Research Article| Volume 212, ISSUE 1, P55-62, September 2010

Heart rate reduction with ivabradine improves erectile dysfunction in parallel to decrease in atherosclerotic plaque load in ApoE-knockout mice



      To determine the effect of heart rate reduction with ivabradine on atherosclerotic lesions and erectile dysfunction.


      Two different treatment regimes with ivabradine were applied in wild-type (C57/B6) and ApoE−/−-mice to study effects of ivabradine on erectile function and atherosclerosis in animals with and without present endothelial dysfunction. Preventive effects of ivabradine were evaluated in animals fed a high-cholesterol diet in parallel to treatment with ivabradine (orally via chow, 10 mg/kg per day). The other treatment regime started treatment with a high-cholesterol diet for 4 weeks to induce endothelial dysfunction. Thereafter, treatment with ivabradine (orally via chow, 15 mg/kg per day) was started in ApoE−/− mice for 3 months. Vital parameters were measured using the tail-cuff method. Erectile function was assessed by pharmacological stimulation of corpora cavernosa in organ bath chambers. Atherosclerotic plaque formation, oxidative stress, eNOS and collagen content were determined.


      Treatment with ivabradine significantly reduced heart rate (p < 0.01), with no effect on blood pressure. Aortic atherosclerotic lesion size decreased with ivabradine in both treatment regimes (p < 0.05). Endothelium-dependent relaxation of corpora cavernosa significantly decreased in ApoE−/−-mice with a restoration by ivabradine in prevention and reversal. Dihydroethidium-stained penile sections (p < 0.05) and lipid peroxidase assay (p < 0.05) revealed a reduction in superoxide production in ivabradine-treated animals. Penile eNOS-expression increased and collagen content significantly decreased (p < 0.01) in ivabradine-treated animals.


      Ivabradine improves penile endothelial function by reduction of oxidative stress and penile fibrosis. Beneficial effects were achieved in prevention and manifest endothelial dysfunction.


      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


        • Bohm M.
        • Baumhakel M.
        • Probstfield J.L.
        • et al.
        Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomised AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND).
        American Heart Journal. 2007; 154: 94-101
        • Feldman H.A.
        • Goldstein I.
        • Hatzichristou D.G.
        • Krane R.J.
        • McKinlay J.B.
        Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.
        The Journal of Urology. 1994; 151: 54-61
        • Solomon H.
        • Man J.W.
        • Jackson G.
        Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator.
        Heart. 2003; 89: 251-253
        • Baumhakel M.
        • Bohm M.
        Erectile dysfunction correlates with left ventricular function and precedes cardiovascular events in cardiovascular high-risk patients.
        International Journal of Clinical Practice. 2007; 61: 361-366
        • Kirby M.
        • Jackson G.
        • Betteridge J.
        • Friedli K.
        Is erectile dysfunction a marker for cardiovascular disease?.
        International Journal of Clinical Practice. 2001; 55: 614-618
        • Thompson I.M.
        • Tangen C.M.
        • Goodman P.J.
        • et al.
        Erectile dysfunction and subsequent cardiovascular disease.
        JAMA. 2005; 294: 2996-3002
        • Kannel W.B.
        • Kannel C.
        • Paffenbarger Jr., R.S.
        • Cupples L.A.
        Heart rate and cardiovascular mortality: the Framingham Study.
        American Heart Journal. 1987; 113: 1489-1494
        • Diaz A.
        • Bourassa M.G.
        • Guertin M.C.
        • Tardif J.C.
        Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease.
        European Heart Journal. 2005; 26: 967-974
        • Fox K.
        • Ford I.
        • Steg P.G.
        • Tendera M.
        • Ferrari R.
        Ivabradine for patients with stable coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2008; 372: 807-816
        • Skantze H.B.
        • Kaplan J.
        • Pettersson K.
        • et al.
        Psychosocial stress causes endothelial injury in cynomolgus monkeys via beta 1-adrenoceptor activation.
        Atherosclerosis. 1998; 136: 153-161
        • DiFrancesco D.
        Cardiac pacemaker I(f) current and its inhibition by heart rate-reducing agents.
        Current Medical Research and Opinion. 2005; 21: 1115-1122
        • Colin P.
        • Ghaleh B.
        • Monnet X.
        • et al.
        Contributions of heart rate and contractility to myocardial oxygen balance during exercise.
        American Journal of Physiology. 2003; 284: H676-H682
        • Custodis F.
        • Baumhakel M.
        • Schlimmer N.
        • et al.
        Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice.
        Circulation. 2008; 117: 2377-2387
        • Xie D
        • Odronic S.I.
        • Wu F.
        • et al.
        A mouse model of hypercholesterolemia-induced erectile dysfunction.
        The Journal of Sexual Medicine. 2007; 4: 898-907
        • Behr-Roussel D.
        • Darblade B.
        • Oudot A.
        • et al.
        Erectile dysfunction in hypercholesterolemic atherosclerotic apolipoprotein E knockout mice.
        The Journal of Sexual Medicine. 2006; 3: 596-603
        • Baumhaekel M.
        • Schlimmer N.
        • Buyukafsar K.
        • Arikan O.
        • Boehm M.
        Nebivolol, but not Metoprolol improves endothelial function of the corpus cavernosum in ApoE-knockout-mice.
        The Journal of Pharmacology and Experimental Therapeutics. 2008;
        • Buyukafsar K.
        • Un I.
        Effects of the Rho-kinase inhibitors, Y-27632 and fasudil, on the corpus cavernosum from diabetic mice.
        European Journal of Pharmacology. 2003; 472: 235-238
        • Baumhakel M.
        • Custodis F.
        • Schlimmer N.
        • Laufs U.
        • Bohm M.
        Improvement of endothelial function of the corpus cavernosum in apolipoprotein E knockout mice treated with irbesartan.
        The Journal of Pharmacology and Experimental Therapeutics. 2008; 327: 692-698
        • Laufs U.
        • Wassmann S.
        • Czech T.
        • et al.
        Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis.
        Arteriosclerosis, Thrombosis and Vascular Biology. 2005; 25: 809-814
        • Yavuzgil O
        • Altay B.
        • Zoghi M.
        • et al.
        Endothelial function in patients with vasculogenic erectile dysfunction.
        International Journal of Cardiology. 2005; 103: 19-26
        • Feldman H.A.
        • Johannes C.B.
        • Derby C.A.
        • et al.
        Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study.
        Preventive Medicine. 2000; 30: 328-338
        • Harrison D.G.
        Cellular and molecular mechanisms of endothelial cell dysfunction.
        The Journal of Clinical Investigation. 1997; 100: 2153-2157
        • Beere P.A.
        • Glagov S.
        • Zarins C.K.
        Retarding effect of lowered heart rate on coronary atherosclerosis.
        Science. 1984; 226 (New York, N.Y): 180-182
        • Reil J.C.
        • Bohm M.
        The role of heart rate in the development of cardiovascular disease.
        Clinical Research in Cardiology. 2007; 96: 585-592
        • Drouin A.
        • Gendron M.E.
        • Thorin E.
        • et al.
        Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice.
        British Journal of Pharmacology. 2008; 154: 749-757
        • Reil J.C.
        • Bohm M.
        BEAUTIFUL results–the slower, the better?.
        Lancet. 2008; 372: 779-780
        • Baumhakel M.
        • Schlimmer N.
        • Bohm M.
        Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome.
        International Journal of Impotence Research. 2008; 20: 493-500
        • Bassiouny H.S.
        • Zarins C.K.
        • Kadowaki M.H.
        • Glagov S.
        Hemodynamic stress and experimental aortoiliac atherosclerosis.
        Journal of Vascular Surgery. 1994; 19: 426-434
        • Burnett A.L.
        • Musicki B.
        • Jin L.
        • Bivalacqua T.J.
        Nitric oxide/redox-based signalling as a therapeutic target for penile disorders.
        Expert Opinion on Therapeutic Targets. 2006; 10: 445-457