Cell and Tissue Research

, Volume 314, Issue 3, pp 351–359 | Cite as

Loss of purinergic P2X receptor innervation in human detrusor and subepithelium from adults with sensory urgency

  • Fiona R. Ray
  • Kate H. Moore
  • Mitchell A. Hansen
  • Julian A. Barden
Regular Article

Abstract

Purinergic P2X receptors associated with the parasympathetic nerves supplying human bladder smooth muscle (detrusor) are implicated in control of detrusor contractility. The relative abundance of all seven subtypes colocalised with synaptic vesicles on parasympathetic nerves was examined in specimens from normal adult bladder and in adults with the urodynamics findings of sensory urgency (SU) to determine how receptor distribution varied in patients with a small bladder capacity. Alteration in control of detrusor innervation was examined with P2X subtype-specific antibodies and an antibody (SV2) against synaptic vesicles, using immunofluorescence and confocal microscopy. Detrusor samples were taken from: controls, at cystectomy for cancer or cystoscopic biopsy for haematuria (n=22, age 33–88 years) and adults with sensory urgency at cystoscopy/cystodistension (n=11, age 37–70 years). Normal adult specimens contained detrusor muscle innervated by parasympathetic nerves possessing large varicosities (1.2 μm) distributed along their length. These mostly all showed colocalised patches of presynaptic P2X1,2,3,5 subtypes while presynaptic subtypes P2X4,6,7 were present in only 6–18% of varicosities. Detrusor nerve varicosities from SU patients revealed general loss of all presynaptic P2X subtypes with the proportion containing receptors reducing to only 0.5–5% depending on P2X subtype. The same loss was recorded from the sensory nerves in the surrounding lamina propria. This specific loss of P2X receptors may impair control of detrusor distension and contribute to the pathophysiology of sensory urgency.

Keywords

Purinergic P2X receptors Hypertonia Human urinary incontinence sensory urgency Innervation SU bladder Human 

References

  1. Abrams P (1997) Patient assessment. In: Urodynamics, Chap 4. Springer, London, pp 127–129Google Scholar
  2. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A (2002) The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol Urodyn 21:167–178CrossRefPubMedGoogle Scholar
  3. Barajas-Lopez C, Espinosa-Luna R, Zhu Y (1998) Functional interactions between nicotinic and P2X channels in short-term cultures of guinea-pig submucosal neurons. J Physiol (Lond) 513:671–683Google Scholar
  4. Barden JA, Cottee LJ, Bennett MR (1999) Vesicle-associated proteins and P2X receptor clusters at single sympathetic varicosities in mouse vas deferens. J Neurocytol 28:469–480CrossRefPubMedGoogle Scholar
  5. Barden JA, Sluyter R, Gu BJ, Wiley JS (2003) Specific detection of non-functional P2X7 receptors in HEK293 cells and B-lymphocytes. FEBS Lett 538:159–162CrossRefPubMedGoogle Scholar
  6. Bayliss M, Wu C, Newgreen D, Mundy AR, Fry CH (1999) A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol 162:1833–1839PubMedGoogle Scholar
  7. Bo X, Burnstock G (1995) Characterization and autoradiographic localisation of [3H] alpha, beta-methylene adenosine 5’-triphosphate binding sites in human urinary bladder. Br J Urol 76:297–302PubMedGoogle Scholar
  8. Boehm S (1999) ATP stimulates sympathetic transmitter release via presynaptic P2X purinoceptors. J Neurosci 19:737–746PubMedGoogle Scholar
  9. Bolego C, Pinna C, Abbracchio MP, Cattabeni F, Puglisi L (1995) The biphasic response of rat vesical smooth muscle to ATP. Br J Pharmacol 114:1557–1562PubMedGoogle Scholar
  10. Bower WF, Moore KH, Shepherd RB, Adams R (1996) The epidemiology of childhood enuresis in Australia. Br J Urol 78:602–606PubMedGoogle Scholar
  11. Brading AF, Inoue R (1991) Ion channels and excitatory transmission in the smooth muscle of the urinary bladder. Zeit Kardiol 80 (Suppl 7):47–53Google Scholar
  12. Brown C, Burnstock G, Cocks T (1979) Effects of adenosine 5’-triphosphate (ATP) and β, γ-methylene ATP on the rat urinary bladder. Br J Pharmacol 65:97–102PubMedGoogle Scholar
  13. Burnstock G, Cocks T, Kasakov L, Wong HK (1978) Direct evidence for ATP release from non-adrenergic, non-cholinergic (“purinergic”) nerves in the guinea-pig taenia coli and bladder. Eur J Pharmacol 49:145–149CrossRefPubMedGoogle Scholar
  14. 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 407:1011–1015CrossRefPubMedGoogle Scholar
  15. Dutton JE, Hansen MA, Barden JA, Bennett MR (1999) Development of the distribution of single P2X homomeric and heteromeric receptor clusters on smooth muscle cells in relation to nerve varicosities in the rat urinary bladder. J Neurocytol 28:3–15Google Scholar
  16. Evans RJ, Lewis C, Virginio C, Lundstrom K, Buell G, Surprenant A, North RA (1996) Ionic permeability of, and divalent cation effects on, two ATP-gated cation channels (P2X receptors) expressed in mammalian cells. J Physiol 497:413–422PubMedGoogle Scholar
  17. Gosling JA, Dixon JS (1975) The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra. Br J Urol 47:549–558PubMedGoogle Scholar
  18. Hansen MA, Balcar VJ, Barden JA, Bennett MR (1998) The distribution of single P2X1-receptor clusters on smooth muscle in relation to nerve varicosities in the rat urinary bladder. J Neurocytol 27:529–539CrossRefPubMedGoogle Scholar
  19. Hay-Smith J, Herbison P, Ellis G, Moore K (2002) Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev 3:CD003781Google Scholar
  20. Hunskar S, Arnold EP, Burgio K, Diokno AC, Herzog AR, Mallett VT (2000) Epidemiology and natural history of urinary incontinence: review article. Int Urogynacol J 11:301–319CrossRefGoogle Scholar
  21. Kukley M, Barden JA, Steinhäuser C, Jabs R (2001) Distribution of P2X receptors on astrocytes in juvenile rat hippocampus. Glia 36:11–21CrossRefPubMedGoogle Scholar
  22. Lee H, Bardini M, Burnstock G (2000) Distribution of P2X receptors in the urinary bladder and the ureter of the rat. J Urol 163:2002–2007PubMedGoogle Scholar
  23. Longhurst PA, Schwegel T, Folander K, Swanson R (1996) The human P2X1 receptor: molecular cloning, tissue distribution, and localisation to chromosome 17. Biochim Biophys Acta 1308:185–188CrossRefPubMedGoogle Scholar
  24. Moore KH (1999) Detrusor instability in the female: controversies in diagnosis, etiology and management. Crit Rev Phys Rehab Med 11:35–61Google Scholar
  25. Moore KH, Gilpin SA, Dixon JS, Richmond DH, Sutherst JR (1992) An increase of presumptive sensory nerves of the urinary bladder in idiopathic detrusor instability. Br J Urol 70:370–372PubMedGoogle Scholar
  26. Moore KH, Ray FR, Barden JA (2001) Loss of purinergic P2X3 and P2X5 receptor innervation in human detrusor from adults with urge incontinence. J Neurosci 21:U17–U22Google Scholar
  27. Nakazawa K (1998) ATP-activated current and its interaction with acetylcholine-activated current in rat sympathetic neurons. J Neurosci 14:740–750Google Scholar
  28. O’Reilly BA, Kosaka AH, Chang TK, Ford APDW, Popert R, McMahon SB (2001) A quantitative analysis of purinoceptors expression in the bladders of patients with symptomatic outlet obstruction. BJU Int 87:617–622CrossRefPubMedGoogle Scholar
  29. O’Reilly BA, Kosaka AH, Knight GF, Chang TK, Ford APDW, Rymer JM, Popert R, Burnstock G, McMahon SB (2002) P2X receptors and their role in female idiotypic detrusor instability. J Urol 167:157–164PubMedGoogle Scholar
  30. Searl TJ, Redman RS, Silinsky EM (1998) Mutual occlusion of P2X ATP receptors and nicotinic receptors on sympathetic neurons of the guinea-pig. J Physiol (Lond) 510:783–791Google Scholar
  31. Smet P, Moore KH, Jonavicius J (1997) Distribution and colocalisation of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder. Lab Invest 77:37–49PubMedGoogle Scholar
  32. Sperlagh B, Erdelyi F, Szabo G, Vizi ES (2000) Local regulation of [3H]-noradrenaline release from the isolated guinea-pig right atrium by P2X-receptors located on the axon terminals. Br J Pharmacol 131:1775–1783PubMedGoogle Scholar
  33. Tagliani M, Candura SM, Di Nucci A, Franceschett GP, D’Agostino G, Ricotti P, Fiori E, Tonini M (1997) A re-appraisal of the nature of the atropine-resistant contraction to electrical field stimulation in the human isolated detrusor muscle. Naunyn Schmiedebergs Arch Pharmacol 356:750–755PubMedGoogle Scholar
  34. Theobald RJ Jr (1995) Purinergic and cholinergic components of bladder contractility and flow. Life Sci 56:445–454CrossRefPubMedGoogle Scholar
  35. Yunaev MA, Barden JA, Bennett MR (2000) Changes in the distribution of different subtypes of P2X receptor clusters on smooth muscle cells in relation to nerve varicosities in the pregnant rat urinary bladder. J Neurocytol 29:99–108CrossRefPubMedGoogle Scholar
  36. Zhou X, Galligan JJ (1998) Non-additive interaction between nicotinic cholinergic and P2X purine receptors in guinea-pig enteric neurons in culture. J Physiol (Lond) 513:685–697Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Fiona R. Ray
    • 1
  • Kate H. Moore
    • 2
  • Mitchell A. Hansen
    • 1
  • Julian A. Barden
    • 1
    • 3
  1. 1.Protein Structure Laboratory, The Institute for Biomedical Research and Department of Anatomy and HistologyThe University of SydneyAustralia
  2. 2.The Detrusor Muscle Laboratory, Department of Urogynaecology, St. George HospitalThe University of New South WalesAustralia
  3. 3.Department of Anatomy and Histology, Anderson Stuart Building, F13The University of SydneyAustralia

Personalised recommendations