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

被引:25
作者
Cruz, JWMC
Oliveira, MA
Hohman, TC
Fortes, ZB
机构
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo, Brazil
[2] Wyeth Ayerst Res, Princeton, NJ 08543 USA
基金
巴西圣保罗研究基金会;
关键词
tolrestat; leukocyte-endothelial interaction; diabetes mellitus; polyol pathway;
D O I
10.1016/S0014-2999(00)00057-1
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
One of the most devastating secondary complications of diabetes is the blunted inflammatory response that becomes evident even in the very early stages of poorly controlled diabetes mellitus. While the etiology of this diminished response is not clearly understood, it has been linked to a decrease in the respiratory burst of neutrophils, as well as a decrease in microvessel response to inflammatory mediators and defective leukocyte-endothelial interactions. Using video microscopy to visualize vessels of the internal spermatic fascia, we have characterized leukocyte-endothelial interactions in alloxan induced diabetic and in galactosemic rats by quantitating the number of leukocytes rolling along the venular endothelium and the number of leukocytes sticking to the vascular wall after topical application of zymosan-activated plasma or leukotriene B-4 (1 ng/ml), as well as after the application 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 rate, both treatments significantly (P < 0.001) reduced the number of leukocytes rolling along the venular endothelium by about 70% and the number of adhered leukocytes in postcapillary venules by 60%. These effects were not observed in diabetic and galactosemic animals treated with an aldose reductase inhibitor. Thr results suggest that impaired leukocyte-endothelial cell interactions are a consequence of an enhanced flux through the polyol pathway. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:163 / 174
页数:12
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