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.

  • Review
  • Published:

Reactive oxygen species and erectile dysfunction: possible role of NADPH oxidase

International Journal of Impotence Research volume 19, pages 265–280 (2007)Cite this article

Abstract

Erectile dysfunction (ED) is a widespread condition, the incidence of which is increasing globally. ED is also indicative of underlying vasculopathy and represents a predictor of more serious cardiovascular disorders. Understanding the aetiology of ED may therefore provide invaluable pointers to the pathobiology of other cardiovascular diseases (CVDs) and syndromes. It follows, too, that therapeutic interventions that are successful in treating ED may, ipso facto, be effective in treating the early stages of conditions that include atherosclerosis, angina, plaque rupture and diabetic angiopathy. One common pathological denominator in both CVD and ED is oxidative stress, that is, the overproduction of reactive oxygen species (ROS), in particular, superoxide (O2•−) and hydrogen peroxide (H2O2). In this review, therefore, we consider the aetiology and pathobiology of O2•− in promoting ED and focus on NADPH oxidase as an inducible source of O2•− and H2O2. Therapeutic strategies aimed at reducing oxidative stress to improve erectile function are also discussed.

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

Similar content being viewed by others

References

  1. Aytac IA, McKinlay JB, Krane RJ . The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999; 84: 50–56.

    Article  Google Scholar 

  2. Roumeguere T, Wespes E, Carpentier Y, Hoffman P, Schulman CC . Erectile dysfunction is associated with a high prevalence of hyperlipidemia and coronary heart disease risk. Eur Urol 2003; 44: 355–359.

    PubMed  Google Scholar 

  3. Kloner RA, Mullin SH, Shook T, Matthews R, Mayeda G, Burstein S et al. Erectile dysfunction in the cardiac patient: how common and how should we treat it. J Urol 2003; 170: S46–S50.

    PubMed  Google Scholar 

  4. Solomon H, Mann JW, Jackson G . Erectile dysfunction and the cardiovascular patient. Heart 2003; 89: 251–254.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Barrett-Connor E . Cardiovascular risk stratification and cardiovascular risk factors associated with erectile dysfunction: assessing cardiovascular risk in men with erectile dysfunction. Clin Cardiol 2004; 274: I8–13.

    Google Scholar 

  6. Kostis JB, Jackson G, Rosen R, Barrett-Connor K, Billups A, Burnett C et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol 2005; 96: 313–321.

    PubMed  Google Scholar 

  7. Andersson KE . Pharmacology of penile erection. Pharmacol Rev 2001; 53: 417–450.

    CAS  PubMed  Google Scholar 

  8. Lue TF . Erectile dysfunction. N Engl J Med 2000; 432: 1802–1813.

    Google Scholar 

  9. Carson CC, Lue TF . Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int 2005; 96: 257–280.

    CAS  PubMed  Google Scholar 

  10. Giuliano F, Rampin O . Neural control of erection. Physiol Behav 2004; 83: 189–201.

    CAS  PubMed  Google Scholar 

  11. Argiolas A, Melis MR . Central control of penile erection: role of the paraventricular nucleus of the hypothalamus. Prog Neurobiol 2005; 76: 1–21.

    CAS  PubMed  Google Scholar 

  12. Goldstein I, Udelson D . Axial penile rigidity: determinants and relation to hemodynamic parameters. Int J Impot Res 1998; 10: S28–S33.

    PubMed  Google Scholar 

  13. Schwartz AN, Wang KY, Mack LA . Evaluation of normal erectile function with colour flow Doppler sonography. Am J Roentgenol 1989; 153: 1153–1160.

    Google Scholar 

  14. Fournier GR, Juenemann KP, Lue TF, Tanagho EA . Mechanisms of venous occlusion during canine penile erection: an anatomic demonstration. J Urol 1987; 137: 163–167.

    PubMed  Google Scholar 

  15. Aboseif SR, Lue TF . Haemodynamics of penile erection. Urol Clin N Amer 1988; 15: 1–7.

    CAS  Google Scholar 

  16. Shirai M, Ishii N . Haemodynamics of erection in man. Arch Androl 1981; 6: 27–32.

    CAS  PubMed  Google Scholar 

  17. Vardi Y, Siroky MB . Hemodynamics of pelvic nerve induced erection in a canine model. I. Pressure and flow. J Urol 1990; 144: 794–797.

    CAS  PubMed  Google Scholar 

  18. Saenz-de Tejada IS, Moroukian P, Tessier J, Kim JJ, Goldstein I, Frohrib D . Trabecular smooth muscle modulates the capacitor function of the penis. Studies on a rabbit model. Am J Physiol 1991; 260: H1590–H1595.

    CAS  PubMed  Google Scholar 

  19. Goldstein I, Udelson D . Axial penile rigidity: determinants and relation to hemodynamic parameters. Int J Impot Res 1998; 10: S28–S33.

    PubMed  Google Scholar 

  20. Schwartz AN, Wang KY, Mack LA . Evaluation of normal erectile function with colour flow Doppler sonography. Am J Roentgenol 1989; 153: 1153–1160.

    Google Scholar 

  21. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J . Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1990; 170: 843–850.

    CAS  PubMed  Google Scholar 

  22. Rajfer J, Aronson WJ, Bush PA, eDorey F, Ignarro I . 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.

    CAS  PubMed  Google Scholar 

  23. Toda N, Ayajiki K, Okamura T . Nitric oxide and penile erection. Pharmacol Ther 2005; 106: 233–266.

    CAS  PubMed  Google Scholar 

  24. Nangle MR, Cotter MA, Cameron NE . An in vitro investigation of aorta and corpus cavernosum from eNOS and iNOS gene deficient mice. Pflugers Arch Eur J Physiol 2004; 448: 139–145.

    CAS  Google Scholar 

  25. Bivalacqua TJ, Champion HC, Mehta YS, Abdel-Mageed AC, Sikka SC, Ignarro LJ 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.

    PubMed  Google Scholar 

  26. Burnett AL . Novel nitric oxide signaling mechanisms regulate the erectile response. Int J Impot Res 2004; 16: S15–S19.

    CAS  PubMed  Google Scholar 

  27. Musicki B, Burnett AL . Endothelial dysfunction in diabetic erectile dysfunction. Int J Impot Res 2006 (E-pub: in press).

  28. Burnett AL . Novel nitric oxide signaling mechanisms regulate the erectile response. Int J Impot Res 2004; 16(Suppl 1): S15–S19.

    CAS  PubMed  Google Scholar 

  29. Hurt KJ, Sezen SF, Champion HC, Crone JK, Palese MA, Huanget PL et al. Alternatively spliced neuronal nitric oxide synthase mediates penile erection. PNAS 2006; 103: 3440–3443.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nangle MR, Cotter MA, Cameron NE . An in vitro investigation of aorta and corpus cavernosum from eNOS and nNOS gene-deficient mice. Pflugers Arch 2004; 448: 139–145.

    CAS  PubMed  Google Scholar 

  31. Hofmann F . The biology of cyclic GMP dependent protein kinases. J Biol Chem 2005; 280: 1–4.

    CAS  PubMed  Google Scholar 

  32. Jeremy JY, Yim AP, Wan S, Angelini GD . Oxidative stress, nitric oxide and vascular disease. J Cardiovasc Surg 2002; 17: 324–327.

    Google Scholar 

  33. Jeremy JY, Rowe D, Emsley AM, Newby AC . Nitric oxide and vascular smooth muscle cell proliferation. Cardiovasc Res 1999; 43: 658–665.

    PubMed  Google Scholar 

  34. Muzaffar S, Shukla N, Angelini GD, Jeremy JY . NADPH oxidases: a promiscuous target for cardiovascular drugs? Trends Cardiovasc Med 2005; 15: 278–282.

    CAS  PubMed  Google Scholar 

  35. Jeremy JY, Ballard SA, Naylor AM, Miler MA, Angelini GD . Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum, in vitro. Br J Urol Int 1997; 79: 958–963.

    CAS  Google Scholar 

  36. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM . 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.

    CAS  PubMed  Google Scholar 

  37. Corbin J, Rannels S, Neal D, Chang P, Grimes K, Beasley A et al. Sildenafil citrate does not affect cardiac contractility in human or dog heart. Curr Med Res Opin 2003; 19: 747–752.

    CAS  PubMed  Google Scholar 

  38. Palumbo F, Bettocchi C, Selvaggi FP, Pryor JP, Ralph DJ . Sildenafil: efficacy and safety in daily clinical practice. Eur Urol 2001; 40: 176–180.

    CAS  PubMed  Google Scholar 

  39. Rosen RC, Kostis JB . Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003; 92: 9M–18M.

    CAS  PubMed  Google Scholar 

  40. Cashen DE, MacIntyyre DE, Martin WJ . Effects of sildenafil on erectile activity in mice lacking neuronal or endothelial nitric oxide synthase. Br J Pharmacol 2002; 136: 693–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Shukla N, Jones RAW, Persad R, 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: 224–231.

    CAS  PubMed  Google Scholar 

  42. Muzaffar S, Shukla N, Angelini GD, Jeremy JY . Sildenafil citrate and sildenafil nitrate are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells. Br J Pharmacol 2005; 146: 109–117.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kouparris AJ, Jeremy JY, Muzaffar S, Angelini GD, Shukla N . Sildenafil inhibits the formation of superoxide and the expression of gp47phox NADPH oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells. Br J Urol Int 2005; 96: 423–427.

    Google Scholar 

  44. Malmstrom BG . Enzymology of oxygen. Ann Rev Biochem 1982; 51: 21–59.

    CAS  PubMed  Google Scholar 

  45. Betteridge DJ . What is oxidative stress? Metabolism 2000; 49: 3–8.

    CAS  PubMed  Google Scholar 

  46. Shah AM, Channon KM . Free radicals and redox signalling in cardiovascular disease. Heart 2004; 90: 486–487.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kojda G, Harrison D . Interaction between NO and reactive oxygen species: pathological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 1999; 43: 562–571.

    CAS  PubMed  Google Scholar 

  48. Hensley K, Robinson KA, Gabbita SP, Salsman S, Floyd RA . Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med 2000; 28: 1456–1462.

    CAS  PubMed  Google Scholar 

  49. Bergendi L, Bens L, Durackova Z, Ferencik M . Chemistry, physiology and pathology of free radicals. Life Sci 1999; 65: 1865–1874.

    CAS  PubMed  Google Scholar 

  50. Patel RP, Moellering D, Murphy-Ullrich J, Jo H, Beckman JS, Darley-Usmar VM . Cell signaling by reactive nitrogen and oxygen species in atherosclerosis. Free Radic Biol Med 2000; 28: 1780–1794.

    CAS  PubMed  Google Scholar 

  51. 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.

    CAS  PubMed  Google Scholar 

  52. Cai H, Harrison DG . Endothelial dysfunction in cardiovascular diseases. The role of oxidant stress. Circ Res 2000; 87: 840–844.

    CAS  PubMed  Google Scholar 

  53. Cai H, Griendling KK, Harrison DG . The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 2003; 24: 471–478.

    CAS  PubMed  Google Scholar 

  54. Jeremy JY, Shukla N, Muzaffar S, Angelini GD . Reactive oxygen species, vascular disease and cardiovascular surgery. Curr Vasc Pharmacol 2004; 2: 229–236.

    CAS  PubMed  Google Scholar 

  55. Beckman JS, Koppenol WH . Nitric oxide, superoxide and peroxynitrite: the good the bad and the ugly. Am J Physiol 1996; 271: C1424–C1437.

    CAS  PubMed  Google Scholar 

  56. Young IS, Woodside JV . Antioxidants in health and disease. J Clin Pathol 2001; 54: 176–186.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Dweik RA . Nitric oxide, hypoxia, and superoxide: the good, the bad, and the ugly!. Thorax 2005; 60: 265–267.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Folkerts G, Kloek J, Muijsers RB, Nijkamp FP . Reactive nitrogen and oxygen species in airway inflammation. Eur J Pharmacol 2001; 429: 251–262.

    CAS  PubMed  Google Scholar 

  59. Li JM, Shah AM . Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol 2004; 287: R1014–R1030.

    CAS  Google Scholar 

  60. Martin W, McAllister KHM, Paisley K . NANC neurotransmission in the bovine retractor penis muscle is blocked by superoxide anion following inhibition of superoxide dismutase with diethyldthiocarbamate. Neuropharmacology 1994; 33: 1293–1301.

    CAS  PubMed  Google Scholar 

  61. Gillespie JS, Sheng H . The effects of pyrogallol and hydroquinone on the response to NANC nerve stimulation in the rat anococcygeus and the bovine retractor penis muscles. Br J Pharmacol 1990; 99: 194–196.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bivalacqua TT, Armstrong JS, Biggerstaff J, Abdel Mageed AB, Kadowotz PJ, Hellstrom WJ et al. Gene transfer of SOD to the penis reduces superoxide formation and improves erectile function in aged rats. Am J Physiol 2003; 284: H1408–H1421.

    CAS  Google Scholar 

  63. Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M . Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 2000; 20: 2175–2183.

    CAS  PubMed  Google Scholar 

  64. Landmesser U, Harrison DG, Drexler H . Oxidant stress – a major cause of reduced endothelial nitric oxide availability in cardiovascular disease. Eur J Clin Pharmacol 2006; 62(Suppl 13): 13–19.

    CAS  Google Scholar 

  65. Mungrue IN, Bredt DS, Stewart DJ, Husain M . From molecules to mammals: what's NOS got to do with it? Acta Physiol Scand 2003; 179: 123–135.

    CAS  PubMed  Google Scholar 

  66. Alderton WK, Cooper CE, Knowles RG . Nitric oxide synthases: structure, function and inhibition. Biochem J 2001; 357: 593–615.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Li H, Poulos TL . Structure–function studies on nitric oxide synthases. J Inorg Biochem 2005; 99: 293–305.

    CAS  PubMed  Google Scholar 

  68. Govers R, Rabelink TJ . Cellular regulation of endothelial nitric oxide synthase. Am J Physiol 2001; 280: F193–F206.

    CAS  Google Scholar 

  69. Boo YC, Kim HJ, Song H, Fulton D, Sessa W, Jo H . Coordinated regulation of endothelial nitric oxide activity by phoapshorylation and subcellular localization. Free Rad Biol Med 2006; 41: 144–153.

    CAS  PubMed  Google Scholar 

  70. Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R . Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 2001; 88: 68–75.

    Google Scholar 

  71. Church JE, Fulton D . Differences in eNOS activity because of subcellular localization are dictated by phosphorylation state rather than the local calcium environment. J Biol Chem 2006; 281: 1477–1488.

    CAS  PubMed  Google Scholar 

  72. Jagnandan D, Sessa WC, Fulton D . Intracellular location regulates calcium-calmodulin-dependent activation of organelle-restricted eNOS. Am J Cell Physiol 2005; 289: C1024–C1033.

    CAS  Google Scholar 

  73. Chiarugi P . PTPs versus PTKs: the redox side of the coin. Free Rad Res 2005; 39: 353–364.

    CAS  Google Scholar 

  74. Rahman I, Adcock IM . Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 2006; 28: 219–242.

    CAS  PubMed  Google Scholar 

  75. Butt E, Bernhardt M, Smolenski A . Endothelial nitric-oxide synthase (Type III) is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases. J Biol Chem 2000; 275: 5179–5187.

    CAS  PubMed  Google Scholar 

  76. Michell BJ, Chen ZP, Tiganis T, Stapleton D, Katsis F, Power DA et al. Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem 2001; 276: 17625–17628.

    CAS  PubMed  Google Scholar 

  77. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999; 400: 597–601.

    Google Scholar 

  78. Fulton D, Church JE, Ruan L, Sood G, Kemp BE, Jennings IG et al. Src kinase activates endothelial nitric-oxide synthase by phosphorylating Tyr-83. J Biol Chem 2005; 280: 3594–35952.

    Google Scholar 

  79. Peterson TE, Poppa V, Ueba H, Wu A, Yan C, Berk BC . Opposing effects of reactive oxygen species and cholesterol on endothelial nitric oxide synthase and endothelial cell caveolae. Circ Res 1999; 85: 29–37.

    CAS  PubMed  Google Scholar 

  80. Jin L, Ying Z, Webb RC . Activation of the Rho/Rho kinase pathway by reactive oxygen species in the rat aorta. Am J Physiol 2006; 287: H1495–H1500.

    Google Scholar 

  81. Laufs U, Liao JK . Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998; 273: 24266–24271.

    CAS  PubMed  Google Scholar 

  82. Shimokawa H, Takeshita A . Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 2005; 25: 1767–1775.

    CAS  PubMed  Google Scholar 

  83. Thony B, Auerbach G, Blau N . Tetrahydrobiopterin biosynthesis regeneration and functions. Biochem J 2000; 347: 1–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial nitric oxide synthase in hypertension: role of the NAD(P)H oxidase. J Clin Invest 2003; 111: 1201–1209.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Gloire G, Legrand-Poels S, Piette J . NFκappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 2006 (E-pub; in press).

  86. Simon AR, Rai U, Fanburg BL, Cochran BH . Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol 1998; 275: C1640–C1652.

    CAS  PubMed  Google Scholar 

  87. Carballo M, Conde M, El Bekay R, Martín-Nieto J, Camacho MJ, Monteseirín J et al. Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes. J Biol Chem 1999; 274: 17580–17586.

    CAS  PubMed  Google Scholar 

  88. Darnell Jr JE, Kerr IM, Stark GR . Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264: 1415–1421.

    CAS  PubMed  Google Scholar 

  89. Cuzzocrea S . Shock, inflammation and PARP. Pharmacol Res 2005; 52: 72–82.

    CAS  PubMed  Google Scholar 

  90. Hayashi T, Juliet PA, Kano-Hayashi H, Tsunekawa T, Dingqunfang D, Sumi D et al. NADPH oxidase inhibitor, apocynin, restores the impaired endothelial-dependent and -independent responses and scavenges superoxide anion in rats with type 2 diabetes complicated by NO dysfunction. Diab Obes Metab 2005; 7: 334–343.

    CAS  Google Scholar 

  91. Cotter MA, Cameron NE . Effect of the NAD(P)H oxidase inhibitor, apocynin, on peripheral nerve perfusion and function in diabetic rats. Life Sci 2003; 73: 1813–1824.

    CAS  PubMed  Google Scholar 

  92. Shukla N, Koupparis A, Persad R, Angelini GD, Jeremy JY . Penicillamine administration reverses the inhibitory effect of hyperhomocysteinaemia on endothelium-dependent relaxation and superoxide formation in the aorta of the rabbit. Eur J Pharmacol 2006; 531: 201–208.

    CAS  PubMed  Google Scholar 

  93. Li L, Fink GD, Watts SW, Northcott CA, Galligan JJ, Pagano PJ et al. Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation 2003; 107: 1053–1058.

    CAS  PubMed  Google Scholar 

  94. Jacobson GM, Dourron HM, Liu J, Carretero OA, Reddy DJ, Andrzejewskiet T et al. Novel NAD(P)H oxidase inhibitor suppresses angioplasty-induced superoxide and neointimal hyperplasia of rat carotid artery. Circ Res 2003; 92: 637–643.

    CAS  PubMed  Google Scholar 

  95. Muzaffar S, Shukla N, Angelini GD, Jeremy JY . Hypoxia simultaneously induces the expression of gp91phox and endothelial nitric oxide synthase in the pulmonary artery. Thorax 2005; 60: 305–313.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bleeke T, Zhang H, Madamanchi N, Patterson C, Faber JE . Catecholamine-induced vascular wall growth is dependent on generation of reactive oxygen species. Circ Res 2004; 94: 37–45.

    CAS  PubMed  Google Scholar 

  97. Zhang H, Schmeiber A, Garlichs CD, Plötze K, Damme U, Mügge A et al. Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res 1999; 44: 215–222.

    CAS  PubMed  Google Scholar 

  98. Muzaffar S, Shukla N, Lobo C, Angelini GD, Jeremy JY . Iloprost inhibits NADPH oxidase expression and superoxide release in porcine pulmonary arteries and cells stimulated with thromboxane A2, isoprostane F2 α and cytokines. Br J Pharmacol 2004; 141: 488–496.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Dong F, Zhang X, Wold LE, Ren Q, Zhang Z, Ren J . Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ET(B) receptor, NADPH oxidase and caveolin-1. Br J Pharmacol 2005; 145: 323–333.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. McNally JS, Davis ME, Giddens DP, Saha A . Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol 2003; 285: H2290–H2297.

    CAS  Google Scholar 

  101. Muzaffar S, Shukla N, Angelini GD, Jeremy JY . Superoxide auto-augments superoxide formation and upregulates gp91(phox) expression in porcine pulmonary artery endothelial cells: Inhibition by iloprost. Eur J Pharmacol 2006; 538: 108–114.

    CAS  PubMed  Google Scholar 

  102. Muzaffar S, Jeremy JY, Angelini GD, Shukla N . The role of the endothelium and nitric oxide synthases in modulating superoxide formation induced by endotoxin and cytokines in porcine pulmonary arteries. Thorax 2003; 58: 598–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Muzaffar S, Shukla N, Angelini GD, Jeremy JY . Nitroaspirins and morpholinosydnonimine, but not aspirin, inhibit the formation of superoxide and the expression of gp91phox induced by endotoxin and cytokines in pig pulmonary artery vascular smooth muscle cells and endothelial cells. Circulation 2004; 110: 1140–1147.

    CAS  PubMed  Google Scholar 

  104. Muzaffar S, Shukla N, Angelini GD, Jeremy JY . Prednisolone augments superoxide formation in porcine pulmonary artery endothelial cells through upregulation of NADPH oxidase. Br J Pharmacol 2005; 145: 688–697.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Michal V . Arterial disease as a cause of impotence. Clinics Endocrinol Metab 1982; 11: 725–748.

    CAS  Google Scholar 

  106. Virag R, Bouilly P, Frydman D . Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet 1985; 1(8422): 181–184.

    CAS  PubMed  Google Scholar 

  107. Ross R . Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115–126.

    CAS  PubMed  Google Scholar 

  108. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Bräsen J, Skatchkov M et al. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis. Circulation 1999; 99: 2027–2033.

    CAS  PubMed  Google Scholar 

  109. Guzik TZ, West NE, Black E, McDonald D, Ratnatunga C, Pillai R et al. Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res 2000; 86: E85–E90.

    CAS  PubMed  Google Scholar 

  110. Kim SC . Hyperlipidemia and erectile dysfunction. Asian J Androl 2000; 2: 161–166.

    CAS  PubMed  Google Scholar 

  111. Azadzoi KM, Goldstein I . Erectile dysfunction due to atherosclerotic vascular disease: the development of an animal model. J Urol 1992; 147: 1675–1681.

    CAS  PubMed  Google Scholar 

  112. Kim JH, Klyachkin ML, Svendsen E, Davies MG, Hagen PO, Carson III CC . Experimental hypercholesterolaemia in rabbits induces cavernosal atherosclerosis with endothelial and smooth muscle cell dysfunction. J Urol 1994; 151: 198–205.

    CAS  PubMed  Google Scholar 

  113. Kim SC, Kim IK, Seo KK, Baek KJ, Lee MY . Involvement of superoxide radical in the impaired endothelium-dependant relaxation of cavernous smooth muscle in hypercholesterolaemic rabbits. Urol Res 1997; 25: 341–346.

    CAS  PubMed  Google Scholar 

  114. Grein U, Schubert GE . Arteriosclerosis of penile arteries. Urol Int 2002; 68: 261–264.

    PubMed  Google Scholar 

  115. Seo KK, Yun HY, Kim SC . Involvement of endothelial NOS in the impaired endothelium dependent relaxation of cavernosal smooth muscle in hypercholesterolaemic rabbits. J Androl 1999; 20: 298–306.

    CAS  PubMed  Google Scholar 

  116. Mugge A, Brandes RP, Boger RH, Dwenger A, Bode Boger S, Kienke S et al. Vascular release of superoxide radicals is enhanced in hypercholesterolaemic rabbits. J Cardiovasc Pharmacol 1994; 24: 994–998.

    CAS  PubMed  Google Scholar 

  117. Rizvi K, Hapson JP, Harvey JN . Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Fam Pract 2002; 567: 95–98.

    Google Scholar 

  118. Nangle MR, Cotter MA, Cameron NE . Effects of rosuvastatin on nitric oxide-dependent function in aorta and corpus cavernosum of diabetic mice: relationship to cholesterol biosynthesis pathway inhibition and lipid lowering. Diabetes 2003; 52: 2396–2402.

    CAS  PubMed  Google Scholar 

  119. Osborne T . Statin treatment improves erectile dysfunction in sildenafil nonresponders. Nat Clin Pract Urol 2006; 3: 239–240.

    Google Scholar 

  120. Solomon H, Samarasinghe YP, Feher MD, Man J, Rivas-Toro H, Lumb PJ et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract 2006; 60: 141–145.

    CAS  PubMed  Google Scholar 

  121. Endres M, Laufs U . Effects of statins on endothelium and signalling mechanisms. Stroke 2004; 35: 2708–2711.

    CAS  PubMed  Google Scholar 

  122. Gazzaruso C . Erectile dysfunction and coronary atherothrombosis in diabetic patients: pathophysiology, clinical features and treatment. Expert Rev Cardiovasc Ther 2006; 4: 173–1780.

    CAS  PubMed  Google Scholar 

  123. Kloner RA . Assessment of cardiovascular risk in patients with erectile dysfunction: focus on the diabetic patient. Endocrine 2004; 23: 125–129.

    CAS  PubMed  Google Scholar 

  124. De Angelis L, Marfella MA, Siniscalchi M, Marino L, Nappo F, Giugliano F et al. Erectile and endothelial dysfunction in type II diabetes: a possible link. Diabetologia 2001; 44: 1155–1160.

    CAS  PubMed  Google Scholar 

  125. Zheng H, Fan W, Li G, Tam T . Predictors for erectile dysfunction among diabetics. Diab Res Clin Pract 2005; 71: 313–319.

    Google Scholar 

  126. Cameron NE, Eaton SEM, Cotter MA, Tesfayre S . Vascular factors and metabolic interactions in the pathogenesis of diabetic angiopathy. Diabetologia 2001; 44: 1973–1988.

    CAS  PubMed  Google Scholar 

  127. Burnett AL . Metabolic syndrome, endothelial dysfunction, and erectile dysfunction: association and management. Curr Urol Rep 2005; 6: 470–475.

    PubMed  Google Scholar 

  128. Saenz de Tejada IS, Goldstein I, Azadzoi K, Krane RJ, Cohen RA . Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. New Eng J Med 1989; 320: 1025–1030.

    CAS  PubMed  Google Scholar 

  129. Cartledge JJ, Eardley I, Morrison JFB . Nitric oxide-mediated corpus cavernosal smooth muscle relaxation is impaired in ageing and diabetes. BJU Int 2001; 87: 394–401.

    CAS  PubMed  Google Scholar 

  130. Azadzoi K, Tejada ISD . Diabetes mellitus impairs neurogenic and endothelium dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1992; 148: 1587–1591.

    CAS  PubMed  Google Scholar 

  131. Yildrim S, Ayan S, Sarioglu Y, Gültekin Y, Bütüner C . The effects of long-term oral administration of L-arginine on the erectile response of rabbits with alloxan-induced diabetes. BJU Int 1999; 83: 679–685.

    Google Scholar 

  132. 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.

    CAS  PubMed  Google Scholar 

  133. Thompson C, Mumtaz FH, Khan M, Mikhalidis DP, Wallis RW, Morgna RJ 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.

    CAS  PubMed  Google Scholar 

  134. West IC . Radicals and oxidative stress in diabetes. Diab Med 2000; 17: 171–180.

    CAS  Google Scholar 

  135. Hayden MR, Tyagi SC . Neural redox stress and remodelling in metabolic syndrome, type 2 diabetes and diabetic neuropathy. Med Sci Monit 2004; 10: RA291–RA307.

    CAS  PubMed  Google Scholar 

  136. Khan M, Thompson CS, Jeremy JY, Mumtaz FH, Mikhailidis DP, Morgan RJ . The effect of superoxide dismutase on nitric oxide-mediated and electrical field stimulated diabetic rabbit cavernosal smooth muscle relaxation. BJU Int 2000; 87: 98–103.

    Google Scholar 

  137. 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.

    CAS  Google Scholar 

  138. Vincent AM, McLean LL, Backus C, Feldman EL . Short-term hyperglycemia produces oxidative damage and apoptosis in neurons. FASEB J 2005; 19: 638–640.

    CAS  PubMed  Google Scholar 

  139. Didion SP, Faraci FM . Angiotensin II produces superoxide-mediated impairment of endothelial function in cerebral arterioles. Stroke 2003; 34: 2038–2042.

    CAS  PubMed  Google Scholar 

  140. Coppey LJ, Gellett JS, Davidson EP, Yorek MA . Preventing superoxide formation in epineurial arterioles of the sciatic nerve from diabetic rats restores endothelium-dependent vasodilation. Free Radic Res 2003; 37: 33–40.

    CAS  PubMed  Google Scholar 

  141. Coppey LJ, Gellett JS, Davidson EP, Yorek MA . Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Br J Pharmacol 2001; 134: 21–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Coppey LJ, Davidson EP, Dunlap JA, Lund DD, Yorek MA . Slowing of motor nerve conduction velocity is streptozotocin-induced diabetic rats is preceded by impaired vasodilation in arterioles that overlie the sciatic nerve. Int J Exp Diabetes Res 2000; 1: 131–143.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Cameron NE, Cotter MA, Low PA . Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol 1991; 261: E1–E8.

    CAS  PubMed  Google Scholar 

  144. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA . Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 2001; 50: 1927–1937.

    CAS  PubMed  Google Scholar 

  145. Galili O, Sattler KJ, Herrmann J, Woodrum J, Olson M, Lerman L et al. Experimental hypercholesterolemia differentially affects adventitial vasa vasorum and vessel structure of the left internal thoracic and coronary arteries. J Thorac Cardiovasc Surg 2005; 129: 762–772.

    Google Scholar 

  146. Barker SG, Talbert A, Cottam S, Baskerville PA, Martin JE . Arterial initimal hyperplasia after occlusion of the adventitial vasa vasorum in the pig. Arterioscler Thromb 1993; 13: 70–77.

    CAS  PubMed  Google Scholar 

  147. McCully KS . Homocysteine and vascular disease. Nature Med 1996; 2: 386–389.

    CAS  PubMed  Google Scholar 

  148. Moat SJ, Doshi SN, Lang D, McDowell IWF, Lewis MJ, Goodfellow J . Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol 2004; 287: H1–H7.

    CAS  Google Scholar 

  149. Jones RWA, Jeremy JY, Koupparis A, Persad R, Shukla N . Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia. Br J Urol Int 2005; 95: 125–130.

    Google Scholar 

  150. Kouparris A, Jeremy JY, Angelini GD, Persad R, Shukla N . The administration of penicillamine reverses the inhibitory effect of hyperhomocysteinaemia on carbachol-stimulated relaxation of the rabbit cavernosum. Br J Urol 2006; 98: 440–444.

    Google Scholar 

  151. Loscalzo J . The oxidant stress of hyperhomocysteinaemia. J Clin Invest 1996; 98: 5–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Emsley A, Jeremy JY, Gomes G, Angelini GD, Plane F . Copper interacts with homocysteine to inhibit nitric oxide formation in the rat isolated aorta. Br J Pharmacol 1999; 126: 1034–1040.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Khan M, Thompson CS, Emsley A, Mumtaz F, Mikhailidis D, Angelini G et al. Homocysteine and copper interact to markedly inhibit the relaxation of the rabbit corpus cavernosum. New risk factors for angiopathic erectile dysfunction? Br J Urol 1999; 84: 720–724.

    CAS  Google Scholar 

  154. Shukla N, Thompson C, Angelini GD, Mikhailidis DP, Jeremy JY . Low concentrations of copper augment the impairment of endothelium-dependent relaxation of aortae from diabetic rabbits. Metabolism 2004; 53: 1315–1321.

    CAS  PubMed  Google Scholar 

  155. Shukla N, Maher J, Masters J, Angelini GD, Jeremy JY . Does oxidative stress change ceruloplasmin from a protective to a vasculopathic factor? Atherosclerosis 2006; 187: 238–250.

    CAS  PubMed  Google Scholar 

  156. Shukla N, Angelini GD, Jeremy JY . Homocysteine as a risk factor for nephropathy and retinopathy in type 2 diabetes. Diabetologia 2003; 46: 766–772.

    Google Scholar 

  157. Soinio M, Marniemi J, Laakso M, Lehto S, Ronnema T . Elevated plasma homocysteine levels is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Am J Coll Phys 2004; 140: 94–100.

    Google Scholar 

  158. Dusing R . Sexual dysfunction in male patients with hypertension: influence of antihypertensive drugs. Drugs 2005; 65: 773–786.

    PubMed  Google Scholar 

  159. Agarwal A, Nandipati KC, Sharma RK, Zippe CD, Raina R . Role of oxidative stress in the pathophysiolgy of erection. J Androl 2006; 27: 335–347.

    CAS  PubMed  Google Scholar 

  160. Cifuentes ME, Pagano PJ . Targeting reactive oxygen species in hypertension. Curr Opin Nephrol Hypertens 2006; 15: 179–186.

    CAS  PubMed  Google Scholar 

  161. Ferrario CM, Levy P . Sexual dysfunction in patients with hypertension: implications for therapy. J Clin Hypertens 2002; 4: 424–432.

    Google Scholar 

  162. Fogari R, Zoppi I . Effects of antihypertensive therapy on sexual activity in hypertensive men. Curr Hypertens Rep 203; 4: 202–210.

    Google Scholar 

  163. Van Ahlen H, Wahle K, Kupper W, Yassin A, Reblin T, Neureither M . Safety and efficacy of vardenafil, a selective phosphodiesterase 5 inhibitor, in patients with erectile dysfunction and arterial hypertension treated with multiple antihypertensives. J Sex Med 2005; 2: 856–864.

    CAS  PubMed  Google Scholar 

  164. Parikh P, McDaniel MC, Ashen MD, Joseph I, Miller JI, Sorrentino M et al. Diets and cardiovascular disease. J Am Coll Cardiol 2005; 45: 1379–1387.

    CAS  PubMed  Google Scholar 

  165. Kostis JB, Jackson G, Rosen R, Barrett-Connor E, Kevin Billups K, Burnett AL et al. Sexual dysfunction and cardiac risk (The Second Princeton Concensus Conference). Am J Cardiol 2005; 96: 313–321.

    PubMed  Google Scholar 

  166. Cocores JA, Miller NS, Pottash AC, Gold MS . Sexual dysfunction in abusers of cocaine and alcohol. Am J Drug Alcohol Abuse 1988; 14: 169–173.

    CAS  PubMed  Google Scholar 

  167. Rosen M, Greenfield A, Walker T . Cigarette smoking: an independent risk factor for atherosclerosis in the hypogastric-cavernous arterial bed of men with arteriogenic impotence. J Urol 1991; 145: 759–763.

    CAS  PubMed  Google Scholar 

  168. Shabsigh R, Fishman IJ, Schum C, Dunn JK . Cigarette smoking and other vascular risk factors in vasculogenic impotence. Urology 1991; 38: 227–231.

    CAS  PubMed  Google Scholar 

  169. Jeremy JY, Mikhailidis DP . Smoking and erectile dysfunction. J Roy Soc Health 1998; 118: 151–155.

    CAS  Google Scholar 

  170. Koupparis A, Jeremy JY, Persad R, Angelini GD, Shukla N . Smoking and erectile dysfunction: the role of NADPH oxidase. Br J Urol Int 2004; 94: 257–258.

    Google Scholar 

  171. Azadzoi KM, Goldstein I, Siroky MB, Traish AM, Krane RJ, Saenz de Tejada I . Mechanism of ischemia induced cavernosal smooth muscle cell relaxation in a rabbit model of vasculogenic erectile dysfunction. J Urol 1998; 160: 2216–2222.

    CAS  PubMed  Google Scholar 

  172. Azadzoi KM, Krane RJ, Sanz de Tajeda I, Goldstein I, Siroky MB . Relative roles of cyclooxygenase and nitric oxide synthase pathways in ischemia induced increased contraction of cavernosal smooth muscle. J Urol 1999; 161: 1324–1328.

    CAS  PubMed  Google Scholar 

  173. Azadzoi KM, Master TA, Siroky MB . Effect of chronic ischemia on constitutive and inducible nitric oxide synthase expression in erectile tissue. J Androl 2004; 25: 282–388.

    Google Scholar 

  174. Kim N, Vardi Y, Padma-Nathan H, Goldstein I, Saenz de Tejada I . Oxygen tension regulates the nitric oxide pathway: physiological role in penile erection. J Clin Invest 1993; 91: 437–442.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Moreland R . Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence. Int J Impot Res 1998; 10: 113–120.

    CAS  PubMed  Google Scholar 

  176. Knipsel H, Andresen R . Evaluation of vasculogenic impotence by monitoring of cavernous oxygen tension. J Urol 1993; 149: 1276–1282.

    Google Scholar 

  177. Ikeda E . Cellular responses to tissue hypoxia and its involvement in disease progression. Pathol Int 2005; 55: 603–610.

    CAS  PubMed  Google Scholar 

  178. Bertuglia S, Giusti A . Microvascular oxygenation, oxidative stress, NO suppression and superoxide dismutase during postischemic reperfusion. Am J Physiol Heart Circ Physiol 2003; 285: H1064–H1071.

    CAS  PubMed  Google Scholar 

  179. Bremer YA, Salloum F, Ockaili R, Chou E, Moskowiotz WB, Kukreja RC . Sildenafil citrate (viagra) induces cardioprotective effects after ischemia/reperfusion injury in infant rabbits. Pediatr Res 2005; 57: 22–27.

    CAS  PubMed  Google Scholar 

  180. Semple PD, Beastall GH, Brown TM, Semple GC . Sex hormone suppression and sexual impotence in hypoxic pulmonary fibrosis. Sexual dysfunction and erectile impotence in chronic obstructive pulmonary disease. Thorax 1984; 39: 46–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Aasebo U, Gyltnes A, Bremnes RM, Aakvaag A, Slordal L . Reversal of sexual impotence in male patients with chronic obstructive pulmonary disease and hypoxaemia with long term oxygen therapy. J Steroid Biochem Med Biol 1993; 46: 799–803.

    CAS  Google Scholar 

  182. Jeremy JY, Mikhailidis DP . Prostaglandins and the penis: possible role in impotence. Sex Marital Ther 1990; 5: 155–165.

    Google Scholar 

  183. Jeremy JY, Mikhailidis DP . Prostanoids and impotence: aetiological and therapeutic implications. Br J Sex Med 1989; 16: 411–415.

    Google Scholar 

  184. Jeremy JY, Mikhailidis DP . Prostaglandins and the aetiology and treatment of erectile dysfunction. In: Ledda A (ed). Vascular Andrology. Springer Verlag: Berlin, 1996, pp 19–28.

    Google Scholar 

  185. Urciuoli R, Cantisani TA, Carlini IM, Giuglietti M, Botti FM . Prostaglandin E1 for treatment of erectile dysfunction. Cochraen Dataabase Syst Rev 2004; (2): CD001784.

  186. Jeremy JY, Mehta D, Bryan AJ, Lewis D, Angelini GD . Platelets, oxidant stress and erectile dysfunction: an hypothesis. Cardiovasc Res 2000; 46: 50–54.

    CAS  PubMed  Google Scholar 

  187. Jeremy JY, Mikhailidis DP, Thompson CS, Dandona P . Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: pathological implications. Diabetologia 1985; 28: 365–368.

    CAS  PubMed  Google Scholar 

  188. Jeremy JY, Mikhailidis DP, Thompson CS, Dandona P . The effect of cigarette smoke and diabetes mellitus on muscarinic stimulation of prostacyclin synthesis by the rat penis. Diab Res 1986; 3: 467–469.

    CAS  Google Scholar 

  189. Jeremy JY, Thompson CS, Barradas MA, Dandona P . Duration and not severity determines effects on prostacyclin synthesis in the rat aorta, penis and bladder. Prog Lipid Res 1986; 25: 505–507.

    Google Scholar 

  190. Jeremy JY, Morgan RJ, Mikhailidis DP, Dandona P . Prostacyclin synthesis by the corpora cavernosa of the human penis: evidence for muscarinic control. Prostagl Leuk Med 1986; 23: 211–216.

    CAS  Google Scholar 

  191. Jeremy JY, Mikhailidis DP, Dandona P . Muscarinic stimulation of prostacyclin synthesis by the rat penis. Eur J Pharmacol 1986; 123: 67–71.

    CAS  PubMed  Google Scholar 

  192. Fink AN, Frishman WH, Azizad M, Agarwal Y . Use of prostacyclin and its analogues in the treatment of cardiovascular disease. Heart Dis 1999; 1: 29–40.

    CAS  PubMed  Google Scholar 

  193. Ueno Y, Koike H, Nakamura Y, Ochi Y, Annoh S, Nishio S . Effects of beraprost sodium, a prostacyclin analogue, on diabetic neuropathy in streptozotocin-induced diabetic rats. Jpn J Pharmacol 1996; 70: 177–182.

    CAS  PubMed  Google Scholar 

  194. Ono Y, Katoh M, Hirayma A, Koike T . Improvement in blood flow and diabetic neuropathy by thromboxane A2 dual blocker KDI-792. Prostagl Leukot Essent Fatty Acids 1995; 53: 139–145.

    CAS  Google Scholar 

  195. Dines KC, Cotter MA, Cameron NE . Effectiveness of natural oils as sources of gamma-linolenic acid to correct peripheral nerve conduction velocity abnormalities in diabetic rats: modulation by thromboxane A2 inhibition. Prostagl Leukot Essent Fatty Acids 1996; 55: 159–165.

    CAS  Google Scholar 

  196. Morrow JD, Roberts LJ . The isoprostanes: their role as an index of oxidant stress status in human pulmonary disease. Am J Respir Crit Care Med 2002; 166: S25–S30.

    PubMed  Google Scholar 

  197. Hayden MR, Tyagi SC . Neural redox stress and remodelling in metabolic syndrome, type 2 diabetes and diabetic neuropathy. Med Sci Monit 2004; 10: RA291–RA307.

    CAS  PubMed  Google Scholar 

  198. Vincent AM, McLean LL, Backus C, Feldman EL . Short-term hyperglycemia produces oxidative damage and apoptosis in neurons. FASEB J 2005; 19: 638–640.

    CAS  PubMed  Google Scholar 

  199. Mander P, Brown GC . Activation of microglial NADPH oxidase is synergistic with glial iNOS : a dual key mechanism of inflammatory neurodgeneration. J Neuroinflamm 2005; 2: 2–20.

    Google Scholar 

  200. Dai X, Cao X, Kreulen DL . Superoxide anion is elevated in sympathetic neurons in DOCA salt hypertension via activation of NADPH oxidase. Am J Physiol 2006; 290: H1019–H1026.

    CAS  Google Scholar 

  201. Cameron NE, Cotter MA, Low PA . Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol 1991; 261: E1–E8.

    CAS  PubMed  Google Scholar 

  202. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA . Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 2001; 50: 1927–1937.

    CAS  PubMed  Google Scholar 

  203. Low PA, Nickander KK . Oxygen free radical effects in sciatic nerve in experimental diabetes. Diabetes 1991; 40: 873–877.

    CAS  PubMed  Google Scholar 

  204. Gocmen C, Secilmis A, Kumcu EK, Ertu PU, nder S, Dikmen A 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.

    CAS  PubMed  Google Scholar 

  205. 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.

    CAS  PubMed  Google Scholar 

  206. Keegan A, Cotter MA, Cameron NE . Corpus cavernosum dysfunction in diabetic rats: effects of combined alpha-lipoic acid and gamma-linoleic acid treatment. Diabetes Metab Res Rev 2001; 17: 380–386.

    CAS  PubMed  Google Scholar 

  207. Keegan A, Cotter MA, Cameron NE . Effects of chelator treatment on aorta and corpus cavernosum from diabetic rats. Free Rad Biol Med 1999; 27: 536–543.

    CAS  PubMed  Google Scholar 

  208. Keaney JF, Xu A, Cunningham D, Jackson J, Frei B, Vita JA et al. Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest 1995; 195: 2520–2529.

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  212. Jiang F, Drummond GR, Dusting GJ . Suppression of oxidative stress in endothelial and vascular wall. Endothelium 2004; 111: 79–88.

    Google Scholar 

  213. Freyhaus HT, Huuntgeburth M, Wingler K, Schnitker J, Baumer A, Vantler M et al. Inhibition of ROS liberation by the novel Nox inhibitor VAS2870 attenuates PDGF dependent migration but not proliferation in vascular smooth muscle cells. Cardiovasc Res 2006; 71: 331–341.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiac Surgery, Bristol Heart Institute, Bristol Royal Infirmary, The University of Bristol, Bristol, UK

    J Y Jeremy, R A Jones, A J Koupparis, M Hotston, R Persad, G D Angelini & N Shukla

Authors
  1. J Y Jeremy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R A Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A J Koupparis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Hotston
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Persad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G D Angelini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Y Jeremy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jeremy, J., Jones, R., Koupparis, A. et al. Reactive oxygen species and erectile dysfunction: possible role of NADPH oxidase. Int J Impot Res 19, 265–280 (2007). https://doi.org/10.1038/sj.ijir.3901523

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijir.3901523

Keywords

This article is cited by

Search

Advanced search

Quick links