Nitric oxide mediated effects of nebivolol on erectile function in rats with heart failure
1Department of Pharmacology, Hamidiye Pharmacy Faculty, University of Health Sciences, 34668 Istanbul, Turkey
2Department of Pathology, Haydarpasa Numune Training and Research Hospital, University of Health Sciences, 34668 Istanbul, Turkey
3Department of Pharmacology, School of Pharmacy, Istanbul Medipol University, 34815 Istanbul, Turkey
Submitted: 09 February 2021 Accepted: 19 March 2021
Online publish date: 14 July 2021
Background and objective: Heart failure (HF) is a common complication of cardiovascular disease, which leads to functional cardiac abnormalities. Beta-blockers are commonly used to reduce mortality in HF patients; however, they are associated with an increased risk of erectile dysfunction (ED). Nebivolol is a third-generation beta-blocker with also having a Nitric oxide (NO) releasing effect. NO plays a key role in penile erection. The aim of this study was to investigate the NO-mediated effects of nebivolol on ED in HF.
Material and methods: Twenty-four weeks old rats were divided into three groups: sham-operated control (SC), HF-induced control (HFC), and nebivolol-treated (HFNEB). HF was induced by the ligation of the left anterior descending coronary artery. Eight weeks after the ligation, functional, hemodynamic, biologic, and histologic studies were conducted to assess NO-mediated effects of nebivolol.
Results: HF rats displayed impaired erectile function represented by decreased intracavernosal/mean arterial pressure ratio (ICP/MAP). Increased nitrosative damage/decreased antioxidant capacity was consistent with decreased endothelial NOS (eNOS) and increased inducible NOS (iNOS) and neuronal NOS (nNOS) immunoreactivity in this group. Nebivolol treated animals were characterized by improved functional capacity, increased antioxidant and decreased oxidant capacity. Prevention of eNOS and an increase in nNOS immunoreactivity was also signiﬁcant in this group.
Conclusion: Our study showed the positive effects of nebivolol on erectile function in HF. NO-mediated mechanisms behind this effect can be summarized as eNOS mediated dilation of the cavernous body and nNOS mediated smooth muscle relaxation. To the best of our knowledge, this study is the ﬁrst in the literature to discuss all three NOS isoforms in order to explain the NO-mediated effects of nebivolol in ED.
Erectile dysfunction; Nitric oxide; Heart failure; Nitric oxide synthase; Nebivolol
Guldem Mercanoglu,Gulistan Gumrukcu,Caglar Macit. Nitric oxide mediated effects of nebivolol on erectile function in rats with heart failure. Journal of Men's Health. 2021.doi:10.31083/jomh.2021.071.
 Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007; 93: 1137–1146.
 Irwin GM. Erectile dysfunction. Primary Care: Clinics in Office Practice. 2019; 46: 249–255.
 Ponikowski P, Voors AA, Anker SD. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology developed with the special contribution of the heart failure association of the ESC. European Heart Journal. 2016; 37:2129–2200.
 Manolis A, Doumas M, Ferri C, Mancia G. Erectile dysfunction and adherence to antihypertensive therapy: focus on β-blockers. European Journal of Internal Medicine. 2020; 81: 1–6.
 Fogari R, Preti P, Zoppi A, Corradi L, Pasotti C, Rinaldi A, et al. Effect of valsartan and atenolol on sexual behavior in hypertensive postmenopausal women. American Journal of Hypertension. 2004; 17: 77–81.
 Fongemie J, Felix GE. A review of nebviolol pharmacology and clinical evidence. Drugs. 2015; 75: 1349–1371.
 Matsui H, Sopko NA, Hannan JL, Bivalacqua TJ. Pathophysiology of erectile dysfunction. Current Drug Targets. 2015; 16: 411–419.
 Sharp RP, Gales BJ. Nebivolol versus other beta blockers in patients with hypertension and erectile dysfunction. Therapeutic Advances in Urology. 2017; 9: 59–63.
 Mercanoglu G, Safran N, Gungor M, Pamukcu B, Uzun H, Sezgin C, et al. The effects of nebivolol on cardiomyocyte apoptosis after myocardial infarction in rats. Circulation Journal. 2008; 72: 660–670.
 Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American society of echocardiography and the European association of cardiovascular imaging. Journal of the American Society of Echocardiography. 2015; 28: 1–39.e14.
 Azadzoi KM, Master TA, Siroky MB. Effect of chronic ischemia on constitutive and inducible nitric oxide synthase expression in erectile tissue. Journal of Andrology. 2004; 25: 382–388.
 Mercanoglu G, Semen O. Nitric oxide mediated the effects of nebivolol in cardiorenal syndrome. Iranian Journal of Basic Medical Sciences. 2019; 22: 1314–1324.
 Macit C, Ustundag UV, Dagdeviren OC, Mercanoglu G, Sener G. The effects of calorie restriction and exercise on age-related alterations in corpus cavernosum. Front Physiol. 2020; 11: 45.
 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. Journal of Biological Chemistry. 1951; 193: 265–275.
 Rodrigues FL, Lopes RAM, Fais RS, de Oliveira L, Prado CM, Tostes RC, et al. Erectile dysfunction in heart failure rats is associated with increased neurogenic contractions in cavernous tissue and internal pudendal artery. Life Sciences. 2016; 145: 9–18.
 Fraccarollo D, Galuppo P, Bauersachs J. Novel therapeutic approaches to post-infarction remodelling. Cardiovascular Research. 2012; 94: 293–303.
 Riehle C, Bauersachs J. Small animal models of heart failure. Cardio-vascular Research. 2019; 115: 1838–1849.
 Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, et al. Myocardial infarct size and ventricular function in rats. Circulation Research. 1979; 44: 503–512.
 Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997; 96: 526–534.
 von Haehling S, Lainscak M, Springer J, Anker SD. Cardiac cachexia: a systematic overview. Pharmacology & Therapeutics. 2009; 121: 227–252.
 Molcan L, Vesela A, Zeman M. Radiotelemetry measurement of heart rate, blood pressure and locomotory activity of rats in physiological experiment. Slovak Journal of Animal Science 2009; 42: 63–66.
 Agarwal A, Nandipati KC, Sharma RK, Zippe CD, Raina R. Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. Journal of Andrology. 2006; 27: 335–347.
 Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. Urologic Clinics of North America. 2005; 32: 379–395.
 Silva FH, Veiga FJR, Mora AG, Heck RS, De Oliveira CC, Gambero A, et al. A novel experimental model of erectile dysfunction in rats with heart failure using volüme overlod. PLoS ONE. 2017; 12: e0187083.
 Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science. 1992; 257: 401–403.
 Hannan JL, Blaser MC, Oldfield L, Pang JJ, Adams SM, Pang SC, et al. Morphological and functional evidence for the contribution of the pudendal artery in aging-induced erectile dysfunction. Journal of Sexual Medicine. 2010; 7: 3373–3384.
 Zhao S, Liu L, Kang R, Li F, Li E, Zhang T, et al. Shengjing capsule improves erectile function through regulation of nitric oxide-induced relaxation in corpus cavernosum smooth muscle in a castrated rat model. Urology. 2016; 91: 243.e7–243.e12.
 Ferrini MG, Kovanecz I, Sanchez S, Vernet D, Davila HH, Rajfer J, et al. Long-term continuous treatment with sildenafil ameliorates aging-related erectile dysfunction and the underlying corporal fibrosis in the rat. Biology of Reproduction. 2007; 76: 915–923.
 Gonzalez-Cadavid NF, Rajfer J. Molecular pathophysiology and gene therapy of aging-related erectile dysfunction. Experimental Gerontol-ogy. 2004; 39: 1705–1712.
 Shabsigh R, Perelman MA, Lockhart DC, Lue TF, Broderick GA. Health issues of men: prevalence and correlates of erectile dysfunction. Journal of Urology. 2005; 174: 662–667.
 Giagulli VA, Moghetti P, Kaufman JM, Guastamacchia E, Iacoviello M, Triggiani V. Managing erectile dysfunction in heart failure. Endocrine, Metabolic & Immune Disorders Drug Targets. 2013; 13: 125–134.
 Cordero A, Bertomeu-Martínez V, Mazón P, Fácila L, Bertomeu-González V, Conthe P, et al. Erectile dysfunction in high-risk hy-pertensive patients treated with beta-blockade agents. Cardiovascular Therapeutics. 2010; 28: 15–22.
 Baumhäkel M, Schlimmer N, Büyükafşar K, Arikan O, Böhm M. Nebivolol, but not metoprolol, improves endothelial function of the corpus cavernosum in apolipoprotein e-knockout mice. Journal of Pharmacology and Experimental Therapeutics. 2008; 325: 818–823.
Science Citation Index Expanded Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.
Social Sciences Citation Index Social Sciences Citation Index contains over 3,400 journals across 58 social sciences disciplines, as well as selected items from 3,500 of the world’s leading scientific and technical journals. More than 9.37 million records and 122 million cited references date back from 1900 to present.
Current Contents - Social & Behavioral Sciences Current Contents - Social & Behavioral Sciences provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in the social and behavioral sciences.
Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.
SCOPUS Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.
DOAJ DOAJ is a community-curated online directory that indexes and provides access to high quality, open access, peer-reviewed journals.
CrossRef Crossref makes research outputs easy to find, cite, link, assess, and reuse. Crossref committed to open scholarly infrastructure and collaboration, this is now announcing a very deliberate path.
Portico Portico is a community-supported preservation archive that safeguards access to e-journals, e-books, and digital collections. Our unique, trusted process ensures that the content we preserve will remain accessible and usable for researchers, scholars, and students in the future.