Adenosine receptor antagonists and retinal neovascularization in vivo

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 neov ascularization was examined in a mouse pup model of oxygen-induced retinopa thy. METHODS. A previously described model of oxygen-induced retinal neovascular ization in newborn mouse pups was used to examine the effect of various Ado R antagonists on neovascularization. The nonselective AdoR antagonist xanth ine amine congener (XAC), the A(2A)-selective antagonist ZM241385, the A(2B )-selective antagonists 3-N-propylxanthine (enprofylline) and 3-isobutyl-8- pyrrolidinoxanthine (IPDX), and the A(1)-selective antagonist cyclopentyl-1 ,3-dipropylxanthine (CPX) were used. After the hyperoxia exposure the anima ls 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 perfus ed with fluorescein-dextran. WholeMounts of retinas from one eye were prepa red and examined. whereas the retinas of the contralateral eye were embedde d. 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 A(2B) AdoR antagonists. Quantificat ion 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 A(2B)-selective AdoR antagonists inhibited oxygen-induced retinal neovascularization in vivo and may provide a basis for developing p harmacologic therapies for the treatment of proliferative retinopathies.