Influence of tolrestat on the defective leukocyte-endothelial interaction in experimental diabetes

One of the most devastating secondary complications of diabetes is the blun ted inflammatory response that becomes evident even in the very early stage s of poorly controlled diabetes mellitus. While the etiology of this dimini shed response is not clearly understood, it has been linked to a decrease i n the respiratory burst of neutrophils, as well as a decrease in microvesse l response to inflammatory mediators and defective leukocyte-endothelial in teractions. Using video microscopy to visualize vessels of the internal spe rmatic fascia, we have characterized leukocyte-endothelial interactions in alloxan induced diabetic and in galactosemic rats by quantitating the numbe r of leukocytes rolling along the venular endothelium and the number of leu kocytes sticking to the vascular wall after topical application of zymosan- activated plasma or leukotriene B-4 (1 ng/ml), as well as after the applica tion of a local irritant stimulus (carrageenan, 100 mu g). We observed that while 33 days of alloxan-induced diabetes or 7 days of galactosemia had no effect on total or differential leukocyte counts and on the wall shear rat e, both treatments significantly (P < 0.001) reduced the number of leukocyt es rolling along the venular endothelium by about 70% and the number of adh ered leukocytes in postcapillary venules by 60%. These effects were not obs erved in diabetic and galactosemic animals treated with an aldose reductase inhibitor. Thr results suggest that impaired leukocyte-endothelial cell in teractions are a consequence of an enhanced flux through the polyol pathway . (C) 2000 Elsevier Science B.V. All rights reserved.