Nebivolol to attenuate the effects of hyper-homocysteinaemia in rats


      • Four week duration of hyperhomocysteinemia (hHcy) caused significant oxidative stress in brain, kidney, liver, heart tissues.
      • Nebivolol attenuated the oxidative stress in brain, kidney, liver and heart tissues that is caused by hHcy.
      • Four week duration of intermediate hHcy caused vascular structural changes (outward vascular remodelling) in the aorta.
      • Nebivolol prevented aorta against hHcy induced structural changes (especially vascular outward remodelling).
      • Nebivolol slightly decreased the serum levels of homocysteine, and may also be useful to prevent hyperhomocysteinemia.



      This study investigated the prophylactic effect of nebivolol against hyper-homocysteinaemia (hHcy) induced oxidative stress in brain, heart, liver and kidney tissues and histomorphometric changes in the thoracic aorta.


      Twenty-four adult male Wistar rats were divided into a control, nebivolol, hHcy and nebivolol + hHcy group. hHcy was induced by oral administration of l-methionine (1 g/kg/day) for 28 days. 10 mg/kg/day nebivolol was administered orally for 28 days. Malondialdehyde (MDA) and glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities in the tissues were determined. The total cross-sectional area (TCSA), luminal cross-sectional area (LCSA) and intima-media thickness (IMT) were measured in the thoracic aorta.


      Homocysteine (Hcy) levels were lower in the nebivolol + hHcy group than in the hHcy group. Nebivolol treatment significantly decreased high MDA levels in the brain, heart and liver tissues. The level of GSH was higher in the brain, heart and kidney tissues of the nebivolol + hHcy group (P < 0.001). The activity of CAT increased only in the kidney tissue of the nebivolol + hHcy group (P < 0.01), and the activity of SOD was significantly increased in all the tissues in this group. Increased TCSA and IMT in the nebivolol + hHcy group were significantly decreased after nebivolol administration. The LCSA was significantly higher in the hHcy group than the control group, probably due to outward vascular remodelling.


      Nebivolol treatment may be useful in different clinical scenarios where hHcy affects physiopathological pathways.


      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


        • Selhub J.
        Homocysteine metabolism.
        Annu Rev. Nutr. 1999; 19: 217-246
        • Cook J.W.
        • Taylor L.M.
        • Orloff S.L.
        • Landry G.J.
        • Moneta G.L.
        • Porter J.M.
        Homocysteine and arterial disease-experimental mechanisms.
        Vasc. Pharmacol. 2002; 5: 293-300
        • McCully K.S.
        Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.
        Am. J. Pathol. 1969; 56: 111-128
        • Bostom A.G.
        • Silbershatz H.
        • Rosenberg I.H.
        • Selubh J.
        • D'Agostino R.B.
        • Wolf P.A.
        • et al.
        Nonfasting plasma total homocysteine levels and all cause and cardiovascular disease mortality in elderly Framingham men and women.
        Arch. Intern Med. 1999; 159: 1077-1080
        • Refsum H.
        • Ueland P.M.
        • Nygard O.
        • Vollset S.E.
        Homocysteine and cardiovascular disease.
        Annu Rev. Med. 1998; 49: 31-62
        • Murawska-Cialowicz E.
        • Januszewska L.
        • Zuwala-Jagiello J.
        • et al.
        Melatonin decreases homocysteine level in blood of rats.
        J. Physiol. Pharmacol. 2008; 59: 717-729
        • Zhen P.
        • Zhao Q.
        • Hou D.
        • et al.
        Genistein attenuates vascular endothelial impairment in ovariectomized hyperhomocysteinemic rats.
        J. Biomed. Biotechnol. 2012; : 730462
        • Osto E.
        • Cosentino F.
        The role of oxidative stress in endothelial dysfunction and vascular inflammation.
        Nitric Oxide-Biol Ch. 2010; 2: 705-754
        • Victor V.
        • Rocha M.
        • Sola E.
        • Banuls C.
        • Garcia-Malpartida K.
        • Hernandez-Mijares A.
        Oxidative stress, endothelial dysfunction and atherosclerosis.
        Curr. Pharm. Des. 2009; 15: 2988-3002
        • Yamada H.
        • Akahoshi N.
        • Kamata S.
        • et al.
        Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria.
        Free Radic. Biol. Med. 2012; 52: 1716-1726
        • Pravenec M.
        • Kozich V.
        • Krijt J.
        • et al.
        Folate deficiency is associated with oxidative stress, increased blood pressure, and insulin resistance in spontaneously hypertensive rats.
        Am J Hypertens. 2013; 26: 135-140
        • Kuroedov A.
        • Cosentino F.
        • Lüscher T.F.
        Pharmacological mechanisms of clinically favorable properties of a selective beta1-adrenoceptor antagonist, nebivolol.
        Cardiovasc Drug Rev. 2004; 3: 155-168
        • Troost R.
        • Schwedhelm E.
        • Rojczyk S.
        • et al.
        Nebivolol decreases systemic oxidative stress in healthy volunteers.
        Br. J. Clin. Pharmacol. 2000; 50: 377-379
        • de Groot A.A.
        • Mathy M.J.
        • van Zwieten P.A.
        • Peters S.L.
        Antioxidant activity of nebivolol in the rat aorta.
        J. Cardiovasc Pharmacol. 2004; 1: 148-153
        • de Nigris F.
        • Mancini F.P.
        • Balestrieri M.L.
        • Byrns R.
        • Fiorito C.
        • Williams-Ignarro S.
        • Palagiano A.
        • Crimi E.
        • Ignarro L.J.
        • Napoli C.
        Therapeutic dose of nebivolol, a nitric oxide-releasing beta-blocker, reduces atherosclerosis in cholesterol-fed rabbits.
        Nitric Oxide. 2008; 1: 57-63
        • Martí-Carvajal A.J.
        • Solà I.
        • Lathyris D.
        • Karakitsiou D.E.
        • Simancas-Racines D.
        Homocysteine-lowering interventions for preventing cardiovascular events.
        Cochrane Database Syst. Rev. 2013; 1 (CD006612)
        • Debreceni B.
        • Debreceni L.
        The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease.
        Cardiovasc Ther. 2014; 3: 130-138
        • Liu Y.
        • Tian T.
        • Zhang H.
        • Gao L.
        • Zhou X.
        The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: a meta-analysis of randomized controlled trials.
        Atherosclerosis. 2014; 235: 31-35
        • Brigo F.
        • Storti M.
        • Tezzon F.
        • Nardone R.
        Homocysteine-lowering interventions are ineffective in preventing myocardial infarction.
        Int. J. Cardiol. 2013; 168: 5055-5056
        • Ungvari Z.
        • Pacher P.
        • Rischak K.
        • Szollar L.
        • Koller A.
        Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyperhomocysteinemia.
        Arter. Throm Vas. 1999; 19: 1899-1904
        • Placer Z.A.
        • Cushman L.
        • Johnson B.C.
        Estimation of products of lipid peroxidation (malonyl dialdehyde) in biological fluids.
        Anal. Biochem. 1966; 16: 359-364
        • Tietze F.
        Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues.
        Anal. Biochem. 1969; 27: 502-522
        • Bergmeyer H.U.
        • Gawehn K.
        • Grassl M.
        Glucose-6-phosphate dehydrogenase.
        in: Methods of Enzymatic Analysis. vol. 2. Academic Press, New York1974: 458-459
        • Sun Y.
        • Oberley L.W.
        • Li Y.
        A simple method for clinical assay of superoxide dismutase.
        Clin. Chem. 1988; 34: 497-500
        • Lowry O.H.
        • Rosenberough N.J.
        • Farr A.L.
        • Randal R.J.
        Protein measurement with Folin phenol reagent.
        J. Biochem. 1951; 193: 265-275
        • Crossman G.A.
        A modification of Mallory's connective tissue stain with a discussion of the principles involved.
        Anat. Rec. 1937; 69: 33-38
        • Krobock E.
        • Rahbari H.
        • Mehregan A.H.
        Acid orcein and Giemsa stain. Modification of a valuable stain for dermatologic specimens.
        J. Cutan. Pathol. 1978; 5: 37-38
        • Conover W.J.
        Practical Nonparametric Statistics. Some Methods Based on Ranks, Several Independent Samples.
        second ed. John Wiley & Sons, New York1980: 229-239
        • Cao L.
        • Lou X.
        • Zou Z.
        • et al.
        Folic acid attenuates hyperhomocysteinemia-induced glomerular damage in rats.
        Microvasc. Res. 2013; 89: 146-152
        • Zhou J.
        • Møller J.
        • Ritskes-Hoitinga M.
        • Larsen M.L.
        • Austin R.C.
        • Falk E.
        Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice.
        Atherosclerosis. 2003; 168: 255-262
        • Murawska-Cialowicz E.
        • Januszewska L.
        • Zuwala-Jagiello J.
        • et al.
        Melatonin decreases homocysteine level in blood of rats.
        J. Physiol. Pharmacol. 2008; 59: 717-729
        • Zou T.
        • Yang W.
        • Hou Z.
        • Yang J.
        Homocysteine enhances cell proliferation in vascular smooth muscle cells: role of p38 MAPK and p47phox.
        Acta Biochim. Biophys. Sin. 2010; 42: 908-915
        • Yang R.X.
        • Huang S.Y.
        • Yan F.F.
        • et al.
        Danshensu protects vascular endothelia in a rat model of hyperhomocysteinemia.
        Acta Pharmacol. Sin. 2010; 31: 1395-1400
        • Ovechkin A.V.
        • Tyagi N.
        • Sen U.
        • et al.
        3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice.
        Am. J. Physiol. Lung Cell. Mol. Physiol. 2006; 291: 905-911
        • Boyacioglu M.
        • Sekkin S.
        • Kum C.
        • et al.
        The protective effects of vitamin C on the DNA damage, antioxidant defenses and aorta histopathology in chronic hyperhomocysteinemia induced rats.
        Exp. Toxicol. Pathol. 2014; 66: 407-413
        • Erer-Özbek S.
        • Zarifoğlu M.
        • Akgüllü Ç.
        • Bolca N.
        • Ocakoğlu G.
        • Karli N.
        Parkinson Hastalarında L-Dopa Tedavisinin, Plazma Homosistein Düzeyleri ve Bununla İlişkili Karotis İntima-Media Kalınlıkları Üzerine Olan Etkisi.
        Noropsikiyatri Arsivi. 2010; 47: 297-301
        • Dimitrova K.R.
        • DeGroot K.W.
        • Pacquing A.M.
        • et al.
        Estradiol prevents homocysteine-induced endothelial injury in male rats.
        Cardiovasc Res. 2002; 53: 589-596
        • Cockcroft J.R.
        • Chowienczyk P.J.
        • Brett S.E.
        • et al.
        Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism.
        J. Pharmacol. Exp. Ther. 1995; 274: 1067-1071
        • Janssen P.M.
        • Zeitz O.
        • Rahman A.
        • et al.
        Protective role of nebivolol in hydroxyl radical induced injury.
        J. Cardiovasc Pharmacol. 2001; 38: 17-23
        • Akçay A.
        • Acar G.
        • Kurutaş E.
        • et al.
        Beneficial effects of nebivolol treatment on oxidative stress parameters in patients with slow coronary flow.
        Turk Kardiyol. Dern. Ars. 2010; 38: 244-249
        • Guerrero E.I.
        • Ardanaz N.
        • Sevilla M.A.
        • Arévalo M.A.
        • Montero M.J.
        Cardiovascular effects of nebivolol in spontaneously hypertensive rats persist after treatment withdrawal.
        J. Hypertens. 2006; 24: 151-158
        • Heeneman S.
        • Sluimer J.C.
        • Daemen M.J.
        Angiotensin-converting enzyme and vascular remodeling.
        Circ. Res. 2007; 101: 441-454
        • Cao H.
        • Hu X.
        • Zhang Q.
        • et al.
        Homocysteine level and risk of abdominal aortic aneurysm: a meta-analysis.
        PLoS One. 2014; 9: e85831
        • Ceron C.S.
        • Rizzi E.
        • Guimarães D.A.
        • Martins-Oliveira A.
        • Gerlach R.F.
        • Tanus-Santos J.E.
        Nebivolol attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMPs, and decreases vascular remodeling in renovascular hypertension.
        Free Radic. Biol. Med. 2013; 65: 47-56
        • Mendes R.H.
        • Mostarda C.
        • Candido G.O.
        • et al.
        Moderate hyperhomocysteinemia provokes dysfunction of cardiovascular autonomic system and liver oxidative stress in rats.
        Auton. Neurosci-Basic. 2014; 180: 43-47
        • Yi F.
        • Li P.L.
        Mechanisms of homocysteine-induced glomerular injury and sclerosis.
        Am. J. Nephrol. 2008; 28: 254-264
        • Yang Z.Z.
        • Zou A.P.
        Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells.
        Kidney Int. 2003; 63: 1012-1020
        • Oelze M.
        • Daiber A.
        • Brandes R.P.
        • et al.
        Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats.
        Hypertension. 2006; 48: 677-684