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(Investigative Ophthalmology and Visual Science. 2006;47:3550-3555.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1624
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Blocking ET-1 Receptors Does Not Correct Subnormal Retinal Oxygenation Response in Experimental Diabetic Retinopathy

Robin Roberts,1 Hongmei Luan,1 and Bruce A. Berkowitz1,2

1From the Department of Anatomy and Cell Biology and the 2Kresge Eye Institute, Wayne State University, Detroit, Michigan.

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 ({Delta}PO2), 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 {Delta}PO2. In treated and untreated diabetes groups, inferior hemiretinal {Delta}PO2 remained normal (P > 0.05), but superior hemiretinal {Delta}PO2 was subnormal (P < 0.05).

CONCLUSIONS. Because subnormal retinal {Delta}PO2 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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E. D. Gilmore, C. Hudson, R. K. Nrusimhadevara, P. T. Harvey, M. Mandelcorn, W. C. Lam, and R. G. Devenyi
Retinal Arteriolar Diameter, Blood Velocity, and Blood Flow Response to an Isocapnic Hyperoxic Provocation in Early Sight-Threatening Diabetic Retinopathy
Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1744 - 1750.
[Abstract] [Full Text] [PDF]


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