Preservation of Erectile Function by Statins in a Rat Model of Erectile Dysfunction Induced by Hypercholesterolemia

Main Article Content

Bong Hee Park
Dong Seok Han
Seung Mo Yuk
Chang Shik Youn
Eun Bi Kwon
Ki Cheol Park
Hoon Jang


erectile dysfunction, hypercholesterolemia, statin


Background and objective
To assess the effects of hypercholesterolemia (HC) on the quality of erections and to evaluate the effects of stain therapy in a rat model of erectile dysfunction (ED) induced by HC.

Material and methods
Sprague–Dawley rats were randomly divided into three groups (n=12 in each): control, HC, and HC with simvastatin treatment (HC+SS). The control was fed a normal chow diet, and the HC and HC+SS were fed a high-fat and high-cholesterol diet for 12 weeks. The HC+SS received simvastatin once daily via oral gavage for 12 weeks. Subsequently, the intraperitoneal glucose tolerance test (IPGTT), intra-cavernous pressure and mean arterial pressure, lipid profiles, expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), oxidative stress (8-hydroxy-2-deoxygua-nosine, 8-OHdG level), serum testosterone levels, and the ratio of collagen fibers (CF) and smooth muscle (SM) were evaluated in the serum and corpora tissue.

IPGTT was not different among all groups. The HC showed markedly lower erectile parameters than the control. In contrast, the HC+SS showed preserved erectile function, improved lipid profiles, increased eNOS and nNOS, decreased oxidative stress, and minimized change in SM/CF ratio.

Our results suggest that oxidative stress damage by HC may cause ED and that statin therapy may have beneficial effects on preserving erectile function by improving lipid profiles and minimizing dam-age caused by oxidative stress.


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1. Vrentzos GE, Paraskevas KI, Mikhailidis DP. Dyslipidemia as a risk factor for erectile dysfunction. Curr Med Chem 2007;14(16): 1765–70. 1058931
2. Kim SC, Kim IK, Seo KK, Baek KJ, Lee MY. Involvement of superoxide radical in the impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemic rabbits. Urol Res 1997;25(5):341–6. BF01294663
3. Musicki B, Liu T, Strong T, et al. Low-fat diet and exercise preserve eNOS regulation and endo-thelial function in the penis of early atheroscle-rotic  pigs: a molecular analysis. J Sex Med 2008;5(3):552–61.
4. Shukla N, Jones R, Persad R, Angelini GD, Jeremy JY. Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits. Eur J Pharmacol 2005;517(3):224–31. ejphar.2005.05.012
5. Kostis JB, Dobrzynski JM. The effect of statins on erectile dysfunction: a meta-analysis of randomized trials. J Sex Med 2014;11(7):1626–35.
6. Cai X, Tian Y, Wu T, Cao CX, Bu SY, Wang KJ. The role of statins in erectile dysfunction: a sys-tematic review and meta-analysis. Asian J Androl 2014;16(3):461–6.
7. Cui Y, Zong H, Yan H, Zhang Y. The effect of statins on erectile dysfunction: a systematic review and meta-analysis. J Sex Med 2014;11(6):1367–75.
8. Saltzman EA, Guay AT, Jacobson J. Improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: a clinical observation. J Urol 2004;172(1): 255–8. 10458.66
9. Trivedi D, Kirby M, Wellsted DM, et al. Can sim-vastatin improve erectile function and health-related quality of life in men aged >/=40 years with erectile dysfunction? Results of the Erectile Dysfunction and Statins Trial [ISRCTN66772971]. BJU Int 2013;111(2):324–33. 10.1111/j.1464-410X.2012.11241.x
10. Rizvi K, Hampson JP, Harvey JN. Do lipid-low-ering drugs cause erectile dysfunction? A system-atic review. Fam Pract 2002;19(1):95–8. https://
11. Carvajal A, Macias D, Sainz M, et al. HMG CoA reductase inhibitors and impotence: two case series from the Spanish and French drug monitoring sys-tems. Drug Safety 2006;29(2):143–9. https://doi. org/10.2165/00002018-200629020-00004
12. Do C, Huyghe E, Lapeyre-Mestre M, Montastruc JL, Bagheri H. Statins and erectile dysfunction: results of a case/non-case study using the French Pharmacovigilance System Database. Drug Safety 2009;32(7):591–7.
13. Jang H, Bae WJ, Kim SJ, et al. The herbal for-mula KH-204 is protective against erectile dys-function by minimizing oxidative stress and improving lipid profiles in a rat model of erectile dysfunction induced by hypercholesterolaemia. BMC Complement Altern Med 2017;17(1):129.
14. Sullivan ME, Keoghane SR, Miller MA. Vascular risk factors and erectile dysfunction. BJU Int 2001;87(9):838–45.
15. Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med 2007;120(2):151–7. amjmed.2006.06.010
16. Miner M, Billups KL. Erectile dysfunction and dyslipidemia: relevance and role of phosphodies-terase type-5 inhibitors and statins. J Sex Med 2008;5(5):1066–78. j.1743-6109.2008.00783.x
17. Kim JH, Klyachkin ML, Svendsen E, Davies MG, Hagen PO, Carson CC, 3rd, . Experimental hyper-cholesterolemia in rabbits induces cavernosal ath-erosclerosis with endothelial and smooth muscle cell dysfunction. J Urol 1994;151(1):198–205.
18. Behr-Roussel D, Bernabe J, Compagnie S, et al. Distinct mechanisms implicated in atherosclero-sis-induced erectile dysfunction in rabbits. Atherosclerosis 2002;162(2):355–62. https://doi. org/10.1016/S0021-9150(01)00740-7
19. Kim SC, Seo KK, Kim HW, Lee MY. The effects of isolated lipoproteins and triglyceride, combined oxidized low density lipoprotein (LDL) plus tri-glyceride, and combined oxidized LDL plus high density lipoprotein on the contractile and relax-ation response of rabbit cavernous smooth muscle. Int J Androl 2000;23 Suppl 2:26–9. https://doi. org/10.1046/j.1365-2605.2000.00007.x
20. Musicki B, Liu T, Lagoda GA, et al. Hypercholesterolemia-induced erectile dysfunc-tion: endothelial nitric oxide synthase (eNOS) uncoupling in the mouse penis by NAD(P)H oxi-dase. J Sex Med 2010;7(9):3023–32. https://doi. org/10.1111/j.1743-6109.2010.01880.x
21. Lubos E, Handy DE, Loscalzo J. Role of oxida-tive stress and nitric oxide in atherothrombosis. Front Biosci 2008;13:5323–44. 10.2741/3084
22. Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004;122(4):339–52. https://
23. Park EJ, Chun JN, Kim SH, et al. Schisandrin B suppresses TGFbeta1 signaling by inhibiting Smad2/3 and MAPK pathways. Biochem Pharmacol 2012;83(3):378–84. 10.1016/j.bcp.2011.11.002
24. Chen P, Pang S, Yang N, et al. Beneficial effects of schisandrin B on the cardiac function in mice model of myocardial infarction. PLoS One 2013;8(11):e79418. pone.0079418
25. Chun JN, Kim SY, Park EJ, et al. Schisandrin B suppresses TGFbeta1-induced stress fiber forma-tion by inhibiting myosin light chain phosphory-lation. J Ethnopharmacol 2014;152(2):364–71.
26. Chen N, Ko M. Schisandrin B-induced glutathi-one antioxidant response and cardioprotection are mediated by reactive oxidant species production in rat hearts. Biol Pharm Bull 2010;33(5):825–9.
27. Chiu PY, Ko KM. Schisandrin B-induced increase in cellular glutathione level and protection against oxidant injury are mediated by the enhancement of glutathione synthesis and regeneration in AML12 and H9c2 cells. BioFactors 2006;26(4):221–30.
28. Thandavarayan RA, Giridharan VV, Arumugam S, et al. Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage, oxidative stress and inflammation through inhibition of MAPK/p53 signaling. PLoS One 2015;10(3):e0119214. journal.pone.0119214
29. Ignarro LJ, Napoli C, Loscalzo J. Nitric oxide donors and cardiovascular agents modulating the  bioactivity of nitric oxide: an overview. Circ Res 2002;90(1):21–8. hh0102.102330
30. Gotto AM. Statin therapy: where are we? Where do we go next? Am J Cardiol 2001;87(5a):13b–8b.
31. Guijarro C, Blanco-Colio LM, Ortego M, et al. 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 1998;83(5):490–500. RES.83.5.490
32. Liu L, Moesner P, Kovach NL, et al. Integrin-dependent leukocyte adhesion involves geranylger-anylated protein(s). J Biol Chem 1999;274(47): 33334–40.
33. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investiga-tors. N Engl J Med 1996;335(14):1001–9. https://
34. Essig M, Nguyen G, Prie D, Escoubet B, Sraer JD, Friedlander G. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrino-lytic activity in rat aortic endothelial cells. Role of  geranylgeranylation and Rho proteins. Circ Res 1998;83(7):683–90. RES.83.7.683
35. Laufs U, Gertz K, Huang P, et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholes-terolemic mice. Stroke 2000;31(10):2442–9.
36. Wassmann S, Laufs U, Baumer AT, et al. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hyperten-sion via reduced production of reactive oxygen species. Hypertension 2001;37(6):1450–7. https://
37. Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 2003;23(5):729–36. https://doi. org/10.1161/01.ATV.0000063385.12476.A7
38. McFarlane SI, Muniyappa R, Francisco R, Sowers JR. Clinical review 145: pleiotropic effects of statins: lipid reduction and beyond. J Clin Endocrinol Metab 2002;87(4):1451–8. https://doi. org/10.1210/jcem.87.4.8412
39. Corona G, Boddi V, Balercia G, et al. The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction. J Sex Med 2010;7(4 Pt 1):1547–56. j.1743-6109.2009.01698.x
40. Hyyppa MT, Kronholm E, Virtanen A, Leino A,  Jula A. Does simvastatin affect mood and steroid  hormone levels in hypercholesterol-emic  men?  A randomized double-blind trial. Psychoneuroendocrinology 2003;28(2):181–94.
41. Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med 2013;11: 57.
42. Sniderman AD, Thanassoulis G. Do statins lower  testosterone and does it matter? BMC Med 2013;11:58.
43. Martinez-Martos JM, Arrazola M, Mayas MD,  Carrera-Gonzalez MP, Garcia MJ, Ramirez-Exposito MJ. Diet-induced hypercholes-terolemia impaired testicular steroidogenesis in mice through the renin-angiotensin system. Gen Comp Endocrinol 2011;173(1):15–19. https://doi. org/10.1016/j.ygcen.2011.04.015
44. Tanaka M, Nakaya S, Kumai T, Watanabe M, Matsumoto N, Kobayashi S. Impaired testicular function in rats with diet-induced hypercholester-olemia and/or streptozotocin-induced diabetes mellitus. Endocr Res 2001;27(1–2):109–17. https://
45. Feng Y, Zhu Y, Chen X, Sha J, Fan L, Chen Q. Effects of diet-induced hypercholester-olemia on testosterone-regulated protein expres-sion in mice liver. J Nanosci Nanotechnol 2005;5(8):1273–6. 2005.204