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Robin Roberts, Hongmei Luan, Bruce A. Berkowitz; Blocking ET-1 Receptors Does Not Correct Subnormal Retinal Oxygenation Response in Experimental Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2006;47(8):3550-3555. doi: https://doi.org/10.1167/iovs.05-1624.
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purpose. To test the hypothesis that bosentan (a dual ETA/ETB receptor antagonist) corrects a subnormal retinal oxygenation response in the STZ-induced diabetic rat.
methods. In benchtop experiments, ET-1 was acutely injected into the vitreous of control and 5- to 7-day bosentan-treated nondiabetic rats. Major retinal vessel diameters were analyzed from ADPase-stained flatmounts. Retinal oxygenation (ΔPo 2), an established early surrogate marker of drug treatment efficacy, was measured by MRI during a 2-minute carbogen inhalation challenge in four groups: control rats (n = 7), control rats treated with bosentan (n = 7), 3-month diabetic rats (n = 9), and 3-month diabetic rats treated with bosentan (n = 5). Effect of baseline differences was studied in control rats breathing either room air (n = 5) or 12% oxygen breathing (n = 5) before a 2-minute carbogen provocation.
results. ET-1 produced a significant (P < 0.05) reduction in retinal arterial diameter that was suppressed (P > 0.05) in rats fed bosentan chow admix. For all groups, no MRI baseline signal intensity differences were found (P > 0.05). Also, comparisons between baseline room air and 12% conditions and control rats fed normal chow or a bosentan admix both produced similar (P > 0.05) panretinal ΔPo 2. In treated and untreated diabetes groups, inferior hemiretinal ΔPo 2 remained normal (P > 0.05), but superior hemiretinal ΔPo 2 was subnormal (P < 0.05).
conclusions. Because subnormal retinal ΔPo 2 after drug treatment is a biomarker of subsequent vascular histopathology, the present data raise the possibility that retinal ET-1 does not play a key role in the pathogenesis of diabetic retinopathy.
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