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:

Experimental priapism is associated with increased oxidative stress and activation of protein degradation pathways in corporal tissue

Abstract

Priapism is a debilitating disease for which there is at present no clinically accepted pharmacological intervention. It has been estimated that priapism lasting more than 24 h in patients is associated with a 44–90% rate of ED. In this investigation, we determined in two animal models of priapism (opiorphin-induced priapism in the rat and priapism in a mouse model of sickle cell disease) if there is evidence for an increase in markers of oxidative stress in corporal tissue. In both animal models, we demonstrate that priapism results in increased levels of lipid peroxidation, glutathione S-transferase activity and oxidatively damaged proteins in corporal tissue. Using western blot analysis, we demonstrated there is upregulation of the ubiquitination ligase proteins, Nedd-4 and Mdm-2, and the lysosomal autophage protein, LC3. The antiapoptotic protein, Bcl-2, was also upregulated. Overall, we demonstrate that priapism is associated with increased oxidative stress in corporal tissue and the activation of protein degradation pathways. As oxidative stress is known to mediate the development of ED resulting from several etiologies (for example, ED resulting from diabetes and aging), we suggest that damage to erectile tissue resulting from priapism might be prevented by treatments targeting oxidative stress.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF et al. American Urological Association guideline on the management of priapism. J Urol 2003; 170 (4 Part 1): 1318–1324.

    Article  Google Scholar 

  2. El-Bahnasawy MS, Dawood A, Farouk A . Low-flow priapism: risk factors for erectile dysfunction. BJU Int 2002; 89: 285–290.

    Article  CAS  Google Scholar 

  3. Pryor J, Akkus E, Alter G, Jordan G, Lebret T, Levine L et al. Priapism. J Sex Med 2004; 1: 116–120.

    Article  Google Scholar 

  4. Bennett N, Mulhall J . Sickle cell disease status and outcomes of African-American men presenting with priapism. J Sex Med 2008; 5: 1244–1250.

    Article  Google Scholar 

  5. Sood S, James W, Bailon MJ . Priapism associated with atypical antipsychotic medications: a review. Int Clin Psychopharmacol 2008; 23: 9–17.

    Article  Google Scholar 

  6. Nunes KP, Costa-Goncalves A, Lanza LF, Cortes SF, Cordeiro MN, Richardson M et al. Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile function. Toxicon 2008; 51: 1197–1206.

    Article  CAS  Google Scholar 

  7. Fowler Jr JE, Koshy M, Strub M, Chinn SK . Priapism associated with the sickle cell hemoglobinopathies: prevalence, natural history and sequelae. J Urol 1991; 145: 65–68.

    Article  Google Scholar 

  8. Emond AM, Holman R, Hayes RJ, Serjeant GR . Priapism and impotence in homozygous sickle cell disease. Arch Intern Med 1980; 140: 1434–1437.

    Article  CAS  Google Scholar 

  9. Kanika ND, Tar M, Tong Y, Kuppam DS, Melman A, Davies KP . The mechanism of opiorphin-induced experimental priapism in rats involves activation of the polyamine synthetic pathway. Am J Physiol Cell Physiol 2009; 297: C916–C927.

    Article  CAS  Google Scholar 

  10. Tong Y, Tar M, Melman A, Davies K . The opiorphin gene (ProL1) and its homologues function in erectile physiology. BJU Int 2008; 102: 736–740.

    Article  Google Scholar 

  11. Tong Y, Tar M, Davelman F, Christ G, Melman A, Davies KP . Variable coding sequence protein A1 as a marker for erectile dysfunction. BJU Int 2006; 98: 396–401.

    Article  CAS  Google Scholar 

  12. Burnett AL, Chang AG, Crone JK, Huang PL, Sezen SE . Noncholinergic penile erection in mice lacking the gene for endothelial nitric oxide synthase. J Androl 2002; 23: 92–97.

    Article  CAS  Google Scholar 

  13. Champion HC, Bivalacqua TJ, Takimoto E, Kass DA, Burnett AL . Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA 2005; 102: 1661–1666.

    Article  CAS  Google Scholar 

  14. Mi T, Abbasi S, Zhang H, Uray K, Chunn JL, Xia LW et al. Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J Clin Invest 2008; 118: 1491–1501.

    Article  CAS  Google Scholar 

  15. Morris CR . Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology Am Soc Hematol Educ Program 2008; 1: 177–185.

    Article  Google Scholar 

  16. Kato GJ, Gladwin MT, Steinberg MH . Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007; 21: 37–47.

    Article  Google Scholar 

  17. Hsu LL, Champion HC, Campbell-Lee SA, Bivalacqua TJ, Manci EA, Diwan BA et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 2007; 109: 3088–3098.

    Article  CAS  Google Scholar 

  18. Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005; 294: 81–90.

    Article  CAS  Google Scholar 

  19. Durante W, Johnson FK, Johnson RA . Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol 2007; 34: 906–911.

    Article  CAS  Google Scholar 

  20. Yuan J, Desouza R, Westney OL, Wang R . Insights of priapism mechanism and rationale treatment for recurrent priapism. Asian J Androl 2008; 10: 88–101.

    Article  CAS  Google Scholar 

  21. Burnett AL . Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health. J Androl 2008; 29: 3–14.

    Article  CAS  Google Scholar 

  22. Dai Y, Zhang Y, Phatarpekar P, Mi T, Zhang H, Blackburn MR et al. Adenosine signaling, priapism and novel therapies. J Sex Med 2009; 6 (Suppl 3): 292–301.

    Article  CAS  Google Scholar 

  23. Jeremy JY, Angelini GD, Khan M, Mikhailidis DP, Morgan RJ, Thompson CS et al. Platelets, oxidant stress and erectile dysfunction: an hypothesis. Cardiovasc Res 2000; 46: 50–54.

    Article  CAS  Google Scholar 

  24. Azadzoi KM, Schulman RN, Aviram M, Siroky MB . Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants. J Urol 2005; 174: 386–393.

    Article  CAS  Google Scholar 

  25. Bivalacqua TJ, Armstrong JS, Biggerstaff J, Abdel-Mageed AB, Kadowitz PJ, Hellstrom WJ et al. Gene transfer of extracellular SOD to the penis reduces O2-* and improves erectile function in aged rats. Am J Physiol Heart Circ Physiol 2003; 284: H1408–H1421.

    Article  CAS  Google Scholar 

  26. Deng W, Bivalacqua TJ, Champion HC, Hellstrom WJ, Murthy SN, Kadowitz PJ . Superoxide dismutase—a target for gene therapeutic approach to reduce oxidative stress in erectile dysfunction. Methods Mol Biol 2010; 610: 213–227.

    Article  CAS  Google Scholar 

  27. Jones RW, Rees RW, Minhas S, Ralph D, Persad RA, Jeremy JY . Oxygen free radicals and the penis. Expert Opin Pharmacother 2002; 3: 889–897.

    Article  CAS  Google Scholar 

  28. 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 2005; 2: 187–197; discussion 197-8.

    Article  CAS  Google Scholar 

  29. Agarwal A, Nandipati KC, Sharma RK, Zippe CD, Raina R . Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. J Androl 2006; 27: 335–347.

    Article  CAS  Google Scholar 

  30. Evliyaoglu Y, Kayrin L, Kaya B . Effect of pentoxifylline on veno-occlusive priapism-induced corporeal tissue lipid peroxidation in a rat model. Urol Res 1997; 25: 143–147.

    Article  CAS  Google Scholar 

  31. Evliyaoglu Y, Kayrin L, Kaya B . Effect of allopurinol on lipid peroxidation induced in corporeal tissue by veno-occlusive priapism in a rat model. Br J Urol 1997; 80: 476–479.

    Article  CAS  Google Scholar 

  32. Tong Y, Tar M, Monrose V, DiSanto M, Melman A, Davies KP . hSMR3A as a marker for patients with erectile dysfunction. J Urol 2007; 178: 338–343.

    Article  CAS  Google Scholar 

  33. Habig WH, Pabst MJ, Jakoby WB . Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 1974; 249: 7130–7139.

    CAS  PubMed  Google Scholar 

  34. Ohkawa H, Ohishi N, Yagi K . Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351–358.

    Article  CAS  Google Scholar 

  35. Melman A, Biggs G, Davies K, Zhao W, Tar MT, Christ GJ . Gene transfer with a vector expressing Maxi-K from a smooth muscle-specific promoter restores erectile function in the aging rat. Gene Therapy 2008; 15: 364–370.

    Article  CAS  Google Scholar 

  36. Melman A, Zhao W, Davies KP, Bakal R, Christ GJ . The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo. J Urol 2003; 170: 285–290.

    Article  CAS  Google Scholar 

  37. Mizushima N, Yoshimori T . How to interpret LC3 immunoblotting. Autophagy 2007; 3: 542–545.

    Article  CAS  Google Scholar 

  38. Ezaki J, Kominami E . The intracellular location and function of proteins of neuronal ceroid lipofuscinoses. Brain Pathol 2004; 14: 77–85.

    Article  CAS  Google Scholar 

  39. Plant PJ, Correa J, Goldenberg N, Bain J, Batt J . The inositol phosphatase MTMR4 is a novel target of the ubiquitin ligase Nedd4. Biochem J 2009; 419: 57–63.

    Article  CAS  Google Scholar 

  40. Lin HK, Wang L, Hu YC, Altuwaijri S, Chang C . Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J 2002; 21: 4037–4048.

    Article  CAS  Google Scholar 

  41. Hsu L, Diwan B, Ward JM, Noguchi CT . Pathology of ‘Berkeley’ sickle-cell mice includes gallstones and priapism. Blood 2006; 107: 3414–3415.

    Article  CAS  Google Scholar 

  42. Kanika ND, Tar M, Tong Y, Kuppam DS, Melman A, Davies KP . The mechanism of opiorphin-induced experimental priapism in rats involves activation of the polyamine synthetic pathway. Am J Physiol Cell Physiol 2009; 297: C916–C927.

    Article  CAS  Google Scholar 

  43. Claudino MA, Franco-Penteado CF, Corat MA, Gimenes AP, Passos LA, Antunes E et al. Increased cavernosal relaxations in sickle cell mice priapism are associated with alterations in the NO-cGMP signaling pathway. J Sex Med 2009; 6: 2187–2196.

    Article  CAS  Google Scholar 

  44. Bivalacqua TJ, Musicki B, Hsu LL, Gladwin MT, Burnett AL, Champion HC . Establishment of a Transgenic Sickle-Cell Mouse Model to Study the Pathophysiology of Priapism. J Sex Med 2009; 6: 2494–2504.

    Article  Google Scholar 

  45. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ . Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993; 75: 241–251.

    Article  CAS  Google Scholar 

  46. Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS et al. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science 1993; 262: 1274–1277.

    Article  CAS  Google Scholar 

  47. Beckman JS, Koppenol WH . Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 1996; 271 (5 Part 1): C1424–C1437.

    Article  CAS  Google Scholar 

  48. Khan MA, Thompson CS, Mumtaz FH, Mikhailidis DP, Morgan RJ, Bruckdorfer RK et al. The effect of nitric oxide and peroxynitrite on rabbit cavernosal smooth muscle relaxation. World J Urol 2001; 19: 220–224.

    Article  CAS  Google Scholar 

  49. Kaul DK, Zhang X, Dasgupta T, Fabry ME . Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress. Am J Physiol Heart Circ Physiol 2008; 295: H39–H47.

    Article  CAS  Google Scholar 

  50. Kaul DK, Liu XD, Chang HY, Nagel RL, Fabry ME . Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice. J Clin Invest 2004; 114: 1136–1145.

    Article  CAS  Google Scholar 

  51. Friguet B . Oxidized protein degradation and repair in ageing and oxidative stress. FEBS Lett 2006; 580: 2910–2916.

    Article  CAS  Google Scholar 

  52. Gonzalez-Cadavid NF . Mechanisms of penile fibrosis. J Sex Med 2009; 6 (Suppl 3): 353–362.

    Article  Google Scholar 

  53. Melman A, Gingell JC . The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999; 161: 5–11.

    Article  CAS  Google Scholar 

  54. Kovanecz I, Ferrini MG, Vernet D, Nolazco G, Rajfer J, Gonzalez-Cadavid NF . Pioglitazone prevents corporal veno-occlusive dysfunction in a rat model of type 2 diabetes mellitus. BJU Int 2006; 98: 116–124.

    Article  CAS  Google Scholar 

  55. Ferrini MG, Davila HH, Kovanecz I, Sanchez SP, Gonzalez-Cadavid NF, Rajfer J . Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat. Urology 2006; 68: 429–435.

    Article  Google Scholar 

  56. Gonzalez-Cadavid NF, Rajfer J . Molecular pathophysiology and gene therapy of aging-related erectile dysfunction. Exp Gerontol 2004; 39: 1705–1712.

    Article  CAS  Google Scholar 

  57. Hebbel RP, Eaton JW, Balasingam M, Steinberg MH . Spontaneous oxygen radical generation by sickle erythrocytes. J Clin Invest 1982; 70: 1253–1259.

    Article  CAS  Google Scholar 

  58. Neidlinger NA, Larkin SK, Bhagat A, Victorino GP, Kuypers FA . Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction. J Biol Chem 2006; 281: 775–781.

    Article  CAS  Google Scholar 

  59. Krajewski ML, Hsu LL, Gladwin MT . The proverbial chicken or the egg? Dissection of the role of cell-free hemoglobin versus reactive oxygen species in sickle cell pathophysiology. Am J Physiol Heart Circ Physiol 2008; 295: H4–H7.

    Article  CAS  Google Scholar 

  60. Kawakami T, Urakami S, Hirata H, Tanaka Y, Nakajima K, Enokida H et al. Superoxide dismutase analog (Tempol: 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) treatment restores erectile function in diabetes-induced impotence. Int J Impot Res 2009; 21: 348–355.

    Article  CAS  Google Scholar 

  61. Muneer A, Cellek S, Ralph DJ, Minhas S . The investigation of putative agents, using an in vitro model, to prevent cavernosal smooth muscle dysfunction during low-flow priapism. BJU Int 2008; 102: 988–992.

    Article  Google Scholar 

  62. 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. Biol Reprod 2007; 76: 915–923.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant awarded by the NIH/NIDDK to Kelvin P Davies (R01DK077665).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K P Davies.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kanika, N., Melman, A. & Davies, K. Experimental priapism is associated with increased oxidative stress and activation of protein degradation pathways in corporal tissue. Int J Impot Res 22, 363–373 (2010). https://doi.org/10.1038/ijir.2010.27

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijir.2010.27

Keywords

This article is cited by

Search

Quick links