Antiangiogenic effects of β₂‐adrenergic receptor blockade in a mouse model of oxygen‐induced retinopathy

Abstract

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07530.x Abstract Oxygen‐induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta‐adrenergic receptor (β‐AR) blockade with propranolol has been shown to ameliorate different aspects of retinal dysfunction in response to hypoxia. In the present study, we used the OIR model to investigate the role of distinct β‐ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that β2‐AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas β1‐ and β3‐AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that β‐AR blockers are indeed effective at the receptor level. In addition, the specificity of ICI 118,551 on retinal angiogenesis has been demonstrated by the finding that in mouse retinal explants, β2‐AR silencing prevents ICI 118,551 effects on hypoxia‐induced vascular endothelial growth factor accumulation. In OIR mice, ICI 118,551 is effective in increasing electroretinographic responses suggesting that activation of β2‐ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that β2‐ARs are localized to several retinal cells, particularly to Müller cells suggesting the possibility that β2‐ARs play a role in regulating vascular endothelial growth factor production by these cells. The present results suggest that pathogenic angiogenesis, a key change in many hypoxic/ischemic vision‐threatening retinal diseases, depends at least in part on β2‐AR activity and indicate that β2‐AR blockade can be effective against retinal angiogenesis.

Pharmacokinetics and local safety profile of propranolol eye drops in rabbits

“…Recent research studies performed in mice with oxygeninduced retinopathy (OIR), a worldwide used model for ROP (7), have demonstrated that norepinephrine accumulation and β-adrenoreceptor (β-AR) activation induce a HIF-1α-driven modulation of VEGF and IGF-1 and participate in mechanisms contributing to the shift from the avascular to the proliferative phase (8)(9)(10). Following these observations, two independent prospective pilot trials have demonstrated that oral propranolol administered to preterm newborns suffering from a precocious phase of ROP is effective in counteracting the progression of the disease (11,12), even though not sufficiently safe (11).…”

Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants

“…Several cationic drugs, such as memantine, propranolol and clonidine, have recently been reported to exert a neuroprotective effect in the brain and retina, [18][19][20] and these reports support the substantial contribution of the study of cationic drug transport at the BRB in developing future treatments for retinal disease. In the in vivo transport study of verapamil in rats, the apparent influx clearance of [ 3 H] verapamil (K in, verapamil, retina ) was calculated to be 614 µL/(min·g retina), which was much greater than that of paracellular transport markers, 21) supporting the facilitative influx transport system The correlation of an initial uptake rate (log V) of compounds undergoing carrier-mediated transport (A) and passive diffusion (B) in TR-iBRB2 cells with the RUI in rats was studied, and a linear relationship described by Eqs.…”

“…Among such cationic neuroprotectants, propranolol reduces the expression of vascular endothelial growth factor (VEGF), and clonidine induces basic fibroblast growth factor (bFGF) to exert a neuroprotective effect. 19,20) In the in vivo transport study, the measured RUI values of [ (Fig. 2C), and were inhibited in the presence of cationic drugs, such as verapamil and pyrilamine.…”

“…Because of the neuroprotective effects of cationic drugs, as previously reported, [18][19][20] the influx transport system of cationic drugs at the BRB is expected to be helpful in the delivery of neuroprotectants into the retina. Among such cationic neuroprotectants, propranolol reduces the expression of vascular endothelial growth factor (VEGF), and clonidine induces basic fibroblast growth factor (bFGF) to exert a neuroprotective effect.…”

Author Response: Different Efficacy of Propranolol in Mice with Oxygen-Induced Retinopathy: Could Differential Effects of Propranolol Be Related to Differences in Mouse Strains?

“…We found that propranolol is not effective in suppressing ROP, although we cannot rule out the possibility that unanticipated genetic differences in 129S6 versus C57BL/6J mice might contribute to the different results in the two studies. We suggest that propranolol should be tested in C57BL/6 mice (and other strains) using dosing comparable to the human trial, and standard evaluation of neovascularization and vasoobliteration in retinal flat mounts with induced retinopathy, 11,12 to provide the strongest basis possible for a clinical evaluation.Additional studies by Bagnoli et al 13,14 have examined different experimental beta-adrenergic receptor inhibitors and agonists, such as ICI 118,551 and isoproterenolol, in oxygeninduced retinopathy using the more standard method of angiogenesis staining and quantification. These studies certainly are helpful and necessary for identifying any specific betaadrenergic receptors that might regulate retinal angiogenesis.…”