Role of the Adrenergic System in a Mouse Model of Oxygen-Induced Retinopathy: Antiangiogenic Effects of β-Adrenoreceptor Blockade

Ristori, Chiara; Filippi, Luca; Monte, Massimo Dal; Martini, Davide; Cammalleri, Maurizio; Fortunato, Pina; Marca, Giancarlo la; Fiorini, Patrizio; Bagnoli, Paola

doi:10.1167/iovs.10-5536

Cited by 144 publications

(182 citation statements)

References 70 publications

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“…Both treatments normalised BP in diabetic Ren-2 rats; however, only ARB reduced retinal vasculopathy and improved the electroretinogram [24,38]. Similar comparisons in OIR may not necessarily be informative given that β-blockers have anti-proliferative effects in OIR [39], and whether this occurs by a BPdependent mechanism is uncertain as BP cannot be measured in P18 rodents. We therefore examined this question in normotensive mice with OIR, and our finding that aliskiren reduced neoangiogenesis and avascular retina in this model indicates that the beneficial effects of aliskiren on vasculopathy were not necessarily related to its antihypertensive properties.…”

Section: Discussionmentioning

confidence: 99%

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

et al. 2011

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Aim/hypothesis We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy. Methods Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg −1 day −1 , pump), or diabetic + lisinopril (10 mg kg −1 day −1 , drinking water) rats were evaluated over 16 weeks. For oxygeninduced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg −1 day −1 , pump) or lisinopril (10 mg kg −1 day −1 , drinking water) was administered during retinopathy development between postnatal days 12 and 18. Results Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg −1 day −1 aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg −1 day −1 aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg −1 day −1 aliskiren and normalised by 30 mg kg −1 day −1 aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels. Conclusions/interpretation Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

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Section: Discussionmentioning

confidence: 99%

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

et al. 2011

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“…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).…”

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confidence: 99%

Pharmacokinetics and local safety profile of propranolol eye drops in rabbits

et al. 2014

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Background: Oral propranolol, a nonselective β-blocker, is able to reduce the progression of retinopathy of prematurity in newborns, but it appeared unsafe. This study aimed to find, in rabbits, a propranolol eye drop concentration able to induce lower plasma but higher retinal concentrations than those obtained after oral administration. Methods: Male New Zealand white rabbits were treated with oral propranolol (0.25 mg/kg/6 h) for 5 d, and propranolol concentrations were measured after 1, 2, 3, and 6 h in plasma, aqueous humor, vitreous humor, and retina. These concentrations were compared with those obtained after the administration of one drop of 25 μl of propranolol 0.1% prepared in saline, applied every 6 h to both eyes for 5 d. A Draize eye test and histological analyses were performed to assess eye drop tolerability. results: The administration of eye drops produced retinal concentrations similar to, but plasma concentrations significantly lower than, those measured after oral administration. The local tolerability profile was excellent. conclusion: Propranolol eye drops are able to ensure high retinal and low plasma concentrations of propranolol, and this finding opens the perspective of possible topical treatment with propranolol in newborns with retinopathy of prematurity.

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“…Notably, in a mouse model of proliferative retinopathy, the pharmacological blockade of β-AR with propranolol has been demonstrated to reduce retinal levels of HIF-1α and, consequently, of proangiogenic factors (VEGF and IGF-1), markedly reducing retinal neoangiogenesis (35).…”

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confidence: 99%

Expression of β-adrenergic receptors in pediatric malignant brain tumors

et al. 2012

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Abstract. β-adrenergic receptors (β-ARs) are G protein-coupled receptors that activate signal transduction pathways involved in angiogenesis, resulting in enhanced tumor vascularization and more aggressive growth. In this study, we evaluated the expression of β-ARs in a population of 12 children affected by malignant primary brain tumors. We found a significant expression of β1-and β2-ARs in all 12 samples as well as the 3 cell lines tested (U87MG, T98G and DAOY). The mean absolute β1-AR mRNA level standardized to GAPDH was 5.81 (range, -7.91 to 11.29) for brain tumors and 8.59 (range, 6.046 to 12.59) for cell lines (U87MG, DAOY and T98G), respectively. The mean absolute β2-AR mRNA level was 4.74 (range, -9.30 to 8.45) for tumor specimens and 7.64 (range, 5.85 to 8.88) for cell lines. These real-time quantitative (qRT)-PCR expression data were confirmed by immunohistochemical analysis. Our study evaluated the presence of β1-and β2-ARs in malignant pediatric brain tumors and brain tumor cell lines.

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Role of the Adrenergic System in a Mouse Model of Oxygen-Induced Retinopathy: Antiangiogenic Effects of β-Adrenoreceptor Blockade

Cited by 144 publications

References 70 publications

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Pharmacokinetics and local safety profile of propranolol eye drops in rabbits

Expression of β-adrenergic receptors in pediatric malignant brain tumors

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