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Propranolol inhibition of beta-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy

Journal article
Authors J. Chen
J. S. Joyal
C. J. Hatton
A. M. Juan
D. T. Pei
C. G. Hurst
D. Xu
A. Stahl
Ann Hellström
L. E. Smith
Published in Investigative Ophthalmology and Visual Science
Volume 53
Issue 6
Pages 2968-77
ISSN 0146-0404
Publication year 2012
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Pages 2968-77
Language en
Keywords Administration, Oral, Adrenergic beta-Antagonists/*administration & dosage, Angiopoietin-1/genetics/metabolism, Angiopoietin-2/genetics/metabolism, Animals, Animals, Newborn, Cell Proliferation, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Endothelial Cells/drug effects, Enzyme-Linked Immunosorbent Assay, Erythropoietin/genetics/metabolism, Gene Expression Profiling, Humans, Infant, Newborn, Injections, Intraperitoneal, Injections, Subcutaneous, Mice, Oxygen/toxicity, Propranolol/*administration & dosage, RNA/metabolism, Receptors, Adrenergic, beta/metabolism, Receptors, Vascular Endothelial Growth Factor/genetics/metabolism, Retina/cytology, Retinal Neovascularization/metabolism/*prevention & control, Retinopathy of Prematurity/metabolism/*prevention & control, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Vascular Endothelial Growth Factor A/genetics/metabolism
Subject categories Other Medical Sciences


PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective beta-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. METHODS: Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. RESULTS: None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. CONCLUSIONS: Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of beta-adrenergic receptors is an appropriate therapeutic approach for treating ROP.

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