Azelnidipine has anti-atherosclerotic effects independent of its blood pressure-lowering actions in monkeys and mice.
Calcium channel blockers (CCBs) have been shown to improve clinical outcomes in atherosclerotic vascular disease. The mechanisms underlying the vasculoprotective effects of a third-generation calcium channel blocker, azelnidipine, are incompletely understood. We asked whether azelnidipine attenuates atherosclerosis in monkeys and mice beyond its blood pressure-lowering effects. Cynomolgus monkeys were randomized to three groups after 4 weeks of a high cholesterol diet: control group (no treatment) and 3 and 10mg/kg daily azelnidipine; these doses have no effect on systemic arterial pressure or heart rate. Atherosclerosis was induced in the aorta by balloon injury, and the diet and treatment were continued for an additional 24 weeks. Azelnidipine did not affect blood lipid profiles, but reduced the development of atherosclerosis as detected by the elimination of local oxidative stress and reduced expression of monocyte chemoattractant protein-1 and platelet-derived growth factor. Azelnidipine also reduced the proliferation and migration of vascular smooth muscle cells in vitro. In atherosclerotic ApoE-knockout (ApoE-KO) mice fed a high cholesterol diet, azelnidipine but not amlodipine reduced the development of atherosclerosis. Neither drug changed the lipid profiles or systolic blood pressure of the mice. Thus, azelnidipine at clinically relevant doses exhibited anti-atherosclerotic effects in monkeys and mice independent of its blood pressure-lowering effects, suggesting that azelnidipine might be as a "vasculoprotective calcium channel blocker".
Nakano
Kaku
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: egashira@cardiol.med.kyushu-u.ac.jp.
Ohtani
Kisho
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Gang
Zhao
Z
Department of Cardiovascular Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Iwata
Eiko
E
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Miyagawa
Miho
M
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Sunagawa
Kenji
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000187:drug effects; D011897:Random Allocation; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D004095:Dihydropyridines; D010982:Platelet-Derived Growth Factor; D001383:Azetidinecarboxylic Acid; C061679:azelnidipine