Polyol pathway, 2,3-diphosphoglycerate in erythrocytes and diabetic neuropathy in rats.
The relationship between the 2,3-diphosphoglycerate concentration in red blood cells as a biological indicator of tissue hypoxia and diabetic neuropathy, and the effect of a potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2'5'-dioxospiro [chroman-4,4'-imidazolidine]-2-carboxamide (SNK-860), on both were investigated in streptozotocin-induced diabetic rats. Diabetic rats demonstrated significantly delayed motor nerve conduction velocity and reduced sciatic nerve blood flow. Altered biochemical features in the sciatic nerves, including a marked accumulation of sorbitol and fructose, myo-inositol depletion and decreased Na+/K(+)-ATPase activity were also detected in diabetic rats. These defects were accompanied by a decrease in the red blood cell 2,3-diphosphoglycerate concentration. Treatment with SNK-860 partially or completely ameliorated these abnormalities. These observations suggest that a decrease in the red blood cell 2,3-diphosphoglycerate concentration is one of the factors contributing to tissue hypoxia, which results in diabetic neuropathy, and that this decrease is mediated through an aldose reductase inhibitor-sensitive pathway.
Nakamura
J
J
Third Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Koh
N
N
Sakakibara
F
F
Hamada
Y
Y
Wakao
T
T
Hara
T
T
Mori
K
K
Nakashima
E
E
Naruse
K
K
Hotta
N
N
D019794:2,3-Diphosphoglycerate; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003929:Diabetic Neuropathies / Q000097:blood / Q000378:metabolism*; D004163:Diphosphoglyceric Acids / Q000097:blood / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D008297:Male; D009046:Motor Neurons / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000097:blood
D004163:Diphosphoglyceric Acids; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D019794:2,3-Diphosphoglycerate; D013012:Sorbitol; C077139:fidarestat; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase