Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats

International Journal of Impotence Research volume 24, pages 114–121 (2012)Cite this article

Abstract

Recently, the relationship between advanced glycation end products (AGEs) and erectile dysfunction (ED) has been reported. The present study aimed to investigate whether a combination of an AGE cross-link breaker (alagebrium/ALT-711) and sildenafil could enhance the erectile capacity in streptozotocin (STZ) diabetic rats. Additionally, we assessed the effect of that treatment option on some molecules that have been suggested to have crucial roles in AGE-related ED pathways. Four groups of animals were utilized: (1) age-matched control rats, (2) STZ-induced diabetic rats (40 mg kg−1 i.p.), (3) STZ rats+sildenafil (5 mg kg−1 p.o.), (4) STZ rats treated with a combination of sildenafil (5 mg kg−1 p.o)+alagebrium/ALT-711 (10 mg kg−1 p.o.) for the final 1 month of the 2 months of diabetes period. At 2 months after i.p. injection of STZ, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue AGEs, MDA (malondialdehyde), cyclic guanosine monophosphate (cGMP) (ELISA), endothelial nitric oxide (NO) synthase (eNOS), inducible NO synthase (iNOS) (western blot), nuclear factor (NF)-κB, mitogen-activated protein (MAP) kinase (immunohistochemistry) and apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) analyses were performed in all groups of rats. STZ diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve) after CNS when compared with control rats (P<0.05). The increase in both ICP and area under the erectile curve of STZ diabetic rats treated with a combination of sildenafil+alagebrium/ALT-711 as well as in STZ diabetic rats treated with sildenafil alone was significantly greater than STZ diabetic rats. Additionally, combination treatment decreased AGE, MDA, iNOS, NF-κB, MAP kinase and apoptosis levels, whereas it preserved cGMP contents in diabetic penile tissue. Decreased AGE, MDA, iNOS, NF-κB, MAP kinase and increased cGMP levels at the combination (sildenafil+alagebrium/ALT-711) therapy group increased both the peak ICP and total ICP to CNS in the STZ diabetic rats, which was similar to the response observed in control rats. These results may explain the role of AGEs in diabetes-related ED and the effect of an AGE cross-link breaker alagebrium/ALT-711+sildenafil therapy on some critical molecules related to AGE-related ED pathways.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJG . Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl 2003; 24 (Suppl): S17–S37.

    Article  CAS  Google Scholar 

  2. Moore CR, Wang R . Pathophysiology and treatment of diabetic erectile dysfunction. Asian J Androl 2006; 8: 675–684.

    Article  Google Scholar 

  3. Bivalacqua TJ, Usta MF, Kendirci M, Pradhan L, Alvarez X, Champion HC et al. Superoxide anion production in the rat penis impairs erectile function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy. J Sex Med 2009; 2: 187–198.

    Article  Google Scholar 

  4. Usta MF, Bivalacqua TJ, Yang DY, Ramanitharan A, Sell DR, Visvanathan A et al. protective effect of aminoguanidine on erectile function in streptozotocin diabetic rats. J Urol 2003; 170: 1437–1442.

    Article  CAS  Google Scholar 

  5. Usta MF, Bivalacqua TJ, Koksal IT, Toptas B, Surmen S, Hellstrom WJG . The protective effect of aminoguanidine on erectile function in diabetic rats is not related to the timing of treatment. BJU Int 2004; 94: 429–432.

    Article  CAS  Google Scholar 

  6. Usta MF, Kendirci M, Gür S, Foxwell NA, Bivalacqua TJ, Cellek S et al. The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: preventive versus curative treatment. J Sex Med 2006; 3: 242–252.

    Article  CAS  Google Scholar 

  7. Rendell MS, Rajfer J, Wicker PA, Smith MD . Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA 1999; 281: 421–426.

    Article  CAS  Google Scholar 

  8. De Young L, Yu D, Freeman D, Brock GB . Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model. Int J Imp Res 2003; 15: 347–354.

    Article  CAS  Google Scholar 

  9. Kasai K, Nakamura T, Kase N, Hiraoka T, Suziki R, Koqure F et al. Increased glycosylation of proteins from cataractous lenses in diabetes. Diabetologia 1983; 25: 36–38.

    Article  CAS  Google Scholar 

  10. Wasowicz W, Neve J, Peretz A . Optimized steps in fluorometric determination of thiobarbituric acid reactive substances in serum: importance of extraction pH and influence of sample preservation and storage. ClinChem 1993; 39: 2522–2526.

    CAS  Google Scholar 

  11. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ . Protein measurement with the Folin phenol reagent. J BiolChem 1951; 193: 265–275.

    CAS  Google Scholar 

  12. Bivalacqua TJ, Usta MF, Champion HC, Leungwattanakij S, Dabisch PA, McNamara DB et al. Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Imp Res 2004; 16: 21–29.

    Article  CAS  Google Scholar 

  13. Akingba AG, Burnett AL . Endothelial nitric oxide synthase protein expression, localization, and activity in the penis of the alloxan-induced diabetic rat. Mol Urol 2001; 5: 189–197.

    Article  CAS  Google Scholar 

  14. Usta MF, Tuncer M, Baykal A, Ciftcioglu MA, Erdogru T, Koksal IT et al. Impact of chronic renal failure and peritoneal dialysis fluids on advanced glycation end product and iNOS levels in penile tissue: an experimental study. Urology 2002; 59: 953–957.

    Article  CAS  Google Scholar 

  15. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA . Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Eng J Med 1998; 338: 1397–1404.

    Article  CAS  Google Scholar 

  16. Ahn GJ, Yu JY, Choi SM, Kang KK, Ahn BO, Kwon JW et al. Chronic administration of phosphodiesterase 5 inhibitor improves erectile and endothelial function in a rat model of diabetes. Int J Androl 2005; 28: 260–266.

    Article  CAS  Google Scholar 

  17. Park K, Ryu KS, Li WJ, Kim SW, Paick JS . Chronic treatment with a type 5 phosphodiesterase inhibitor suppresses apoptosis of corporal smooth muscle by potentiating Akt signalling in a rat model of diabetic erectile dysfunction. Eur Urol 2008; 53: 1282–1289.

    Article  CAS  Google Scholar 

  18. De Young LX, Domes T, Lim K, Carson J, Brock GB . Endothelial rehabilitation: the impact of chronic PDE5 inhibitors on erectile function and protein alterations in cavernous tissue of diabetic rats. Eur Urol 2008; 54: 213–220.

    Article  CAS  Google Scholar 

  19. Seftel AD, Vaziri ND, Ni Z, Razmjouei K, Fogarty J, Hampel N et al. Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition, and possible effect through iNOS and eNOS. Urology 1997; 50: 1016–1026.

    Article  CAS  Google Scholar 

  20. Bierhaus A, Ziegler R, Nawroth PP . Molecular mechanisms of diabetic angiopathy-clues for innovative therapeutic interventions. Horm Res 1998; 50 (Suppl 1): 1–5.

    CAS  PubMed  Google Scholar 

  21. Liu J, Zhao S, Tang J, Li Z, Zhong T, Liu Y et al. Advanced glycation end products and lipopolysaccharide synergistically stimulate proinflammatory cytokine/chemokine production in endothelial cells via activation of both mitogen-activated protein kinases and nuclear factor-kappaB. FEBS J 2009; 276: 4598–4606.

    Article  CAS  Google Scholar 

  22. Nangle MR, Cotter MA, Cameron NE . Correction of nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition. Int J Imp Res 2006; 18: 258–263.

    Article  CAS  Google Scholar 

  23. Angulo J, Peiró C, Cuevas P, Gabancho S, Fernández A, González-Corrochano R et al. The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men. J Sex Med 2009; 6: 373–387.

    Article  CAS  Google Scholar 

  24. Alici B, Gumustas H, Ozkara H, Akkus E, Demirel G, Yencilek F et al. Apoptosis in the erectile tissues of diabetic and healthy rats. BJU Int 2000; 85: 326–329.

    Article  CAS  Google Scholar 

  25. Yamanaka M, Shirai M, Shiiina H, Tanaka Y, Tsujimura A, Matsumia K et al. Diabetes induced erectile dysfunction and apoptosis in penile crura are recovered by insulin treatment in rats. J Urol 2003; 170: 291–297.

    Article  CAS  Google Scholar 

  26. Gonzales-Cadavid NF, Rajfer J . The pleiotropic effects of inducible nitric oxide synthase (iNOS) on the physiology and pathology of penile erection. Curr Pharm Des 2005; 11: 4041–4046.

    Article  Google Scholar 

  27. Cellek S, Rodrigo J, Lobos E, Fernandez P, Serrano J, Moncada S . Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. Diabetes 2003; 52: 2353–2362.

    Article  CAS  Google Scholar 

  28. Cellek S, Qu W, Schmidt AM, Moncada S . Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: a new insight into selective nitrergic neuropathy in diabetes. Diabetologia 2004; 47: 331–339.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Akdeniz University Research Foundation. ALT-711 and sildenafil were kindly provided by Alteon, Parsipanny, NJ, USA and by Pfizer, New York, NY, USA, respectively. Part of the present study was awarded as a ‘Basic Science Abstract Award Recipient’ during the SMS Meeting, Las Vegas, NV, USA.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Akdeniz University, School of Medicine, Antalya, Turkey

    N Gurbuz, G Sagdic & A Baykal

  2. Department of Urology, Akdeniz University, School of Medicine, Antalya, Turkey

    A Sanli & M F Usta

  3. Department of Pathology, Akdeniz University, School of Medicine, Antalya, Turkey

    A Ciftcioglu & I Bassorgun

Authors
  1. N Gurbuz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Sagdic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Sanli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Ciftcioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Bassorgun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Baykal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M F Usta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M F Usta.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gurbuz, N., Sagdic, G., Sanli, A. et al. Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats. Int J Impot Res 24, 114–121 (2012). https://doi.org/10.1038/ijir.2011.54

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijir.2011.54

Keywords

This article is cited by

Search

Advanced search

Quick links