Abstract
Although the 'purinergic nerve hypothesis' proposed by Burnstock in the early 1970s was met with considerable skepticism, it is now accepted that certain neurons use a purine nucleotide or nucleoside such as ATP or adenosine as a neurotransmitter. Likewise, early studies indicated that the human bladder is devoid of purinergic nerves mediating contraction; however, later studies demonstrated that purinergic nerve-mediated bladder contraction is increased in pathologic conditions such as interstitial cystitis. Cloning and sequencing studies have revealed four subtypes of adenosine receptors and eight subtypes of P2Y receptors, all of which are G-protein-coupled receptors. There are no reports of the cellular location of these receptors in the human bladder. P2X receptors are ligand-gated ion channels, and seven subunits have been cloned and sequenced. Immunohistochemical studies have determined that P2X1,2,4 subunits are on detrusor-muscle cells, P2X1–3,5 subunits are on bladder nerves and P2X2,3,5 subunits are on bladder urothelial cells. Development of purinergic antagonist drugs with selectivity for P2X1 receptors on detrusor muscle cells might be useful for treatment of detrusor overactivity. Antagonists with selectivity for P2X3 receptors on bladder sensory nerves might be clinically beneficial for treatment of urinary urgency, and perhaps chronic pelvic pain.
Key Points
-
Decreased ecto-ATPase in unstable bladders leading to an increased contractile effect of released ATP might be a mechanism of bladder instability in some patients
-
Between 50 and 80 years of age there is an age-associated increase in purinergic-mediated bladder contraction and ATP release and a decrease in cholinergic-mediated bladder contractions and acetylcholine release, which might be one of the mechanisms for the increased incidence of detrusor overactivity in the elderly
-
The functional purinergic receptors on bladder smooth-muscle cells that mediate contraction are either P2X1/P2X2 heteromultimers or P2X1, P2X2 and/or P2X4 homomultimers; development of antagonists to these P2X receptors is likely to be clinically useful in treatment of detrusor overactivity
-
Results from knockout-mice models indicate that the purinergic receptor that mediates bladder sensation and nociception is either a P2X3 homomultimer or a heteromultimer predominantly containing the P2X3 subunit; development of antagonists to this P2X receptor is likely to be clinically useful in the treatment of bladder overactivity, urgency and perhaps even chronic pelvic pain syndromes
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abrams P et al. (2003) The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 61: 37–49
Cowan WD and Daniel EE (1983) Human female bladder and its noncholinergic contractile function. Can J Physiol Pharmacol 61: 1236–1246
Dean DM and Downie JW (1978) Contribution of adrenergic and “purinergic” neurotransmission to contraction in rabbit detrusor. J Pharmacol Exp Ther 207: 431–445
Burnstock G (2001) Purinergic signalling in lower urinary tract. In Handbook of Experimental Pharmacology, 423–515 (Eds Abbracchio MP and Williams M) Berlin: Springer–Verlag
Levin RM et al. (1986) Functional effects of the purinergic innervation of the rabbit urinary bladder. J Pharmacol Exp Ther 236: 452–457
Ruggieri MR et al. (1990) Bladder purinergic receptors. J Urol 144: 176–181
Bayliss M et al. (1999) A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol 162: 1833–1839
Husted S et al. (1983) Direct effects of adenosine and adenine nucleotides on isolated human urinary bladder and their influence on electrically induced contractions. J Urol 130: 392–398
Sjogren C et al. (1982) Atropine resistance of transmurally stimulated isolated human bladder muscle. J Urol 128: 1368–1371
Palea S et al. (1993) Evidence for purinergic neurotransmission in human urinary bladder affected by interstitial cystitis. J Urol 150: 2007–2012
Yoshida M et al. (2001) Age-related changes in cholinergic and purinergic neurotransmission in human isolated bladder smooth muscles. Exp Gerontol 36: 99–109
Birder LA et al. (2003) Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium. Am J Physiol Renal Physiol 285: F423–429
Birder LA et al. (2004) Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis. Am J Physiol Renal Physiol 287: F1084–1091
Birder LA (2005) More than just a barrier: urothelium as a drug target for uriary bladder pain. Am J Physiol 289: F489–495
Vlaskovska M et al. (2001) P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 21: 5670–5677
Cockayne DA et al. (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407: 1011–1015
Inoue R and Brading AF (1991) Human, pig and guinea-pig bladder smooth muscle cells generate similar inward currents in response to purinoceptor activation. Br J Pharmacol 103: 1840–1841
Harvey RA et al. (2002) The contractile potency of adenosine triphosphate and ecto-adenosine triphosphatase activity in guinea pig detrusor and detrusor from patients with a stable, unstable or obstructed bladder. J Urology 168: 1235–1239
Rocha I et al. (2001) Effect on urinary bladder function and arterial blood pressure of the activation of putative purine receptors in brainstem areas. Auton Neurosci 88: 6–15
Drury AN and Szent-Gyorgyi A (1929) The physiological activity of adenine compounds with special reference to their actions upon the mammalian heart. J Physiol (Lond) 68: 213–237
Burnstock G (1978) A basis for distinguishing two types of purinergic receptor. In Cell Membrane Receptors for Drugs and Hormones: A Multidisciplinary Approach 107–118 (Eds Straub RW and Bolis L) New York: Raven Press
Fredholm BB et al. (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53: 527–552
Burnstock G and Kennedy C (1985) Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol 16: 433–440
Burnstock G (2004) Introduction: P2 receptors. Curr Top Med Chem 4: 793–803
Burnstock G (2002) Potential therapeutic targets in the rapidly expanding field of purinergic signalling. Clin Med 2: 45–53
Gopalakrishnan SM et al. (2002) Functional characterization of adenosine receptors and coupling to ATP-sensitive K+ channels in guinea pig urinary bladder smooth muscle. J Pharmacol Exp Ther 300: 910–917
Volpini R et al. (2003) Medicinal chemistry and pharmacology of A2B adenosine receptors. Curr Top Med Chem 3: 427–443
Rubinstein R et al. (1998) Effect of exogenous adenosine and its monophosphate on the contractile response to acetylcholine in the human isolated detrusor muscle strips. J Auton Pharmacol 18: 99–104
Fry CH et al. (2004) Control of bladder function by peripheral nerves: avenues for novel drug targets. Urology 63: 24–31
de Groat WC (2004) The urothelium in overactive bladder: passive bystander or active participant? Urology 64: 7–11
Sui GP et al. (2004) Electrical characteristics of suburothelial cells isolated from the human bladder. J Urol 171: 938–943
Wu C et al. (2004) Purinergic regulation of guinea pig suburothelial myofibroblasts. J Physiol 559: 231–243
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82: 1013–1067
Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346: 967–989
Burnstock G et al. (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: 145–149
Ferguson DR et al. (1997) ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes—a possible sensory mechanism? J Physiol 505: 503–511
Kumar V et al. (2004) Characteristics of adenosine triphosphatase release from porcine and human normal bladder. J Urol 172: 744–747
Yoshida M et al. (2004) Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology 63: 17–23
Sun Y et al. (2001) Augmented stretch activated adenosine triphosphate release from bladder uroepithelial cells in patients with interstitial cystitis. J Urol 166: 1951–1956
Sun Y et al. (2001) Stretch-activated release of adenosine triphosphate by bladder uroepithelia is augmented in interstitial cystitis. Urology 57: 131
Sun Y and Chai TC (2002) Effects of dimethyl sulphoxide and heparin on stretch-activated ATP release by bladder urothelial cells from patients with interstitial cystitis. BJU Int 90: 381–385
Sun Y et al. (2002) Effect of doxazosin on stretch-activated adenosine triphosphate release in bladder urothelial cells from patients with benign prostatic hyperplasia. Urology 60: 351–356
Pandita RK and Andersson KE (2002) Intravesical adenosine triphosphate stimulates the micturition reflex in awake, freely moving rats. J Urol 168: 1230–1234
Smith CP et al. (2005) Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A. Neurochem Int 47: 291–297
Wang EC et al. (2005) ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells. J Clin Invest 115: 2412–2422
O'Reilly BA et al. (2002) P2X receptors and their role in female idiopathic detrusor instability. J Urol 167: 157–164
Ray FR et al. (2003) Loss of purinergic P2X receptor innervation in human detrusor and subepithelium from adults with sensory urgency. Cell Tissue Res 314: 351–359
Elneil S et al. (2001) Distribution of P2X(1) and P2X(3) receptors in the rat and human urinary bladder. Pharmacology 63: 120–128
Moore KH et al. (2001) Loss of purinergic P2X(3) and P2X(5) receptor innervation in human detrusor from adults with urge incontinence. J Neurosci 21: RC166
Tempest HV et al. (2004) P2X and P2X receptor expression in human bladder urothelium and changes in interstitial cystitis. BJU Int 93: 1344–1348
Palea S et al. (1995) Evidence for the presence of both pre- and postjunctional P2-purinoceptor subtypes in human isolated urinary bladder. Br J Pharmacol 114: 35–40
Apostolidis A et al. (2005) Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following detrusor injections of botulinum toxin for human detrusor overactivity. J Urol 174: 977–983
Brady CM et al. (2004) P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol 46: 247–253
Burnstock G (2001) Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 22: 182–188
Palea S et al. (1994) ADP beta S induces contraction of the human isolated urinary bladder through a purinoceptor subtype different from P2X and P2Y. J Pharmacol Exp Ther 269: 193–197
Jarvis MF et al. (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: 17179–17184
Wu G et al. (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: 45–53
Rettinger J et al. (2005) Profiling at recombinant homomeric and heteromeric rat P2X receptors identifies the suramin analogue NF449 as a highly potent P2X1 receptor antagonist. Neuropharmacology 48: 461–468
Vial C and Evans RJ (2000) P2X receptor expression in mouse urinary bladder and the requirement of P2X(1) receptors for functional P2X receptor responses in the mouse urinary bladder smooth muscle. Br J Pharmacol 131: 1489–1495
Yiangou Y et al. (2001) Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int 87: 774–779
Sun Y and Chai TC (2004) Up-regulation of P2X3 receptor during stretch of bladder urothelial cells from patients with interstitial cystitis. J Urol 171: 448–452
Menzies J et al. (2003) P2X7 subunit-like immunoreactivity in the nucleus of visceral smooth muscle cells of the guinea pig. Auton Neurosci 106: 103–109
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Ruggieri, M. Mechanisms of Disease: role of purinergic signaling in the pathophysiology of bladder dysfunction. Nat Rev Urol 3, 206–215 (2006). https://doi.org/10.1038/ncpuro0456
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpuro0456
This article is cited by
-
P2 purinergic receptor dysregulation in urologic disease
Purinergic Signalling (2022)
-
RETRACTED ARTICLE: Sulforaphane Improves Ischemia-Induced Detrusor Overactivity by Downregulating the Enhancement of Associated Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in Rat Bladder
Scientific Reports (2016)
-
Purinergic signalling in the urinary tract in health and disease
Purinergic Signalling (2014)
-
A nationwide population-based study on bladder pain syndrome/interstitial cystitis and ED
International Journal of Impotence Research (2013)
-
Lack of specificity shown by P2Y6 receptor antibodies
Naunyn-Schmiedeberg's Archives of Pharmacology (2013)