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.
Obrosova
I G
IG
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, MSRB 11, Room 5570, Ann Arbor, MI 48109-0678, USA. iobrosso@umich.edu
Stevens
M J
MJ
Lang
H J
HJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002458:Cell Fractionation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007656:Ketoglutaric Acids / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D000975:Antioxidants; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D007656:Ketoglutaric Acids; D010879:Piperazines; D011743:Pyrimidines; C402002:SDI 157; D009243:NAD; D005632:Fructose; D019344:Lactic Acid; D018698:Glutamic Acid; D013012:Sorbitol; D008063:Thioctic Acid; D000641:Ammonia; D019289:Pyruvic Acid; C026411:sorbinil; D005947:Glucose; D011224:Prazosin