Kazan medical journalKazan medical journal0368-48142587-9359Eco-Vector890110.17816/KMJ2018-462Review ArticleP2-receptors of the urinary bladder as potential targets for novel drugsZiganshinA Uauziganshin@gmail.comBedovaD Vauziganshin@gmail.comZubkovE Aauziganshin@gmail.comSitdykovaM Eauziganshin@gmail.comKazan State Medical University1506201899346246628052018Copyright © 2018, Ziganshin A.U., Bedova D.V., Zubkov E.A., Sitdykova M.E.2018<p>Purinergic P2 receptors, the basic endogenous agonist of which is adenosine triphosphoric acid (ATP), are widely spread in the organs and tissues of human and animals including urogenitary system. Physiologically, in the peripheral nervous system the role of P2 receptors in most cases is not leading, they only complement or modulate the action of main neuromediators (acetylcholine, norepinephrine). But in pathology the role of P2 receptors significantly increases and often takes the lead in the pathogenesis of one or another disease. In particular, it was determined that purinergic component of contractile bladder response increases from 2-5% in normal state to 40% in some pathological processes (such as interstitial cystitis, neurogenic bladder, urinary obstruction). In the bladder of experimental animals different subtypes of P2 receptors were revealed, their functional role was established in normal conditions and models of pathological processes. Certain subtypes of P2 receptors were also detected in the human bladder, including in some urinary tract diseases. The level of ATP in patients urine was established to significantly increase in lower urinary tract obstruction that holds certain promise for the diagnosis of these diseases. Variety and large representation of P2 receptors in lower urinary tract make them attractive as potential targets for novel drugs. On this evidence, evaluation of effect of P2 receptor agonists and antagonists as well as medications affecting the metabolism of endogenous nucleotides and nucleosides, is one of promising direction for the search for new urological drugs.</p>P2 receptorsATPectonucleotidasesurinary bladderР2-рецепторыАТФэктонуклеотидазымочевой пузырь[Burnstock G. Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future. Bioessays. 2012; 34 (3): 218–225. DOI: 10.1002/bies.201100130.][Burnstock G. Purinergic signalling in the urinary tract in health and disease. Purinergic Signal. 2014; 10 (1): 103–155. DOI: 10.1007/s11302-013-9395-y.][Andersson K.-E. Purinergic signaling in the urinary bladder. Auton. Neurosci. Bas. Clin. 2015; 191: 78–81. DOI: 10.1016/j.autneu.2015.04.012.][Ziganshin A.U., Ziganshina L.E. P2-retseptory: perspektivnaya mishen' dlya budushchikh lekarstv. (P2 receptors: promising target for future drugs.) Moscow: GEOTAR-Media. 2009; 136 p. (In Russ.)][Ziganshin A.U., Ziganshin B.A. P2 receptors — promising targets for future drugs. Cur. Top. Pharmacol. 2012; 16: 45–51.][Alexander S.P., Devenport A.P., Kelly E. et al. The Concise Guide to Pharmacology 2015/16: G protein-coupled receptors. Br. J. Pharmacol. 2015; 172 (24): 5744–5869. DOI: 10.1111/bph.13348.][Alexander S.P., Peters J.A., Kelly E. et al. The Concise Guide to Pharmacology 2015/16: Ligand-gated ion channels. Br. J. Pharmacol. 2015; 172 (24): 5870–5903. DOI: 10.1111/bph.13350.][Burnstock G. Purine and pyrimidine receptors. Cell. Mol. Life Sci. 2007; 64 (12): 1471–1483. DOI: 10.1007/s00018-007-6497-0.][Burnstock G., Verkhratsky A. Evolutionary origins of the purinergic signalling system. Acta. Physiol. (Oxf.). 2009; 195 (4): 415–447. DOI: 10.1111/j.1748-1716.2009.01957.x.][Burnstock G. Purinergic signalling: from discovery to current developments. Exp. Physiol. 2014; 99 (1): 16–34. DOI: 10.1113/expphysiol.2013.071951.][Burnstock G. Purinergic signalling in lower urinary tract. In: Handbook of experimental pharmacology. Vol. 151/I. Purinergic and pyrimidinergic signalling I — molecular, nervous and urinogenitary system function. M.P. Abbracchio, M. Williams eds. Springer-Verlag, Berlin. 2001; 423–515. DOI: 10.1007/978-3-662-09604-8_15.][Ziganshin A.U., Hoyle C.H.V., Bo X. et al. PPADS selectively antagonizes P2X-purinoceptor-mediated responses in the rabbit urinary bladder. Br. J. Pharmacol. 1993; 110: 1491–1495. DOI: 10.1111/j.1476-5381.1993.tb13990.x.][Ziganshin A.U., Ralevic V., Burnstock G. Contractility of urinary bladder and vas deferens after sensory denervation by capsaicin treatment of newborn rats. Br. J. Pharmacol. 1995; 114: 166–170. DOI: 10.1111/j.1476-5381.1995.tb14921.x.][Lee H.Y., Bardini M., Burnstock G. Distribution of P2X receptors in the urinary bladder and the ureter of the rat. J. Urol. 2000; 163: 2002–2007. DOI: 10.1016/S0022-5347(05)67618-5.][Chopra B., Gever J., Barrick S.R. et al. Expression and function of rat urothelial P2Y receptors. Am. J. Physiol. Renal. Physiol. 2008; 294: F821–F829. DOI: 10.1152/ajprenal.00321.2006.][Kennedy C. The role of purines in the peripheral nervous system. In: Purinergic and pyrimidinergic signalling. M. Abbracchio, M. Williams editors. Springer, New York. 2001; 296–297.][Vial C., Evans R.J. P2X receptor expression in mouse urinary bladder and the requirement of P2X1 receptors for functional P2X receptor responses in the mouse urinary bladder smooth muscle. Br. J. Pharmacol. 2000. 131: 1489–1495. DOI: 10.1038/sj.bjp.0703720.][Cockayne D.A., Hamilton S.G., Zhu Q.M. et al. Urinary bladder hyporeflexia and reduced pain-related behavior in P2X3-deficient mice. Nature. 2000. 407: 1011–1015. DOI: 10.1038/35039519.][Martins J.P., Silva R.B., Coutinho-Silva R. et al. The role of P2X7 purinergic receptors in inflammatory and nociceptive changes accompanying cyclophosphamide-induced haemorrhagic cystitis in mice. Br. J. Pharmacol. 2012; 165 (1): 183–196. DOI: 10.1111/j.1476-5381.2011.01535.x.][Obara K., Lepor H., Walden P.D. Localization of P2Y1 purinoceptor transcripts in the rat penis and urinary bladder. J. Urol. 1998. 160: 587–591. DOI: 10.1016/S0022-5347(01)62963-X.][Bolego C., Pinna C., Abbracchio M.P. et al. Effects of ADPβS and UTP on the rat urinary bladder smooth muscle. Res. Comm. Mol. Pathol. Pharmacol. 1995; 87: 75–76.][Kira S., Yoshiyama M., Tsuchiya S. et al. P2Y6-deficiency increases micturition frequency and attenuates sustained contractility of the urinary bladder in mice. Sci. Rep. 2017; 7 (1): 771. DOI: 10.1038/s41598-017-00824-2.][Merrill L., Gonzalez E.J., Girard B.M., Vizzard M.A. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat. Rev. Urol. 2016; 13 (4): 193–204. DOI: 10.1038/nrurol.2016.13.][Zimmermann H. Ectonucleotidases in the nervous system. Novartis Foundation Symposium 276. Purinergic signalling in neuron-glial interactions. John Wiley & Sons, Ltd, Chichester. 2006; 113–128. DOI: 10.1002/9780470032244.ch10.][Burnstock G. A basis for distinguishing two types of purinergic receptor. In: R.W. Straub, L. Bolis (eds) Cell membrane receptors for drugs and hormones: a multidisciplinary approach. Raven Press, New York. 1978; 107–118.][Welford L.A., Cusack N.J., Hourani S.M.O. The structure-activity relationships of ectonucleotidases and of excitatory P2-purinoceptors: evidence that dephosphorylation of ATP analogues reduces pharmacological potency. Eur. J. Pharmacol. 1987; 141: 123–130. DOI: 10.1016/0014-2999(87)90418-3.][Hourani S.M.O., Chown J.A. The effects of some possible inhibitors of ectonucleotidases on the breakdown and pharmacological effects of ATP in the guinea-pig urinary bladder. Gen. Pharmacol. 1989; 20: 413–416. DOI: 10.1016/0306-3623(89)90188-2.][Ziganshin A.U., Hoyle C.H.V., Burnstock G. Ecto-enzymes and metabolism of extracellular ATP. Drug Dev. Res. 1994; 32: 134–146. DOI: 10.1002/ddr.430320303.][Ziganshin A.U., Ralevic V., Burnstock G. Contractility of urinary bladder and vas deferens after sensory denervation by capsaicin treatment of newborn rats. Br. J. Pharmacol. 1995; 114: 166–170. DOI: 10.1111/j.1476-5381.1995.tb14921.x.][Ziganshin A.U., Ziganshina L.E., Hoyle C.H.V., Burnstock G. Effects of divalent cations and La3+ on contractility and ecto-ATPase activity in the guinea-pig urinary bladder. Br. J. Pharmacol. 1995; 114: 632–639. DOI: 10.1111/j.1476-5381.1995.tb17186.x.][Ziganshin A.U., Berdnikov E.A., Ziganshina L.E. et al. Effects of α,β-unsaturated sulphones and phosphonium salts on ecto-ATPase activity and contractile responses mediated via P2X-purinoceptors. Gen. Pharmacol. 1995; 26: 527–532. DOI: 10.1016/0306-3623(94)00236-G.][Yu W., Robson S.C., Hill W.G. Expression and distribution of ectonucleotidases in mouse urinary bladder. PLoS One. 2011; 6: e18704. DOI: 10.1371/journal.pone.0018704.][Palea S., Artibani W., Ostardo E. et al. Evidence for purinergic neurotransmission in human urinary bladder affected by interstitial cystitis. J. Urol. 1993; 150: 2007–2012. DOI: 10.1016/S0022-5347(17)35955-4.][Smith D.J., Chapple C.R. In vitro response of human bladder smooth muscle in unstable obstructed male bladders: a study of pathophysiological causes. Neurourol. Urodyn. 1994; 13: 414–415.][O'Reilly B.A., Kosaka A.H., Knight G.F. et al. P2X receptors and their role in female idiopathic detrusor instability. J. Urol. 2002; 167: 157–164. DOI: 10.1016/S0022-5347(05)65403-1.][Andersson K.E., Hedlund P. Pharmacologic perspective on the physiology of the lower urinary tract. Urology. 2002; 60: 13–20. DOI: 10.1016/S0090-4295(02)01786-7.][Hoyle C.H.V., Chapple C., Burnstock G. Isolated human bladder: evidence for an adenine dinucleotide acting on P2X-purinoceptors and for purinergic transmission. Eur. J. Pharmacol. 1989; 174: 115–118. DOI: 10.1016/0014-2999(89)90881-9.][Husted S., Sjögren C., Andersson K.-E. Direct effects of adenosine and adenine nucleotides on isolated human urinary bladder and their influence on electrically induced contractions. J. Urol. 1983; 130: 392–398. DOI: 10.1016/S0022-5347(17)51175-1.][Palea S., Corsi M., Pietra C. et al. ADPβS induces contraction of the human isolated urinary bladder through a purinoceptor subtype different from P2X and P2Y. J. Pharmacol. Exp. Ther. 1994; 269: 193–197. PMID: 8169824.][Palea S., Pietra C., Trist D.G. et al. Evidence for the presence of both pre- and postjunctional P2-purinoceptor subtypes in human isolated urinary bladder. Br. J. Pharmacol. 1995; 114: 35–40. DOI: 10.1111/j.1476-5381.1995.tb14902.x.][Svennersten K., Hallén-Grufman K., De Verdier P.J. et al. Localization of P2X receptor subtypes 2, 3 and 7 in human urinary bladder. BMC Urol. 2015; 15: 81. DOI: 10.1186/s12894-015-0075-9.][Silva-Ramos M., Silva I., Oliveira O. et al. Urinary ATP may be a dynamic biomarker of detrusor overactivity in women with overactive bladder syndrome. PLoS One. 2013; 8: e64696. DOI: 10.1371/journal.pone.0064696.][Cheng Y., Mansfield K.J., Allen W. et al. Correlation between cystometric volumes, ATP release, and pH in women with overactive bladder versus controls. Neurourol. Urodyn. 2013; 32: 969–973. DOI: 10.1002/nau.22344.][Gill K., Horsley H., Kupelian A.S. et al. Urinary ATP as an indicator of infection and inflammation of the urinary tract in patients with lower urinary tract symptoms. BMC Urol. 2015; 15: 7. DOI: 10.1186/s12894-015-0001-1.][Shiina K., Hayashida K.I., Ishikawa K., Kawatani M. ATP release from bladder urothelium and serosa in a rat model of partial bladder outlet obstruction. Biomed. Res. 2016; 37 (5): 299–304. DOI: 10.2220/biomedres.37.299.][Burnstock G. Purinergic signalling: Therapeutic developments. Front. Pharmacol. 2017; 8: 661. DOI: 10.3389/fphar.2017.00661.][Angiolillo D.J., Ferreiro J.L. Platelet adenosine diphosphate P2Y12 receptor antagonism: benefits and limitations of current treatment strategies and future directions. Rev. Esp. Cardiol. 2010; 63 (1): 60–76. DOI: 10.1016/S0300-8932(10)70010-5.][Park D.H., Chung J.K., Seo D.R., Lee S.J. Clinical effects and safety of 3% diquafosol ophthalmic solution for patients with dry eye after cataract surgery: a randomized controlled trial. Am. J. Ophthalmol. 2016; 163: 122-131. e2. DOI: 10.1016/j.ajo.2015.12.002.][Amano S., Inoue K. Effect of topical 3% diquafosol sodium on eyes with dry eye disease and meibomian gland dysfunction. Clin. Ophthalmol. 2017; 11: 1677–1682. DOI: 10.2147/OPTH.S148167.]