World Journal of Urology

, Volume 31, Issue 3, pp 653–658 | Cite as

Nutritional supplementation with l-arginine prevents pelvic radiation-induced changes in morphology, density, and regulating factors of blood vessels in the wall of rat bladder

  • Waldemar S. Costa
  • Monica N. Ribeiro
  • Luiz E. M. Cardoso
  • Maria C. Dornas
  • Cristiane F. Ramos
  • Carla B. M. Gallo
  • Francisco J. B. SampaioEmail author
Original Article



To determine whether l-arginine has protective effects against radiation-induced alterations in the morphology and regulatory factors of vesical blood vessels in rats.


Male rats aged 3–4 months were divided into groups of 10 animals each: (a) controls, consisting of non-treated animals; (b) radiated-only rats; and (c) radiated rats receiving l-arginine supplementation. Radiation was in one session of 10 Gy and was aimed at the pelvic-abdominal region. l-arginine was administered once a day (0.65 g/kg body weight), starting 7 days before radiation and continuing until killing on the 16th day after radiation. The density, relative area, and wall thickness of blood vessels were measured in the vesical lamina propria using histological methods, and the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGF) in the bladder wall was assessed by RT-PCR.


Compared with controls, radiation alone decreased the density and relative area of blood vessels by 32 % (p < 0.01) and 25 % (p < 0.05), respectively, and reduced the arterial wall thickness by 42 % (p < 0.004). VEGF and FGF mRNA levels after radiation were diminished by 67 % (p < 0.002) and 56 % (p < 0.04), respectively. The radiated animals supplemented with l-arginine were not significantly different from controls.


Pelvic radiation leads to significant vesical modifications, as in the morphology of blood vessels and in VEGF and FGF expression. All these changes, however, were prevented by l-arginine treatment. These results emphasize, therefore, the potential use of this amino acid as a radioprotective drug.


Bladder Radiotherapy Blood vessels l-arginine 



This study received grants from the National Council of Scientific and Technological Development (CNPq), Foundation for Research Support of Rio de Janeiro (FAPERJ), and Coordination for the Improvement of Higher Education Personnel (CAPES), Brazil.

Conflict of interest



  1. 1.
    Turina M, Mulhall AM, Mahid SS, Yashar C, Galandiuk S (2008) Frequency and surgical management of chronic complications related to pelvic radiation. Arch Surg 143:46–52PubMedCrossRefGoogle Scholar
  2. 2.
    Marks LB, Carroll PR, Dugan TC, Anscher MS (1995) The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys 31:1257–1280PubMedCrossRefGoogle Scholar
  3. 3.
    Pavlidakey PG, MacLennan GT (2009) Radiation cystitis. J Urol 182:1172–1173PubMedCrossRefGoogle Scholar
  4. 4.
    Walz J, Marcy M, Pianna JT, Brunelle S, Gravis G, Salem N, Bladou F (2011) Identification of the prostate cancer index lesion by real-time elastography: considerations for focal therapy of prostate cancer. World J Urol 29:589–594PubMedCrossRefGoogle Scholar
  5. 5.
    Elliott SP, Malaeb BS (2011) Long-term urinary adverse effects of pelvic radiotherapy. World J Urol 29:35–41PubMedCrossRefGoogle Scholar
  6. 6.
    Jaal J, Dorr W (2006) Radiation induced late damage to the barrier function of small blood vessels in mouse bladder. J Urol 176:2696–2700PubMedCrossRefGoogle Scholar
  7. 7.
    Kruse JJ, te Poele JA, Russell NS, Boersma LJ, Stewart FA (2004) Microarray analysis to identify molecular mechanisms of radiation-induced microvascular damage in normal tissues. Int J Radiat Oncol Biol Phys 58:420–426PubMedCrossRefGoogle Scholar
  8. 8.
    Rodemann HP, Blaese MA (2007) Responses of normal cells to ionizing radiation. Semin Radiat Oncol 17:81–88PubMedCrossRefGoogle Scholar
  9. 9.
    Ersin S, Tuncyurek P, Esassolak M, Alkanat M, Buke C, Yilmaz M, Telefoncu A, Kose T (2000) The prophylactic and therapeutic effects of glutamine- and arginine-enriched diets on radiation-induced enteritis in rats. J Surg Res 89:121–125PubMedCrossRefGoogle Scholar
  10. 10.
    de Aguiar Picanço E, Lopes-Paulo F, Marques RG, Diestel CF, Caetano CE, de Souza MV, Moscoso GM, Pazos HM (2011) l-arginine and glycine supplementation in the repair of the irradiated colonic wall of rats. Int J Colorectal Dis 26:561–568CrossRefGoogle Scholar
  11. 11.
    Zhan Z, Ou D, Piao X, Kim SW, Liu Y, Wang J (2008) Dietary arginine supplementation affects microvascular development in the small intestine of early-weaned pigs. J Nutr 138:1304–1309PubMedGoogle Scholar
  12. 12.
    Mackenzie IS, Rutherford D, MacDonald TM (2008) Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis. Arthritis Res Ther. 10(Suppl 2):S3PubMedCrossRefGoogle Scholar
  13. 13.
    Isidori A, Lo Monaco A, Cappa M (1981) A study of growth hormone release in man after oral administration of amino acids. Curr Med Res Opin 7:475–481PubMedCrossRefGoogle Scholar
  14. 14.
    Bode-Boger SM, Boger RH, Galland A, Tsikas D, Frolich JC (1998) l-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol 46:489–497PubMedCrossRefGoogle Scholar
  15. 15.
    Hossler FE, Monson FC (1995) Microvasculature of the rabbit urinary bladder. Anat Rec 243:438–448PubMedCrossRefGoogle Scholar
  16. 16.
    Jaal J, Dorr W (2006) Radiation-induced damage to mouse urothelial barrier. Radiother Oncol 80:250–256PubMedCrossRefGoogle Scholar
  17. 17.
    Montes GS (1996) Structural biology of the fibres of the collagenous and elastic systems. Cell Biol Int 20:15–27PubMedCrossRefGoogle Scholar
  18. 18.
    Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sorensen FB, Vesterby A et al (1988) Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. Apmis 96:379–394PubMedCrossRefGoogle Scholar
  19. 19.
    de Souza DB, Silva D, Cortez CM, Costa WS, Sampaio FJ (2012) Effects of chronic stress on penile corpus cavernosum of rats. J Androl 33:735–739PubMedCrossRefGoogle Scholar
  20. 20.
    Milliat F, Francois A, Tamarat R, Benderitter M (2008) Role of endothelium in radiation-induced normal tissue damages. Ann Cardiol Angeiol 57:139–148CrossRefGoogle Scholar
  21. 21.
    Youssif M, Shiina H, Urakami S, Gleason C, Nunes L, Igawa M, Enokida H, Tanagho EA, Dahiya R (2005) Effect of vascular endothelial growth factor on regeneration of bladder acellular matrix graft: histologic and functional evaluation. Urology 66:201–207PubMedCrossRefGoogle Scholar
  22. 22.
    Benest AV, Stone OA, Miller WH, Glover CP, Uney JB, Baker AH, Harper SJ, Bates DO (2008) Arteriolar genesis and angiogenesis induced by endothelial nitric oxide synthase overexpression results in a mature vasculature. Arterioscler Thromb Vasc Biol 28:1462–1468PubMedCrossRefGoogle Scholar
  23. 23.
    Schierling W, Troidl K, Troidl C, Schmitz-Rixen T, Schaper W, Eitenmuller IK (2009) The role of angiogenic growth factors in arteriogenesis. J Vasc Res 46:365–374PubMedCrossRefGoogle Scholar
  24. 24.
    Al-Abbasi DS, Al-Janabi AA, Al-Toriahi KM, Jabor TA, Yasseen AA (2009) Expression of VEGF in urinary bladder transitional cell carcinoma in an Iraqi population subjected to depleted uranium: an immunohistochemical study. Appl Immunohistochem Mol Morphol 17:307–311PubMedCrossRefGoogle Scholar
  25. 25.
    Hwang JM, Chan DC, Chang TM, Tsao TY, Tsou SS, Lu RH, Tsai LM (2003) Effects of oral arginine and glutamine on radiation-induced injury in the rat. J Surg Res 109:149–154PubMedCrossRefGoogle Scholar
  26. 26.
    Hagiwara A, Nakayama F, Motomura K, Asada M, Suzuki M, Imamura T, Akashi M (2009) Comparison of expression profiles of several fibroblast growth factor receptors in the mouse jejunum: suggestive evidence for a differential radioprotective effect among major FGF family members and the potency of FGF1. Radiat Res 172:58–65PubMedCrossRefGoogle Scholar
  27. 27.
    Tattini C, Manchio J, Zaporojan V, Carderelli G, Bonassar L, Spangenberger A, Weinzweig J (2008) Role of TGF-beta and FGF in the treatment of radiation-impaired wounds using a novel drug delivery system. Plast Reconstr Surg 122:1036–1045PubMedCrossRefGoogle Scholar
  28. 28.
    Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253PubMedCrossRefGoogle Scholar
  29. 29.
    Murakami M, Nguyen LT, Zhuang ZW, Moodie KL, Carmeliet P, Stan RV, Simons M (2008) The FGF system has a key role in regulating vascular integrity. J Clin Invest 118:3355–3366PubMedCrossRefGoogle Scholar
  30. 30.
    Boodhwani M, Voisine P, Ruel M, Sodha NR, Feng J, Xu SH, Bianchi C, Sellke FW (2008) Comparison of vascular endothelial growth factor and fibroblast growth factor-2 in a swine model of endothelial dysfunction. Eur J Cardiothorac Surg 33:645–650PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Waldemar S. Costa
    • 1
  • Monica N. Ribeiro
    • 1
  • Luiz E. M. Cardoso
    • 1
  • Maria C. Dornas
    • 1
  • Cristiane F. Ramos
    • 1
  • Carla B. M. Gallo
    • 1
  • Francisco J. B. Sampaio
    • 1
    Email author
  1. 1.Urogenital Research UnitState University of Rio de JaneiroRio de JaneiroBrazil

Personalised recommendations