A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates

Kaku Nakano, Kensuke Egashira, Hideo Tada, Yoshiro Kohjimoto, Yasuhiko Hirouchi, Shun Ichi Kitajima, Yasuhisa Endo, Xiao Hang Li, Kenji Sunagawa

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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. METHOD: 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.

Original languageEnglish
Pages (from-to)1881-1889
Number of pages9
JournalJournal of Hypertension
Volume24
Issue number9
DOIs
Publication statusPublished - Sep 1 2006

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Primates
Stents
Calcium
Chemokine CCL2
Neointima
Macaca fascicularis
Iliac Artery
1,4-dihydropyridine
azelnidipine
Vascular Diseases
Vascular Smooth Muscle
Smooth Muscle Myocytes
Smooth Muscle
Blood Vessels
Atherosclerosis
Oxidative Stress
Cholesterol
Diet
Inflammation
Lipids

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates. / Nakano, Kaku; Egashira, Kensuke; Tada, Hideo; Kohjimoto, Yoshiro; Hirouchi, Yasuhiko; Kitajima, Shun Ichi; Endo, Yasuhisa; Li, Xiao Hang; Sunagawa, Kenji.

In: Journal of Hypertension, Vol. 24, No. 9, 01.09.2006, p. 1881-1889.

Research output: Contribution to journalArticle

Nakano, Kaku ; Egashira, Kensuke ; Tada, Hideo ; Kohjimoto, Yoshiro ; Hirouchi, Yasuhiko ; Kitajima, Shun Ichi ; Endo, Yasuhisa ; Li, Xiao Hang ; Sunagawa, Kenji. / A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates. In: Journal of Hypertension. 2006 ; Vol. 24, No. 9. pp. 1881-1889.
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AU - Kohjimoto, Yoshiro

AU - Hirouchi, Yasuhiko

AU - Kitajima, Shun Ichi

AU - Endo, Yasuhisa

AU - Li, Xiao Hang

AU - Sunagawa, Kenji

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N2 - 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. METHOD: 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.

AB - 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. METHOD: 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.

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