AN ALDOSE REDUCTASE INHIBITOR AND AMINOGUANIDINE PREVENT VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION IN RATS WITH LONG-TERM GALACTOSEMIA

Objective: To study the effects of an aldose reductase inhibitor (ARI- 509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents tha t have been reported to prevent or delay diabetic retinopathy, on reti nal vascular abnormalities and the immunocytochemical expression in th e retina of vascular endothelial growth factor (VEGF) in rats maintain ed for up to 2 years on a 50% galactose diet. Methods: Albino rats wer e placed on a control diet, a diet containing 50% galactose, or the 50 % galactose diet containing either ARI-509 or AMG. Treatment with ARI- 509 or AMG was initiated at the beginning of the experiment or after 1 2 months of galactose feeding. After 22 to 24 months, the rats were ki lled and the retinal vasculature from half of one eye was isolated by trypsin-elastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immuno cytochemistry and stained for the presence of VEGF, factor VIII, vimen tin, and glial fibrillary acidic protein. Red blood cells, sciatic ner ves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin.Result s: Galactose-fed animals developed a vascular retinopathy characterize d by severe cellular loss in the retinal capillaries and intensificati on of periodic acid-Schiff staining of the vascular basement membranes . Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, bu t were unaffected in all of the other treatment groups. None of the mt s receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivit y. With the exception of the animals receiving ARI-509 from the beginn ing of the experiment, all of the galactose-fed animals developed dens e cataracts within 6 weeks of the beginning of the galactose diet, Gal actitol levels in animals receiving ARI-509 were 86% to 93% lower in r ed blood cells, retina, and sciatic nerve than these in the other gala ctose-fed groups. Conclusions: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galact osemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsib le for VEGF expression in the retina, and that aldose reductase inhibi tors and AMG have potential roles in preventing such expression and, t hus, perhaps preventing retinal neovascularization.