Minalrestat and leukocyte migration in diabetes mellitus.
BACKGROUND
We recently demonstrated that aldose reductase inhibition was effective in restoring the reduced migratory capacity of leukocytes in diabetic rats. To investigate the mechanism(s) involved in the restoring effect, we used minalrestat, an aldose reductase inhibitor.


METHODS
In sodium pentobarbital-anesthetized (40 mg/kg, intraperitoneally) alloxan-diabetic or galactosemic male Wistar rats, the internal spermatic fascia was exteriorized, and 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 microg), were determined using intravital microscopy. Data from animals that were treated with and those that were not treated with minalrestat (10 mg/kg/d by gavage) were compared.


RESULTS
The reduced number of leukocytes rolling along the venular endothelium (by about 70%) and the number of adhered and migrated leukocytes in postcapillary venules (by 60%) were significantly restored to control values after minalrestat treatment. Total or differential leukocyte counts, venular blood flow velocity or wall shear rate were not altered by minalrestat treatment. The expression of ICAM-1 and P-selectin, cell adhesion molecules involved in the interaction of leukocyte-endothelium, reduced in diabetic rats was restored by minalrestat treatment.


CONCLUSIONS
We conclude that an enhanced flux through the polyol pathway might be involved in the reduced expression of ICAM-1 and P-selectin contributing to the impaired leukocyte-endothelial interactions in diabetes mellitus and that aldose reductase inhibition restores the defect, restoring the reduced expression.
Cruz
J W C M
JW
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524 Cidade Universitária, 05508-900 São Paulo, SP-Brazil.
Soto-Suazo
M W
MW
Hohman
T C
TC
Akamine
E H
EH
Zorn
T T
TT
Fortes
Z B
ZB
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D005632:Fructose / Q000097:blood; D004376:Galactitol / Q000097:blood; D005690:Galactose / Q000097:blood; D005693:Galactosemias / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007094:Imides / Q000494:pharmacology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007958:Leukocyte Count; D036904:Leukocyte Rolling / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019007:P-Selectin / Q000097:blood; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000097:blood
D001786:Blood Glucose; D007094:Imides; D019007:P-Selectin; D015363:Quinolones; D004376:Galactitol; D018799:Intercellular Adhesion Molecule-1; D005632:Fructose; D013012:Sorbitol; D000449:Aldehyde Reductase; C473212:minalrestat; D005690:Galactose