSO]) alone. The animals were then killed and perfused with fluorescein-dextran. Wholemounts of retinas from one eye were prepared and examined, whereas the retinas of the contralateral eye were embedded, sectioned, and stained for counting neovascular nuclei extending beyond the internal limiting membrane into the vitreous.

RESULTS. Angiography of wholemount retinas showed reduction of neovascular tufts in animals treated with selective A2B AdoR antagonists. Quantification of the extraretinal neovascular nuclei showed that only animals treated with XAC, enprofylline, or IPDX showed a significant reduction in retinal neovascularization. By contrast, neither CPX nor ZM241385 had an effect on neovascularization.

CONCLUSIONS. The A2B-selective AdoR antagonists inhibited oxygen-induced retinal neovascularization in vivo and may provide a basis for developing pharmacologic therapies for the treatment of proliferative retinopathies.




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