These experiments were undertaken to assess the role of sorbitol dehydrogenase in mediating sorbitol pathway-linked neural and vascular dysfunction in rats with strep-tozocin-induced diabetes. 2-methyl-4-[N N-dimethylsulfamoyl-piperazino]-pyrimidine (S-0773), a putative inhibitor of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S-0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by S-0773. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase.
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Original Articles|
February 01 1995
Inhibition of Sorbitol Dehydrogenase: Effects on Vascular and Neural Dysfunction in Streptozocin-Induced Diabetic Rats
Ronald G Tilton;
Ronald G Tilton
Department of Pathology, Washington University School of Medicine
St. Louis, Missouri
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Kathy Chang;
Kathy Chang
Department of Pathology, Washington University School of Medicine
St. Louis, Missouri
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Jens R Nyengaard;
Jens R Nyengaard
Department of Pathology, Washington University School of Medicine
St. Louis, Missouri
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Maria Van den Enden;
Maria Van den Enden
Department of Pathology, Washington University School of Medicine
St. Louis, Missouri
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Yasuo Ido;
Yasuo Ido
Department of Pathology, Washington University School of Medicine
St. Louis, Missouri
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Joseph R Williamson
Joseph R Williamson
Department of Pathology, Washington University School of Medicine
St. Louis, Missouri
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Address correspondence and reprint requests to Dr. Ronald G. Tilton, Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, TX 77030.
1
Present address of J.R.N. is Stereological Research Laboratory, Aarhus University, Århus, Denmark
2
M.V.d.E. is Department of Internal Medicine, C2, A. Z. Middelheim Hospital, Antwerp, Belgium.
Diabetes 1995;44(2):234–242
Article history
Received:
November 15 1993
Revision Received:
October 31 1994
Accepted:
October 31 1994
PubMed:
7859946
Citation
Ronald G Tilton, Kathy Chang, Jens R Nyengaard, Maria Van den Enden, Yasuo Ido, Joseph R Williamson; Inhibition of Sorbitol Dehydrogenase: Effects on Vascular and Neural Dysfunction in Streptozocin-Induced Diabetic Rats. Diabetes 1 February 1995; 44 (2): 234–242. https://doi.org/10.2337/diab.44.2.234
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