Cilostazol inhibits high glucose-mediated endothelial-neutrophil adhesion by decreasing adhesion molecule expression via NO production.
OBJECTIVE
Endothelial-neutrophil adhesion is crucial for vascular injury, the major cause of diabetic vascular complications. On the other hand, platelet aggregation inhibitors, frequently used for diabetic patients with intermittent claudication, have been shown to decrease the incidence of atherosclerosis-mediated diseases (acute myocardial infarction and stroke). However, whether these agents act directly on the endothelial reactions to hyperglycemia remains unclear. Therefore, we examined their direct effects on endothelial-neutrophil adhesion and expression of endothelial adhesion molecules induced by high glucose.


RESULTS
After human endothelial cells were cultured in high glucose medium, neutrophils from healthy volunteers were added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring their myeloperoxidase (MPO) activities, and surface expression of endothelial adhesion molecules was determined with an enzyme immunoassay. Of the platelet aggregation inhibitors tested, only cilostazol significantly attenuated the adhesion through decreasing expression of intercellular adhesion molecule-1 (ICAM-1) and P-selectin. In addition, nitric oxide (NO) synthase inhibitors reduced the inhibitory effects of cilostazol, but a protein kinase C (PKC) activator did not.


CONCLUSIONS
Cilostazol may act directly on endothelial cells to inhibit expression of adhesion molecules and neutrophil adhesion induced by high glucose through increasing NO production.
Omi
Hitoshi
H
Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Okayama
Naotsuka
N
Shimizu
Manabu
M
Fukutomi
Tatsuya
T
Nakamura
Atsushi
A
Imaeda
Kenro
K
Okouchi
Masahiro
M
Itoh
Makoto
M
D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D000077407:Cilostazol; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019007:P-Selectin / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D019007:P-Selectin; D013777:Tetrazoles; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C065027:N(G)-iminoethylornithine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D005947:Glucose; D000077407:Cilostazol; D013755:Tetradecanoylphorbol Acetate; D019331:NG-Nitroarginine Methyl Ester