Diabetes-induced changes in retinal NAD-redox status - Pharmacological modulation and implications for pathogenesis of diabetic retinopathy

Diabetes-induced changes in retinal metabolism and function have been linked to increased aldose reductase activity, hypoxia or 'pseudohypoxia' (increase in NADH/NAD(+) attributed to increased sorbitol dehydrogenase activity). To address this controversy, we evaluated the effects of two vasoactive compounds, alpha (1)-adrenoceptor antagonist prazosin and antioxidant DL-alpha -lipoic acid, as well as sorbitol dehydrogenase inhibitor (SDI-157) and aldose reductase inhibitor (sorbinil) on retinal free mitochondrial and cytosolic NAD(+)/NADH ratios in streptozotocin-diabetic rats. Diabetes-induced decrease in mitochondrial and cytosolic NAD(+)/NADH ratios was completely or partially corrected by prazosin and DL-alpha -lipoic acid (despite the fact that prazosin did not affect and DL-alpha -lipoic acid even further increased sorbitol pathway activity) as well as by sorbinil, whereas SDI-157 was totally ineffective. Hypoxia-like metabolic changes in the diabetic retina originate from aldose reductase, but not sorbitol dehydrogenase activity. Copyright (C) 2001 S. Karger AG, Basel.