Effect of aldose reductase inhibitors on glucose-induced changes in sorbitol and myo-inositol metabolism in human neutrophils.
OBJECTIVE
To investigate the influence of glucose and the efficacy of two different aldose reductase (AR) inhibitors, epalrestat and SNK-860, on the polyol pathway and myo-inositol metabolism in human neutrophils.


METHODS
We incubated neutrophils with various concentrations of glucose and AR inhibitors. The neutrophils from healthy volunteers were incubated in the media containing 5-40 mmol/l glucose with or without an AR inhibitor. The sorbitol and myo-inositol contents, and myo-inositol uptake were measured by high performance liquid chromatography and radio isotope technique with 2-[3H]-myo-inositol.


RESULTS
After 2 h incubation, the sorbitol content increased with rising extracellular glucose concentrations, while the myo-inositol content decreased. Both AR inhibitors reduced the sorbitol content in neutrophils exposed to 40 mmol/l glucose medium. A 70% fall in the myo-inositol content in neutrophils exposed to 40mmol/glucose medium was attenuated approximately 40% by the addition of AR inhibitors. myo-Inositol uptake into neutrophils was inhibited by high glucose. AR inhibitors significantly ameliorated the decrease in myo-inositol uptake, but did not completely normalize it.


CONCLUSIONS
Our present in vitro studies showed that the glucose-induced metabolic alterations in human neutrophils were similar to those in tissues prone to diabetic complications, and that AR inhibitors effectively corrected glucose-induced imbalances of the polyol pathway and myo-inositol uptake in neutrophils. In addition, our study suggests that glucose-induced metabolic alterations may result in the neutrophil dysfunction and that an AR inhibitor may be capable ameliorating it.
Suzuki
K
K
3rd Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Kawamura
T
T
Sakakibara
F
F
Sasaki
H
H
Sano
T
T
Sakamoto
N
N
Hotta
N
N
D000328:Adult; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D048289:Imidazolidines; D007294:Inositol / Q000378:metabolism*; D016014:Linear Models; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D012016:Reference Values; D012236:Rhodanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D013012:Sorbitol / Q000378:metabolism*; D053778:Thiazolidines
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D053778:Thiazolidines; C038131:epalrestat; D007294:Inositol; D013012:Sorbitol; D012236:Rhodanine; C077139:fidarestat; D000449:Aldehyde Reductase