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

Pharmacology. 2001;62(3):172-80. doi: 10.1159/000056091.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic alpha-Antagonists / pharmacology
  • Ammonia / metabolism
  • Animals
  • Antioxidants / pharmacology
  • Cell Fractionation
  • Diabetes Mellitus, Experimental / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Fructose / metabolism
  • Glucose / metabolism
  • Glutamic Acid / metabolism
  • Imidazoles / pharmacology*
  • Imidazolidines*
  • Ketoglutaric Acids / metabolism
  • Lactic Acid / metabolism
  • Male
  • Mitochondria / metabolism
  • NAD / metabolism*
  • Oxidation-Reduction
  • Piperazines / pharmacology*
  • Prazosin / pharmacology*
  • Pyrimidines / pharmacology*
  • Pyruvic Acid / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Retina / chemistry
  • Retina / drug effects*
  • Retina / metabolism
  • Sorbitol / metabolism
  • Thioctic Acid / pharmacology*

Substances

  • Adrenergic alpha-Antagonists
  • Antioxidants
  • Enzyme Inhibitors
  • Imidazoles
  • Imidazolidines
  • Ketoglutaric Acids
  • Piperazines
  • Pyrimidines
  • SDI 157
  • NAD
  • Fructose
  • Lactic Acid
  • Glutamic Acid
  • Sorbitol
  • Thioctic Acid
  • Ammonia
  • Pyruvic Acid
  • sorbinil
  • Glucose
  • Prazosin