Inhibition of aldose reductase in five tissues of the streptozotocin-diabetic rat.

For 22 days, streptozotocin-diabetic and normal rats were intubated once daily with ICI 105552 (1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-ylacetic acid, sodium salt: 50 mg/kg body weight) an inhibitor of aldose reductase (EC 1.1.1.21), the first enzyme of the sorbitol pathway. Treatment with ICI 105552 affected neither glycaemia nor tissue glucose nor inositol concentrations yet reduced significantly the abnormal accumulations in diabetes of sorbitol in the lens (70% reduction), sciatic nerve (86%) and seminal vesicles with coagulating glands (S.V.C.G., 55%). ICI 105552 had no effect upon sorbitol accumulated in the diabetic kidney but it reduced the level in controls by 43%. The compound reduced the accumulation of sorbitol in diabetic retina by 58% although variation was too great for the decrease to be significant statistically. Treatment with ICI 105552 produced small (less than or equal to 11%) yet statistically significant increases in the weights of the kidneys, and both liver and kidney weight/100 g residual body weight but did not affect the weights of the body, lens, retina or S.V.C.G. The importance of these findings for the development of potentially chemotherapeutic aldose reductase inhibitors is discussed.