A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates.
BACKGROUND
Calcium antagonists have been shown to reduce atherogenesis and improve clinical outcomes in atherosclerotic vascular disease. No study has so far, however, addressed the effects of calcium antagonists on stent-associated neointimal formation. We therefore investigated whether a third-generation calcium antagonist, azelnidipine, attenuates in-stent neointimal formation in non-human primates.


METHODS
Male cynomolgus monkeys were fed a high cholesterol diet for 4 weeks, and were randomly assigned to three groups: a vehicle group and two other groups treated with azelnidipine at 3 and 10 mg/kg per day for an additional 24 weeks (n = 12 each). Multi-link stents were then implanted in the iliac artery.


RESULTS
Azelnidipine at the high dose reduced neointimal thickness (0.25 +/- 0.02 versus 0.19 +/- 0.02 mm; P < 0.05). Azelnidipine also reduced local oxidative stress and monocyte chemoattractant protein 1 (MCP-1) expression. No difference was found between the three groups in the degrees of injury score, inflammation score, plaque neovascularization, or plasma lipid levels. Azelnidipine also reduced MCP-1-induced proliferation/migration of vascular smooth muscle cells in vitro.


CONCLUSIONS
This study demonstrated for the first time that azelnidipine attenuates in-stent neointimal formation associated with the reduced expression of MCP-1 and smooth muscle proliferation/migration in the neointima. These data in non-human primates suggest potential clinical benefits of azelnidipine as a 'vasculoprotective calcium antagonist' in patients undergoing vascular interventions.
Nakano
Kaku
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Tada
Hideo
H
Kohjimoto
Yoshiro
Y
Hirouchi
Yasuhiko
Y
Kitajima
Shun-ichi
S
Endo
Yasuhisa
Y
Li
Xiao-Hang
XH
Sunagawa
Kenji
K
D000368:Aged; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004095:Dihydropyridines / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007083:Iliac Artery / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D015607:Stents; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects*
D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D004095:Dihydropyridines; D001383:Azetidinecarboxylic Acid; C061679:azelnidipine; D002118:Calcium