The mechanisms of inhibitory actions of gliclazide on neutrophils-endothelial cells adhesion and surface expression of endothelial adhesion molecules mediated by a high glucose concentration.
BACKGROUND
We previously reported that culture of endothelial cells in the presence of high glucose concentrations (27.8 and 55.5 mM) increase neutrophils adhesion because of the increase in endothelial adhesion molecules expression via activation of a protein kinase C (PKC) pathway. The antidiabetic sulfonylurea gliclazide, but not glibenclamide, inhibited these events, but the mechanisms involved were not clarified then. We present hereafter the results of further investigations of that effect with special reference to PKC activation.


METHODS
Human umbilical vein endothelial cells (HUVEC) were cultured for 48 h in a glucose-rich medium and neutrophils from healthy volunteers were then added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring myeloperoxidase (MPO) activities and the surface expression of endothelial adhesion molecules was determined by enzyme immunoassay.


RESULTS
Culture in the presence of a high glucose concentration (27.8 mM for 48 h) increased neutrophils-endothelial cells adhesion and the surface expression of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin on the endothelial cells. These phenomena were significantly inhibited by gliclazide (20 microM). On the other hand, phorbol 12-myristate 13-acetate (PMA), a PKC activator, had an effect similar to a high glucose concentration and that effect was also inhibited by gliclazide.


CONCLUSIONS
These data suggest that gliclazide inhibits high glucose-mediated neutrophils-endothelial cells adhesion and expression of endothelial adhesion molecules through inhibition of a PKC pathway.
Itoh
Makoto
M
First Department of Internal Medicine, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Japan.
Omi
Hitoshi
H
Okouchi
Masahiro
M
Imaeda
Kenro
K
Shimizu
Manabu
M
Fukutomi
Tatsuya
T
Okayama
Naotsuka
N
D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000032:analysis*; D002478:Cells, Cultured; D019040:E-Selectin / Q000032:analysis; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005907:Gliclazide / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D019007:P-Selectin / Q000032:analysis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014471:Umbilical Veins
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D011493:Protein Kinase C; D005907:Gliclazide; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate