Abstract
Erectile dysfunction associated with diabetes mellitus is caused in part by disordered endothelial smooth muscle relaxation, neuropathy, and a decrease in cavernosal nitric oxide synthase (NOS) activity. The purpose of this study was to determine whether a combination of sildenafil and adenoviral gene transfer of endothelial NOS (eNOS) could enhance the erectile response in diabetic rats. Five groups of animals were utilized: (1) age-matched control rats, (2) streptozotocin (STZ)-induced diabetic rats (60 mg/kg i.p.), (3) STZ-rats + sildenafil (2 mg/kg i.v.), (4) STZ-rats transfected with AdCMVβgal or AdCMVeNOS, and (5) STZ-rats transfected with AdCMVeNOS +sildenafil (2 mg/kg i.v.). At 2 months after i.p. injection of STZ, groups 4 and 5 were transfected with the adenoviruses and 1–2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Cyclic 3′,5′-guanosine monophosphate (cGMP) levels were assessed in the cavernosal tissue. 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; AUC) after CNS when compared to control rats. STZ-diabetic rats+AdCMVeNOS had a peak ICP and AUC, which were similar to control animals. STZ-diabetic rats administered sildenafil demonstrated a significant increase in peak ICP at the 5 and 7.5 V settings, while the AUC was significantly increased at all voltage (V) settings. The increase in both ICP and AUC of STZ-diabetic rats transfected with AdCMVeNOS at all V settings was greater than STZ-diabetic rats transfected with AdCMVβgal. STZ-diabetic rats transfected with AdCMVeNOS and administered sildenafil had a significant increase in total ICP that was greater than eNOS gene therapy alone. Cavernosal cGMP levels were significantly decreased in STZ-diabetic rats, but were increased after transfection with AdCMVeNOS to values greater than control animals. In conclusion, overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the peak ICP and total ICP to CNS in the STZ-diabetic rat, which was similar to the response observed in control rats. Moreover, the total erectile response was greater in STZ-diabetic rats receiving eNOS gene therapy plus sildenafil than STZ-rats receiving sildenafil or eNOS gene therapy alone.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 8 print issues and online access
$259.00 per year
only $32.38 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hakim LS, Goldstein I . Diabetic sexual dysfunction. Endocrinol Metab Clin North Am 1996; 25: 379–400.
Bloomgarden ZT . American Diabetes Association Annual Meeting, 1997. Endothelial dysfunction, neuropathy and the diabetic foot, diabetic mastopathy, and erectile dysfunction. Diabetes Care 1998; 21: 183–189.
Burnett AL et al. Nitric oxide: a physiologic mediator of penile erection. Science 1992; 257: 401–403.
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.
Burnett AL . Role of nitric oxide in the physiology of erection. Biol Reprod 1995; 52: 485–489.
Bivalacqua TJ, Champion HC, Hellstrom WJ, Kadowitz PJ . Pharmacotherapy for erectile dysfunction. Trends Pharmacol Sci 2000; 21: 484–489.
Gonzalez-Cadavid NF, Ignarro LJ, Rajfer J . Nitric oxide and the cyclic GMP system in the penis. Mol Urol 1999; 3: 51–59.
Saenz de Tejada I et al. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320: 1025–1030.
Way KJ, Reid JJ . The effects of diabetes on nitric oxide-mediated responses in rat corpus cavernosum. Eur J Pharmacol 1999; 376: 73–82.
Taylor AA . Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus. Endocrinol Metab Clin North Am 2001; 30: 983–997.
Gur S, Ozturk B, Karahan ST . Impaired endothelium-dependent and neurogenic relaxation of corpus cavernosum from diabetic rats: improvement with L-arginine. Urol Res 2000; 28: 14–19.
Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, Champion HC . Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction. Biochem Biophys Res Commun 2001; 283: 923–927.
Vernet D et al. Reduction of penile nitric oxide synthase in diabetic BB/WORdp (type I) and BBZ/WORdp (type II) rats with erectile dysfunction. Endocrinology 1995; 136: 5709–5717.
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.
Goldstein I et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338: 1397–1404.
Jarow JP, Burnett AL, Geringer AM . Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment. J Urol 1999; 162: 722–725.
Champion HC et al. Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat. Proc Natl Acad Sci USA 1999; 96: 11648–11652.
Bivalacqua TJ et al. Adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis improves age-related erectile dysfunction in the rat. Int J Impot Res 2000; 12(Suppl 3): S8–S17.
Magee TR et al. Gene therapy of erectile dysfunction in the rat with penile neuronal nitric oxide synthase. Biol Reprod 2002; 67: 20–28.
Tirney S et al. Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid, adenovirus, and adenovirus-transduced myoblast vectors. Mol Urol 2001; 5: 37–43.
Bivalacqua TJ, Hellstrom WJ . Potential application of gene therapy for the treatment of erectile dysfunction. J Androl 2001; 22: 183–190.
El-Sakka AI et al. Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model. Int J Impot Res 1999; 11: 123–132.
Rehman J et al. Diminished neurogenic but not pharmacological erections in the 2- to 3- month experimentally diabetic F-344 rat. Am J Physiol 1997; 272: H1960–H1971.
Lund DD, Faraci FM, Miller Jr FJ, Heistad DD . Gene transfer of endothelial nitric oxide synthase improves relaxation of carotid arteries from diabetic rabbits. Circulation 2000; 101: 1027–1033.
Bivalacqua TJ et al. Gene transfer of prepro-calcitonin gene related peptide restores erectile function in the aged rat. Biol Reprod 2001; 65: 1371–1377.
Uckert S, Kuthe A, Stief CG, Jonas U . Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. World J Urol 2001; 19: 14–22.
Lin CS et al. Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters. Int J Impot Res 2002; 14: 15–24.
Boolell M et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47–52.
Ballard SA et al. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998; 159: 2164–2171.
Chuang AT, Strauss JD, Murphy RA, Steers WD . Sildenafil, a type-5 CGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro. J Urol 1998; 160: 257–261.
Carter AJ, Ballard SA, Naylor AM . Effect of the selective phosphodiesterase type 5 inhibitor sildenafil on erectile dysfunction in the anesthetized dog. J Urol 1998; 160: 242–246.
Moreland RB, Goldstein I, Kim NN, Traish A . Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor. Trends Endocrinol Metab 1999; 10: 97–104.
Gemalmaz H et al. In vivo and in vitro investigation of the effects of sildenafil on rat cavernous smooth muscle. J Urol 2001; 165: 1010–1014.
Thompson CS et al. The effect of sildenafil on corpus cavernosal smooth muscle relaxation and cyclic GMP formation in the diabetic rabbit. Eur J Pharmacol. 2001; 425: 57–64.
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.
Boulton AJ, Selam JL, Sweeney M, Ziegler D . Sildenafil citrate for the treatment of erectile dysfunction in men with Type II diabetes mellitus. Diabetologia 2001; 44: 1296–1301.
Lowentritt BH et al. Sildenafil citrate after radical retropubic prostatectomy. J Urol 1999; 162: 1614–1617.
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 2003; 284: H1408–H1421.
Zanetti M, Sato J, Katusic ZS, O'Brien T . Gene transfer of endothelial nitric oxide synthase alters endothelium-dependent relaxations in aortas from diabetic rabbits. Diabetologia 2000; 43: 340–347.
Acknowledgements
We thank Drs Donald D Heistad and Beverley Davidson and the University of Iowa Vector Core Laboratory for preparation of the virus. This work was supported in part by a Young Investigator Award from the International Society of Impotence Research and Pfizer Inc. and the American Medical Association to TJ Bivalacqua.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bivalacqua, T., Usta, M., Champion, H. et al. Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Impot Res 16, 21–29 (2004). https://doi.org/10.1038/sj.ijir.3901054
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ijir.3901054
Keywords
This article is cited by
-
The effect of Ferula elaeochytris root extract on erectile dysfunction in streptozotocin-induced diabetic rat
International Journal of Impotence Research (2020)
-
Mesenchymal stem cell-based gene therapy for erectile dysfunction
International Journal of Impotence Research (2016)
-
Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats
International Journal of Impotence Research (2012)
-
Emerging and Novel Therapeutic Approaches in the Treatment of Male Erectile Dysfunction
Current Urology Reports (2011)
-
Advances in Pharmacologic Modulation of Nitric Oxide in Hypertension
Current Cardiology Reports (2010)