Skip to main content

Thank you for visiting 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.

Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat


Phosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30–40% of men with ED do not respond to drug therapy. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors. Decreased expression or activity of neuronal or endothelial NO synthase (NOS), impaired NO release, or NO destruction will preclude sufficient cGMP formation to permit PDE5 inhibitor efficacy. This article discusses the possible reasons for unresponsiveness and strategies to overcome it. Therapeutic approaches proposed to increase available NO in penile tissue include facilitating NO release by using α-2 antagonists, enhancing NO synthesis by providing more substrate for the reaction, and using antioxidants to inhibit NO breakdown by reactive oxygen species.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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


  1. Kim N, Azadzoi KM, Goldstein I, Saenz de Tejada I . A nitric oxide-like factor mediates nonadrenergic, noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J Clin Invest 1991; 88: 112–118.

    Article  CAS  Google Scholar 

  2. Rajfer J et al. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 1992; 326: 90–94.

    Article  CAS  Google Scholar 

  3. Saenz de Tejada I et al. The phosphodiesterase inhibitor selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 2001; 13: 282–289.

    Article  CAS  Google Scholar 

  4. Simonsen U et al. Prejunctional alpha 2-adrenoceptors inhibit nitrergic neurotransmission in horse penile resistance arteries. J Urol 1997; 157: 2356–2360.

    Article  CAS  Google Scholar 

  5. Angulo J et al. Combination of phentolamine and L-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle. Urology 2001; 57: 585–589.

    Article  CAS  Google Scholar 

  6. Pieper GM, Dondlinger LA . Plasma and vascular tissue arginine are decreased in diabetes: acute supplementation restores endothelium-dependent relaxation by augmenting cGMP production. J Pharmacol Exp Ther 1997; 283: 684–691.

    CAS  PubMed  Google Scholar 

  7. Yildirim S et al. The effects of long-term oral administration of L-arginine on erectile response of rabbits with alloxan-induced diabetes. BJU Int 1999; 83: 679–685.

    Article  CAS  Google Scholar 

  8. Moody JA et al. Effects of long-term oral administration of L-arginine on the rat erectile response. J Urol 1997; 158: 942–947.

    Article  CAS  Google Scholar 

  9. Zorgniotti AW, Lizza EF . Effect of large doses of the nitric oxide precursor, L-arginine, on erectile dysfunction. Int J Impot Res 1994; 6: 33–35.

    CAS  Google Scholar 

  10. Angulo J et al. Activation and potentiation of the NO/cGMP pathway by NG-hydroxy-L arginine in rabbit corpus cavernosum under normoxic and hypoxic conditions and aging. Br J Pharmacol 2003; 138: 63–70.

    Article  CAS  Google Scholar 

  11. Bivalacqua TJ et al. Gene transfer of extracellular SOD to the penis reduces superoxide anion and improves erectile function in aged rats. Am J Physiol Heart Circ Physiol, [serial online] 2003, Apr [cited 2002 Dec 27] 284 (4): Available from:

  12. Keegan A, Cotter MA, Cameron NE . Effects of diabetes and treatment with the antioxidant alpha-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats. Diabetologia 1999; 42: 343–350.

    Article  CAS  Google Scholar 

  13. Nishikawa T, Edelstein D, Brownlee M . The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl 2000; 77: S26–S30.

    Article  CAS  Google Scholar 

  14. Gocmen C et al. Effects of vitamin E and sodium selenate on neurogenic and endothelial relaxation of corpus cavernosum in the diabetic mouse. Eur J Pharmacol 2000; 398: 93–98.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to I Sáenz de Tejada.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

de Tejada, I. Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat. Int J Impot Res 16 (Suppl 1), S40–S42 (2004).

Download citation

  • Published:

  • Issue Date:

  • DOI:


  • impotence
  • penis
  • nitric-oxide
  • nitric-oxide synthase
  • nitroprusside
  • adrenergic α-antagonists

This article is cited by


Quick links