Blocking ET-1 receptors does not correct subnormal retinal oxygenation response in experimental diabetic retinopathy.
OBJECTIVE
To test the hypothesis that bosentan (a dual ET(A)/ET(B) 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 (DeltaPo(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 DeltaPo(2). In treated and untreated diabetes groups, inferior hemiretinal DeltaPo(2) remained normal (P > 0.05), but superior hemiretinal DeltaPo(2) was subnormal (P < 0.05).


CONCLUSIONS
Because subnormal retinal DeltaPo(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.
Roberts
Robin
R
Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, USA.
Luan
Hongmei
H
Berkowitz
Bruce A
BA
D000818:Animals; D001081:Apyrase / Q000378:metabolism; D000077300:Bosentan; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D010313:Partial Pressure; D051381:Rats; D012160:Retina / Q000378:metabolism*; D012171:Retinal Vessels / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D001081:Apyrase; D000077300:Bosentan; D010100:Oxygen