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 10 mg/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”.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Pitt B.
        • Byington R.P.
        • Furberg C.D.
        • et al.
        Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events.
        PREVENT Invest Circ. 2000; 102: 1503-1510
      1. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97.

        • Julius S.
        • Kjeldsen S.E.
        • Weber M.
        • et al.
        Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.
        Lancet. 2004; 363: 2022-2031
        • Jorgensen B.
        • Simonsen S.
        • Endresen K.
        • et al.
        Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the Coronary AngioPlasty Amlodipine REStenosis Study (CAPARES).
        J Am Coll Cardiol. 2000; 35: 592-599
        • Nissen S.E.
        • Tuzcu E.M.
        • Libby P.
        • et al.
        Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.
        JAMA. 2004; 292: 2217-2225
        • Poole-Wilson P.A.
        • Lubsen J.
        • Kirwan B.A.
        • et al.
        Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial.
        Lancet. 2004; 364: 849-857
        • Mason R.P.
        • Marche P.
        • Hintze T.H.
        Novel vascular biology of third-generation L-type calcium channel antagonists: ancillary actions of amlodipine.
        Arterioscler Thromb Vasc Biol. 2003; 23: 2155-2163
        • Henry P.D.
        • Bentley K.I.
        Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine.
        J Clin Invest. 1981; 68: 1366-1369
        • Jinno T.
        • Iwai M.
        • Li Z.
        • et al.
        Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan.
        Hypertension. 2004; 43: 263-269
        • Kuramoto K.
        • Ichikawa S.
        • Hirai A.
        • et al.
        Azelnidipine and amlodipine: a comparison of their pharmacokinetics and effects on ambulatory blood pressure.
        Hypertens Res. 2003; 26: 201-208
        • Yagil Y.
        • Lusting A.
        • Azelnidipine
        (CS-905), a novel dihydropyridine calcium channel blocker with gradual onset and prolonged duration of action.
        Cardiovasc Drugs Rev. 1995; 13: 137-148
        • Nakano K.
        • Egashira K.
        • Tada H.
        • et al.
        A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates.
        J Hypertens. 2006; 24: 1881-1889
        • Kitamoto S.
        • Nakano K.
        • Hirouchi Y.
        • et al.
        Cholesterol-lowering independent regression and stabilization of atherosclerotic lesions by pravastatin and by antimonocyte chemoattractant protein-1 therapy in nonhuman primates.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1522-1528
        • Inoue S.
        • Egashira K.
        • Ni W.
        • et al.
        Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice.
        Circulation. 2002; 106: 2700-2706
        • Egashira K.
        Clinical importance of endothelial function in arteriosclerosis and ischemic heart disease.
        Circ J. 2002; 66: 529-533
        • Farb A.
        • Weber D.K.
        • Kolodgie F.D.
        • Burke A.P.
        • Virmani R.
        Morphological predictors of restenosis after coronary stenting in humans.
        Circulation. 2002; 105: 2974-2980
        • Welt F.G.
        • Rogers C.
        Inflammation and restenosis in the stent era.
        Arterioscler Thromb Vasc Biol. 2002; 22: 1769-1776
        • Egashira K.
        • Zhao Q.
        • Kataoka C.
        • et al.
        Importance of monocyte chemoattractant protein-1 pathway in neointimal hyperplasia after periarterial injury in mice and monkeys.
        Circ Res. 2002; 90: 1167-1172
        • Egashira K.
        Molecular mechanisms mediating inflammation in vascular disease: special reference to monocyte chemoattractant protein-1.
        Hypertension. 2003; 41: 834-841
        • Denger S.
        • Jahn L.
        • Wende P.
        • et al.
        Expression of monocyte chemoattractant protein-1 cDNA in vascular smooth muscle cells: induction of the synthetic phenotype: a possible clue to SMC differentiation in the process of atherogenesis.
        Atherosclerosis. 1999; 144: 15-23
        • van de Poll S.W.
        • Delsing D.J.
        • Jukema J.W.
        • et al.
        Raman spectroscopic investigation of atorvastatin, amlodipine, and both on atherosclerotic plaque development in APOE*3 Leiden transgenic mice.
        Atherosclerosis. 2002; 164: 65-71
        • Candido R.
        • Allen T.J.
        • Lassila M.
        • et al.
        Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis.
        Circulation. 2004; 109: 1536-1542
        • Takai S.
        • Kim S.
        • Sakonjo H.
        • Miyazaki M.
        Mechanisms of angiotensin II type 1 receptor blocker for anti-atherosclerotic effect in monkeys fed a high-cholesterol diet.
        J Hypertens. 2003; 21: 361-369
        • Ma J.
        • Kishida S.
        • Wang G.Q.
        • et al.
        Comparative effects of azelnidipine and other Ca2+-channel blockers on the induction of inducible nitric oxide synthase in vascular smooth muscle cells.
        J Cardiovasc Pharmacol. 2006; 47: 314-321
        • Shinomiya K.
        • Mizushige K.
        • Fukunaga M.
        • et al.
        Antioxidant effect of a new calcium antagonist, azelnidipine, in cultured human arterial endothelial cells.
        J Int Med Res. 2004; 32: 170-175
        • Lichtlen P.R.
        • Hugenholtz P.G.
        • Rafflenbeul W.
        • et al.
        Retardation of angiographic progression of coronary artery disease by nifedipine. Results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). INTACT Group investigators.
        Lancet. 1990; 335: 1109-1113
        • Jukema J.W.
        • Zwinderman A.H.
        • van Boven A.J.
        • et al.
        Evidence for a synergistic effect of calcium channel blockers with lipid-lowering therapy in retarding progression of coronary atherosclerosis in symptomatic patients with normal to moderately raised cholesterol levels. The REGRESS Study Group.
        Arterioscler Thromb Vasc Biol. 1996; 16: 425-430