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Therapeutic effects of the putative P2X3/P2X2/3 antagonist A-317491 on cyclophosphamide-induced cystitis in rats

  • Katsuaki ItoEmail author
  • Akihito Iwami
  • Hiromi Katsura
  • Masahiro Ikeda
Original Article

Abstract

It is suggested that ATP and purinergic P2X receptors are involved in overactive bladder. In this study, we investigated the effect of the recently developed P2X3 and P2X2/3 receptor antagonist A-317491 on cyclophosphamide (CYP)-induced cystitis to determine whether a P2X receptor antagonist could be beneficial for the treatment of bladder overactivity induced by CYP. Female Sprague–Dawley (SD) rats were given 150 mg/kg CYP (i.p.). When the micturition activity was observed for 24 h in a conscious and unrestrained condition, CYP-treated rats exhibited increased urinary frequency. Two days after CYP injection, cystometry was performed in conscious rats, in which the bladder was continuously infused with saline (5 ml/h). In CYP-treated rats, non-voiding contractions were interposed between micturitions, suggestive of hyper-reflexia. Intravenous administration of A-317491 (20 or 50 mg/kg) or pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid) tetrasodium (PPADS; a nonselective purinergic receptor antagonist, 10 mg/kg) prolonged the interval of voiding contraction and reduced the non-voiding contractions. On the other hand, oxybutynin (1 mg/kg), a muscarinic receptor antagonist, did not affect the frequency of non-voiding or voiding contractions in CYP-treated rats. A-317491 at the higher dose decreased the amplitude of voiding contractions, but increased the micturition volume. The residual urine in the bladder increased after treatment with CYP; A-317491 and PPADS reduced this, whereas oxybutynin had no effect. These data suggest that A-317491 is effective at improving the signs of CYP-induced cystitis and that the P2X3 or P2X2/3 receptor pathway is involved in bladder overactivity observed during CYP-induced cystitis.

Keywords

Bladder Cyclophosphamide Cystitis A-317391 P2X receptor Cystometry Oxybutynin Urinary frequency 

References

  1. Andersson K-E, Hedlund P (2002) Pharmacologic perspective on the physiology of the lower urinary tract. Urology 60:13–20PubMedCrossRefGoogle Scholar
  2. Angelico P, Velasco C, Guarneri L, Sironi G, Leonardi A, Testa R (2005) Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions. BMC Pharmacol 5:14PubMedCrossRefGoogle Scholar
  3. Birder LA, Ruan HZ, Chopra B, Xiang Z, Barrick S, Buffington CA, Roppolo JR, Ford APDW, de Groat WC, Burnstock G (2004) Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis. Am J Physiol 287:F1084–F1091CrossRefGoogle Scholar
  4. Borvendeg SJ, Al-Khrasani M, Rubini P, Fischer W, Allgaier C, Wirkner K, Himmel HM, Gillen C, Illes P (2003) Subsensitivity of P2X but not vanilloid 1 receptors in dorsal root ganglia of rats caused by cyclophosphamide cystitis. Eur J Pharmacol 474:71–75PubMedCrossRefGoogle Scholar
  5. Brady CM, Apostolidis A, Yiangou Y, Baecker PA, Ford AP, Freeman A, Jacques TS, Fowler CJAnand P (2004) P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol 46:247–253PubMedCrossRefGoogle Scholar
  6. Chopra B, Barrick SR, Meyers S, Beckel JM, Zeidel ML, Ford APDW, de Groat WC, Birder LA (2005) Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium. J Physiol (Lond) 562:859–871CrossRefGoogle Scholar
  7. Cockayne DA, Hamilton SG, Zhu Q-M, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford APDW (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407:1011–1015PubMedCrossRefGoogle Scholar
  8. Cruz F (2004) Mechanisms involved in new therapies for overactive bladder. Urology 63:65–73PubMedCrossRefGoogle Scholar
  9. de Groat WC (2006) Integrative control of the lower urinary tract: preclinical perspective. Br J Pharmacol 147:S25–S40PubMedCrossRefGoogle Scholar
  10. Ford APDW, Gever JR, Nunn PA, Zhong Y, Cefalu JS, Dillon MP, Cockayne DA (2006) Purinoceptors as therapeutic targets for lower urinary tract dysfunction. Br J Pharmacol 147:S132–S143PubMedCrossRefGoogle Scholar
  11. Hedlund P, Streng T, Lee T, Andersson K-E (2007) Effects of tolterodine on afferent neurotransmission in normal and resiniferatoxin treated conscious rats. J Urol 178:326–331PubMedCrossRefGoogle Scholar
  12. Hu VY, Malley S, Dattilio A, Folsom JB, Zvara P, Vizzard MA (2003) COX-2 and prostanoid expression in micturition pathways after cyclophosphamide-induced cystitis in the rat. Am J Physiol 284:R574–R585Google Scholar
  13. Jarvis MF, Burgard EC, McGaraughty S, Honore P, Lynch K, Brennan TJ, Subieta A, van Biesen T, Cartmell J, Bianchi B, Niforatos W, Kage K, Yu H, Mikusa J, Wismer CT, Zhu CZ, Chu K, Lee C-H, Stewart AO, Polakowski JS, Cox BF, Kowaluk E, Williams M, Sullivan JP, Faltynek C (2002) A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc Natl Acad Sci USA 99:17179–17184PubMedCrossRefGoogle Scholar
  14. Jarvis MF, Bianchi B, Uchic JT, Cartmell J, Lee C-H, Williams M, Faltynek C (2004) [3H]A-317491, a novel high-affinity non-nucleotide antagonist that specifically labels human P2X2/3 and P2X3 receptors. J Pharmacol Exp Ther 310:407–416PubMedCrossRefGoogle Scholar
  15. Lewis CNS, Holy C, North RA, Buell G, Surprenant A (1995) Co-expression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 377:432–435PubMedCrossRefGoogle Scholar
  16. Million M, Wang L, Stenzel-Poore MP, Coste SC, Yuan PQ, Lamy C, Rivier J, Buffington T, Tache Y (2007) Enhanced pelvic responses to stressors in female CRF-overexpressing mice. Am J Physiol 292:R1429–R1438Google Scholar
  17. Modiri A-R, Alberts P, Gillberg P-G (2002) Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats. Urology 59:963–968PubMedCrossRefGoogle Scholar
  18. Nazif O, Teichman JMH, Gebhart GF (2007) Neural upregulation in interstitial cystitis. Urology 69:S24–S33CrossRefGoogle Scholar
  19. Nishiguchi J, Hayashi Y, Chancellor MB, de Miguel F, de Groat WC, Kumon H, Yoshimura N (2005) Detrusor overactivity induced by intravesical application of adenosine 5′-triphosphate under different delivery conditions in rats. Urology 66:1332–1337PubMedCrossRefGoogle Scholar
  20. Pandita RK, Andersson KE (2002) Intravesical adenosine triphosphate stimulates the micturition reflex in awake, freely moving rats. J Urol 168:1230–1234PubMedCrossRefGoogle Scholar
  21. Pinna C, Sanvito P, Bolego C, Cignarella A, Puglisi L (2005) Effect of the ATP-sensitive potassium channel opener ZM226600 on cystometric parameters in rats with ligature-intact, partial urethral obstruction. Eur J Pharmacol 516:71–77PubMedCrossRefGoogle Scholar
  22. Rapp DE, Lyon MB, Bales GT, Cook SP (2005) A role for the P2X receptor in urinary tract physiology and in the pathophysiology of urinary dysfunction. Eur Urol 48:303–308PubMedCrossRefGoogle Scholar
  23. Rong W, Spyer KM, Burnstock G (2002) Activation and sensitisation of low and high threshold afferent fibres mediated by P2X receptors in the mouse urinary bladder. J Physiol (Lond) 541:591–600CrossRefGoogle Scholar
  24. Ruggieri MR (2006) Mechanisms of disease: role of purinergic signaling in the pathophysiology of bladder dysfunction. Nature Clin Pract Urol 3:206–215CrossRefGoogle Scholar
  25. Smith CP, Vemulakonda VM, Kiss S, Boone TB, Somogyi GT (2005) Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A. Neurochem Int 47:291–297PubMedCrossRefGoogle Scholar
  26. Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R, Carpenter K, Dickenson A, Boyce S, Hill R, Nebenius-Oosthuizen D, Smith AJH, Kidd EJ, Wood JN (2000) Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407:1015–1017PubMedCrossRefGoogle Scholar
  27. Suzuki M, Ohtake A, Yoshino T, Yuyama H, Hayashi A, Ukai M, Okutsu H, Noguchi Y, Sato S, Sasamata M (2005) Effects of solifenacin succinate (YM905) on detrusor overactivity in conscious cerebral infarcted rats. Eur J Pharmacol 512:61–66PubMedCrossRefGoogle Scholar
  28. Tsukimi Y, Mizuyachi K, Matsumoto H, Sato M, Ng B, Tajimi M (2004) Mechanism of action by which aspirin alleviates detrusor hyperactivity in rats. J Pharmacol Sci 95:101–107PubMedCrossRefGoogle Scholar
  29. Wu G, Whiteside GT, Lee G, Nolan S, Niosi M, Pearson MS, Ilyin VI (2004) A-317491, a selective P2X3/P2X2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats. Eur J Pharmacol 504:45–53PubMedCrossRefGoogle Scholar
  30. Yoshimura N, de Groat WC (1999) Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation. J Neurosci 19:4644–4653PubMedGoogle Scholar
  31. Zhong Y, Banning AS, Cockayne DA, Ford APDW, Burnstock G, McMahon SB (2003) Bladder and cutaneous sensory neurons of the rat express different functional P2X receptors. Neuroscience 120:667–675PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Katsuaki Ito
    • 1
    Email author
  • Akihito Iwami
    • 1
  • Hiromi Katsura
    • 1
  • Masahiro Ikeda
    • 1
  1. 1.Department of Veterinary Pharmacology, Faculty of AgricultureUniversity of MiyazakiMiyazakiJapan

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