Storage dysfunction of the urinary bladder, specifically overactive bladder syndrome, is a condition that occurs frequently in the general population. Historically, pathophysiological and treatment concepts related to overactive bladder have focused on smooth muscle cells. Although these are the central effector, numerous anatomic structures are involved in their regulation, including the urothelium, afferent and efferent nerves, and the central nervous system. Each of these structures involves receptors for—and the urothelium itself also releases—many mediators. Moreover, hypoperfusion, hypertrophy, and fibrosis can affect bladder function. Established treatments such as muscarinic antagonists, β-adrenoceptor agonists, and onabotulinumtoxinA each work in part through their effects on the urothelium and afferent nerves, as do α-adrenoceptor antagonists in the treatment of voiding dysfunction associated with benign prostatic hyperplasia; however, none of these treatments are specifically targeted to the urothelium and afferent nerves. It remains to be explored whether future treatments that specifically act at one of these structures will provide a therapeutic advantage.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Michel MC, Chapple CR. 1.  2009. Basic mechanisms of urgency: basic and clinical evidence. Eur. Urol. 56:298–308 [Google Scholar]
  2. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P. 2.  et al. 2002. The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol. Urodyn. 21:167–78 [Google Scholar]
  3. Barendrecht MM, Oelke M, Laguna MP, Michel MC. 3.  2007. Is the use of parasympathomimetics for treating an underactive urinary bladder evidence-based?. BJU Int. 99:749–52 [Google Scholar]
  4. Osman NI, Chapple CR, Abrams P, Dmochowski R, Haab F. 4.  et al. 2014. Detrusor underactivity and the underactive bladder: a new clinical entity? A review of current terminology, definitions, epidemiology, aetiology and diagnosis. Eur. Urol. 65:389–98 [Google Scholar]
  5. Michel MC, de la Rosette JJMCH, Piro M, Goepel M. 5.  2004. Does concomitant stress incontinence alter the efficacy of tolterodine in patients with overactive bladder?. J. Urol. 172:601–4 [Google Scholar]
  6. Michel MC, Oelke M, Peters SLM. 6.  2005. The neuro-urological connection. Eur. Urol. Suppl. 4:18–28 [Google Scholar]
  7. Coyne KS, Zhou Z, Thompson C, Versi E. 7.  2003. The impact on health-related quality of life of stress, urge and mixed urinary incontinence. BJU Int. 92:731–35 [Google Scholar]
  8. Coyne KS, Kvasz M, Ireland AM, Milsom I, Kopp ZS, Chapple CR. 8.  2012. Urinary incontinence and its relationship to mental health and health-related quality of life in men and women in Sweden, the United Kingdom, and the United States. Eur. Urol. 61:88–95 [Google Scholar]
  9. Margareta N, Ann L, Othon L. 9.  2009. The impact of female urinary incontinence and urgency on quality of life and partner relationship. Neurourol. Urodyn. 28:976–81 [Google Scholar]
  10. Irwin DE, Milsom I, Kopp Z, Abrams P. 10.  2008. Symptom bother and health care-seeking behavior among individuals with overactive bladder. Eur. Urol. 53:1029–39 [Google Scholar]
  11. Stewart WF, van Rooyen JB, Cundiff GW, Abrams P, Herzog AR. 11.  et al. 2003. Prevalence and burden of overactive bladder in the United States. World J. Urol. 20:327–36 [Google Scholar]
  12. Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff JW, Wein AJ. 12.  2001. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 87:760–66 [Google Scholar]
  13. Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z. 13.  et al. 2006. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur. Urol. 50:1306–15 [Google Scholar]
  14. Goepel M, Hoffmann J, Piro M, Rübben H, Michel MC. 14.  2002. Prevalence and physician awareness of symptoms of urinary bladder dysfunction. Eur. Urol. 41:234–39 [Google Scholar]
  15. Krege S, Kinzig-Schppers M, Sörgel F, Baschek R, Michel MC, Rübben H. 15.  2004. Absorption of intravesically applied drugs: comparison of normal and ileal-augmented rabbit bladder. J. Urol. 172:2045–50 [Google Scholar]
  16. Birder LA, de Groat WC. 16.  2007. Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat. Clin. Pract. Urol. 4:46–54 [Google Scholar]
  17. Andersson K-E, McCloskey KD. 17.  2014. Lamina propria: the functional center of the bladder?. Neurourol. Urodyn. 33:9–16 [Google Scholar]
  18. Takeda M, Mochizuki T, Yoshiyama M, Nakagomi H, Kobayashi H. 18.  et al. 2010. Sensor mechanism and afferent signal transduction of the urinary bladder: special focus on transient receptor potential ion channels. LUTS Lower Urin. Tract Symptoms 2:51–60 [Google Scholar]
  19. Ochodnicky P, Humphreys S, Eccles R, Poljakovic M, Wiklund P, Michel MC. 19.  2012. Expression profiling of G-protein-coupled receptors in human urothelium and related cell lines. BJU Int. 110:e293–300 [Google Scholar]
  20. Bahadory F, Moore KH, Liu L, Burcher E. 20.  2013. Gene expression of muscarinic, tachykinin, and purinergic receptors in porcine bladder: comparison with cultured cells. Front. Pharmacol. 4:148 [Google Scholar]
  21. Tully BT, Li M, Sun Y, Berkowitz J, Chai TC. 21.  2009. Defects in muscarinic receptor cell signaling in bladder urothelial cancer cell lines. Urology 74:467–73 [Google Scholar]
  22. Chopra B, Barrick SR, Meyers S, Beckel JM, Zeidel ML. 22.  et al. 2005. Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium. J. Physiol. 562:859–71 [Google Scholar]
  23. Birder LA, Nealen ML, Kiss S, de Groat WC, Caterina MJ. 23.  et al. 2002. β-Adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J. Neurosci. 22:8063–70 [Google Scholar]
  24. Harmon EB, Porter JM, Porter JE. 24.  2005. β-Adrenergic receptor activation in immortalized human urothelial cells stimulates inflammatory responses by PKD-independent mechanisms. Cell Commun. Signal. 3:10 [Google Scholar]
  25. Kumar V, Cross RL, Chess-Williams R, Chapple CR. 25.  2005. Recent advances in basic science for overactive bladder. Curr. Opin. Urol. 15:222–26 [Google Scholar]
  26. Lips KS, Wunsch J, Sarghooni S, Bschleipfer T, Schukowski K. 26.  et al. 2007. Acetylcholine and molecular components of its synthesis and release machinery in the urothelium. Eur. Urol. 51:1042–53 [Google Scholar]
  27. Yoshida M, Masunaga K, Satoji Y, Maeda Y, Nagata T, Inadome A. 27.  2008. Basic and clinical aspects of non-neuronal acetylcholine: expression of non-neuronal acetylcholine in urothelium and its clinical significance. J. Pharmacol. Sci. 106:193–98 [Google Scholar]
  28. Ochodnicky P, Michel-Reher MB, Butter JJ, Seth J, Panicker JN, Michel MC. 28.  2013. Bradykinin modulates spontaneous nerve growth factor production and stretch-induced ATP release in human urothelium. Pharmacol. Res. 70:147–54 [Google Scholar]
  29. Yokoyama O, Tanaka I, Kusukawa N, Yamauchi H, Ito H. 29.  et al. 2011. Antimuscarinics suppress adenosine triphosphate and prostaglandin E2 release from urothelium with potential improvement in detrusor overactivity in rats with cerebral infarction. J. Urol. 185:2392–97 [Google Scholar]
  30. Ochodnicky P, Cruz CD, Yoshimura N, Michel MC. 30.  2011. Nerve growth factor in bladder dysfunction: contributing factor, biomarker and therapeutic target. Neurourol. Urodyn. 30:1227–41 [Google Scholar]
  31. Andersson MC, Tobin G, Giglio D. 31.  2008. Cholinergic nitric oxide release from the urinary bladder mucosa in cyclophosphamide-induced cystitis of the anaesthetized rat. Br. J. Pharmacol. 153:1438–44 [Google Scholar]
  32. Bschleipfer T, Weidner W, Kummer W, Lips KS. 32.  2012. Does bladder outlet obstruction alter the non-neuronal cholinergic system of the human urothelium?. Life Sci. 91:1082–86 [Google Scholar]
  33. Anisuzzaman AS, Morishima S, Suzuki F, Tanaka T, Yoshiki H. 33.  et al. 2008. Assessment of muscarinic receptor subtypes in human and rat lower urinary tract by tissue segment binding assay. J. Pharmacol. Sci. 106:271–79 [Google Scholar]
  34. Zarghooni S, Wunsch J, Bodenbenner M, Brüggmann D, Grando SA. 34.  et al. 2007. Expression of muscarinic and nicotinic acetylcholine receptors in the mouse urothelium. Life Sci. 80:2308–13 [Google Scholar]
  35. Grol S, Essers PBM, van Koeveringe GA, Martinez-Martinez P, de Vente J, Gillespie JI. 35.  2009. M3 muscarinic receptor expression on suburothelial interstitial cells. BJU Int. 104:398–405 [Google Scholar]
  36. Mansfield KJ, Liu L, Mitchelson FJ, Moore KH, Millard RJ, Burcher E. 36.  2005. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing. Br. J. Pharmacol. 144:1089–99 [Google Scholar]
  37. Bschleipfer T, Schukowski K, Weidner W, Grando SA, Schwantes U. 37.  et al. 2007. Expression and distribution of cholinergic receptors in the human urothelium. Life Sci. 80:2303–7 [Google Scholar]
  38. Braverman AS, Lebed B, Linder M, Ruggieri MR Sr. 38.  2007. M2 mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors. Neurourol. Urodyn. 26:63–70 [Google Scholar]
  39. Arrighi N, Bodei S, Lucente A, Michel MC, Zani D. 39.  et al. 2011. Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa. Pharmacol. Res. 64:420–25 [Google Scholar]
  40. Barendrecht MM, Chichester P, Michel MC, Levin RM. 40.  2007. Effect of short-term outlet obstruction on rat bladder nerve density and contractility. Auton. Autacoid Pharmacol. 27:47–54 [Google Scholar]
  41. Wuest M, Kaden S, Hakenberg OW, Wirth MP, Ravens U. 41.  2005. Effect of rilmakalim on detrusor contraction in the presence and absence of urothelium. Naunyn-Schmiedeberg's Arch. Pharmacol. 372:203–12 [Google Scholar]
  42. Michel MC. 42.  2014. Do β-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder?. Naunyn-Schmiedeberg's Arch. Pharmacol. 387:215–24 [Google Scholar]
  43. Klausner AP, Rourke KF, Miner AS, Ratz PH. 43.  2009. Potentiation of carbachol-induced detrusor smooth muscle contractions by β-adrenoceptor activation. Eur. J. Pharmacol. 606:191–98 [Google Scholar]
  44. Hawthorn MH, Chapple CR, Cock M, Chess-Williams R. 44.  2000. Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br. J. Pharmacol. 129:416–19 [Google Scholar]
  45. Murakami S, Chapple CR, Akino H, Sellers DJ, Chess-Williams R. 45.  2007. The role of the urothelium in mediating bladder responses to isoprenaline. BJU Int. 99:669–73 [Google Scholar]
  46. Sadananda P, Chess-Williams R, Burcher E. 46.  2008. Contractile properties of the pig bladder mucosa in response to neurokinin A: a role for myofibroblasts?. Br. J. Pharmacol. 153:1465–73 [Google Scholar]
  47. Cheng J-T, Yu B-C, Tong Y-C. 47.  2007. Changes of M3-muscarinic receptor protein and mRNA expressions in the bladder urothelium and muscle layer of streptozotocin-induced diabetic rats. Neurosci. Lett. 423:1–5 [Google Scholar]
  48. Tong Y-C, Cheng J-T. 48.  2007. Alterations of M2,3-muscarinic receptor protein and mRNA expression in the bladder of the fructose fed obese rat. J. Urol. 178:1537–42 [Google Scholar]
  49. Datta SN, Roosen A, Pullen A, Popat R, Rosenbaum TP. 49.  et al. 2010. Immunohistochemical expression of muscarinic receptors in the urothelium and suburothelium of neurogenic and idiopathic overactive human bladders, and changes with botulinum neurotoxin administration. J. Urol. 184:2578–85 [Google Scholar]
  50. Michel MC, Barendrecht MM. 50.  2008. Physiological and pathological regulation of the autonomic control of urinary bladder contractility. Pharmacol. Ther. 117:297–312 [Google Scholar]
  51. Andersson K-E. 51.  2011. Antimuscarinic mechanisms and the overactive detrusor: an update. Eur. Urol. 59:377–86 [Google Scholar]
  52. Madersbacher H, Knoll M. 52.  1995. Intravesical application of oxybutynin: mode of action controlling detrusor hyperreflexia: preliminary results. Eur. Urol. 28:340–44 [Google Scholar]
  53. Kim Y, Yoshimura N, Masuda H, de Miguel H, Chancellor MB. 53.  2005. Intravesical instillation of human urine after oral administration of trospium, tolterodine and oxybutynin in a rat model of detrusor overactivity. BJU Int. 97:400–3 [Google Scholar]
  54. Chuang Y-C, Thomas CA, Tyagi S, Yoshimura N, Tyagi P, Chancellor MB. 54.  2008. Human urine with solifenacin intake but not tolterodine or darifenacin intake blocks detrusor overactivity. Int. Urogynecol. J. 19:1353–57 [Google Scholar]
  55. Kullmann FA, Downs TR, Artim DE, Limberg BJ, Shah M. 55.  et al. 2011. Urothelial beta3 adrenergic receptors in the rat bladder. Neurourol. Urodyn. 30:144–50 [Google Scholar]
  56. Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S. 56.  2008. Expression and functional role of β-adrenoceptors in the human urinary bladder. Naunyn-Schmiedeberg's Arch. Pharmacol. 377:473–81 [Google Scholar]
  57. Tyagi P, Thomas CA, Yoshimura N, Chancellor MB. 57.  2009. Investigations into the presence of functional β1, β2 and β3-adrenoceptors in urothelium and detrusor of human bladder. Int. Braz. J. Urol. 35:76–83 [Google Scholar]
  58. Kurizaki Y, Ishizuka O, Imamura T, Ishikawa M, Ichino M. 58.  et al. 2013. Relationship between expression of β3-adrenoceptor mRNA in bladder mucosa and urodynamic findings in men with lower urinary tract symptoms. Neurourol. Urodyn. 32:88–91 [Google Scholar]
  59. Otsuka A, Kawasaki H, Matsumoto R, Shinbo H, Kurita Y. 59.  et al. 2013. Expression of β-adrenoceptor subtypes in urothelium, interstitial cells and detrusor of the human urinary bladder. Neurourol. Urodyn. 5:173–80 [Google Scholar]
  60. Nomiya M, Yamaguchi O. 60.  2003. A quantitative analysis of mRNA expression of α1 and β-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J. Urol. 170:649–53 [Google Scholar]
  61. Frazier EP, Mathy M-J, Peters SLM, Michel MC. 61.  2005. Does cyclic AMP mediate rat urinary bladder relaxation by isoproterenol?. J. Pharmacol. Exp. Ther. 313:260–67 [Google Scholar]
  62. Masunaga K, Chapple CR, McKay NG, Yoshida M, Sellers DJ. 62.  2010. The β3-adrenoceptor mediates the inhibitory effects of β-adrenoceptor agonists via the urothelium in pig bladder dome. Neurourol. Urodyn. 29:1320–25 [Google Scholar]
  63. Propping S, Wuest M, Eichhorn B, Grimm M, Wirth M. 63.  et al. 2009. Role of urothelium on β3-adrenoceptor mediated relaxation in human detrusor muscle. Neurourol. Urodyn. 28:870–71 [Google Scholar]
  64. Mangera A, Apostolidis A, Andersson K-E, Dasgupta P, Giannantoni A. 64.  et al. 2014. An updated systematic review and statistical comparison of standardised mean outcomes for the use of botulinum toxin in the management of lower urinary tract disorders. Eur. Urol. 65:981–90 [Google Scholar]
  65. Kuo H-C, Liu H-T, Chuang Y-C, Birder L, Chancellor MB. 65.  2014. Pilot study of liposome-encapsulated onabotulinumtoxinA for patients with overactive bladder: a single-center study. Eur. Urol. 65:1117–24 [Google Scholar]
  66. Michel MC. 66.  2014. OnabotulinumtoxinA: how deep shall it go?. Eur. Urol. 65:1125–27 [Google Scholar]
  67. Hanna-Mitchell AT, Wolf-Johnston AS, Barrick SR, Kanai AJ, Chancellor MB. 67.  et al. 2014. Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. Neurourol. Urodyn. In press. doi: 10.1002/nau.22508 [Google Scholar]
  68. Collins VM, Daly DM, Liaskos M, McKay NG, Sellers D. 68.  et al. 2013. OnabotulinumtoxinA significantly attenuates bladder afferent nerve firing and inhibits ATP release from the urothelium. BJU Int. 112:1018–26 [Google Scholar]
  69. Smith CP, Gangitano DA, Munoz A, Salas NA, Boone TB. 69.  et al. 2008. Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem. Int. 52:1068–75 [Google Scholar]
  70. Ha US, Park EY, Kim JC. 70.  2011. Effect of botulinum toxin on expression of nerve growth factor and transient receptor potential vanilloid 1 in urothelium and detrusor muscle of rats with bladder outlet obstruction-induced detrusor overactivity. Urology 78:721e1–6 [Google Scholar]
  71. Kurizaki Y, Ishizuka O, Imamura T, Ichino M, Ogawa T. 71.  et al. 2011. Relation between expression of α1-adrenoceptor mRNAs in bladder mucosa and urodynamic findings in men with lower urinary tract symptoms. Scand. J. Urol. Nephrol. 45:15–19 [Google Scholar]
  72. Walden PD, Durkin MM, Lepor H, Wetzel JM, Gluchowski C, Gustafson EL. 72.  1997. Localization of mRNA and receptor binding sites for the α1A-adrenoceptor subtype in the rat, monkey and human urinary bladder and prostate. J. Urol. 157:1032–38 [Google Scholar]
  73. Ishihama H, Momota Y, Yanase H, Wang X, de Groat WC, Kawatani M. 73.  2006. Activation of α1D adrenergic receptors in the rat urothelium facilitates the micturition reflex. J. Urol. 175:358–64 [Google Scholar]
  74. Jensen BC, Swigart PM, Simpson PC. 74.  2009. Ten commercial antibodies for alpha-1-adrenergic receptor subtypes are nonspecific. Naunyn-Schmiedeberg's Arch. Pharmacol. 379:409–12 [Google Scholar]
  75. Apodaca G, Balestreire E, Birder LA. 75.  2007. The uroepithelial-associated sensory web. Kidney Int. 72:1057–64 [Google Scholar]
  76. Gillespie JI, van Koeveringe GA, de Wachter SG, de Vente J. 76.  2009. On the origins of the sensory output from the bladder: the concept of afferent noise. BJU Int. 103:1324–33 [Google Scholar]
  77. Andersson K-E. 77.  2010. Detrusor myocyte activity and afferent signaling. Neurourol. Urodyn. 29:97–106 [Google Scholar]
  78. de Groat WC, Yoshimura N. 78.  2010. Changes in afferent activity after spinal cord injury. Neurourol. Urodyn. 29:63–76 [Google Scholar]
  79. Wyndaele J-J. 79.  2010. Investigating afferent nerve activity from the lower urinary tract: highlighting some basic research techniques and clinical evaluation methods. Neurourol. Urodyn. 29:56–62 [Google Scholar]
  80. Nandigama R, Bonitz M, Papadakis T, Schwantes U, Bschleipfer T, Kummer W. 80.  2010. Muscarinic acetylcholine receptor subtypes expressed by mouse bladder afferent neurons. Neuroscience 168:842–50 [Google Scholar]
  81. Bschleipfer T, Nandigama R, Moeller S, Illig C, Weidner W, Kummer W. 81.  2012. Bladder outlet obstruction influences mRNA expression of cholinergic receptors on sensory neurons in mice. Life Sci. 91:1077–81 [Google Scholar]
  82. Kim Y, Yoshimura N, Masuda H, de Miguel F, Chancellor MB. 82.  2005. Antimuscarinic agents exhibit local inhibitory effects on muscarinic receptors in bladder-afferent pathways. Urology 65:238–42 [Google Scholar]
  83. Hedlund P, Streng T, Lee T, Andersson K-E. 83.  2007. Effects of tolterodine on afferent neurotransmission in normal and resiniferatoxin treated conscious rats. J. Urol. 178:326–31 [Google Scholar]
  84. Yokoyama O, Yusup A, Miwa Y, Oyama N, Aoki Y, Akino H. 84.  2005. Effects of tolterodine on an overactive bladder depend on suppression of C-fiber bladder afferent activity in rats. J. Urol. 174:2032–36 [Google Scholar]
  85. Daly DM, Chess-Williams R, Chapple C, Grundy D. 85.  2010. The inhibitory role of acetylcholine and muscarinic receptors in bladder afferent activity. Eur. Urol. 58:22–28 [Google Scholar]
  86. de Laet K, de Wachter S, Wyndaele J-J. 86.  2006. Systemic oxybutynin decreases afferent activity of the pelvic nerve of the rat: new insights into the working mechanism of antimuscarinics. Neurourol. Urodyn. 25:156–61 [Google Scholar]
  87. Iijima K, de Wachter S, Wyndaele J-J. 87.  2007. Effects of the M3 receptor selective muscarinic antagonist darifenacin on bladder afferent activity of the rat pelvic nerve. Eur. Urol. 52:842–49 [Google Scholar]
  88. Yu Y, de Groat WC. 88.  2010. Effects of stimulation of muscarinic receptors on bladder afferent nerves in the in vitro bladder-pelvic afferent nerve preparation of the rat. Brain Res.136143–53 [Google Scholar]
  89. Aizawa N, Homma Y, Igawa Y. 89.  2012. Effects of mirabegron, a novel β3-adrenoceptor agonist, on the primary bladder afferent activity and bladder microcontractions in rats in comparison with those of oxybutynin. Eur. Urol. 62:1166–73 [Google Scholar]
  90. Aizawa N, Igawa Y, Nishizawa O, Wyndaele J-J. 90.  2010. Effects of CL316,243, a β3-adrenoceptor agonist, and intravesical prostaglandin E2 on the primary bladder afferent activity of the rat. Neurourol. Urodyn. 29:771–76 [Google Scholar]
  91. Patra PB, Thorneloe KS. 91.  2011. Enhanced sensitivity to afferent stimulation and impact of overactive bladder therapies in the conscious, spontaneously hypertensive rat. J. Pharmacol. Exp. Ther. 338:392–99 [Google Scholar]
  92. Apostolidis A, Dasgupta P, Fowler CJ. 92.  2006. Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur. Urol. 49:644–50 [Google Scholar]
  93. Lucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE. 93.  2008. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int. 101:366–70 [Google Scholar]
  94. Kanai A, Wyndaele J-J. 94.  2011. Researching bladder afferents—determining the effects of β3-adrenergic receptor agonists and botulinum toxin type-A. Neurourol. Urodyn. 30:684–91 [Google Scholar]
  95. Yoshiyama M, de Groat WC. 95.  2001. Role of spinal α1-adrenoceptor subtypes in the bladder reflex in anesthetized rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280:R1414–19 [Google Scholar]
  96. Yokoyama O, Yusup A, Oyama N, Aoki Y, Tanase K. 96.  et al. 2006. Improvement of bladder storage function by α1-blocker depends on the suppression of C-fiber afferent activity in rats. Neurourol. Urodyn. 25:461–67 [Google Scholar]
  97. Yokoyama O, Ito H, Aoki Y, Oyama N, Miwa Y, Akino H. 97.  2010. Selective α1A-blocker improves bladder storage function in rats via suppression of C-fiber afferent activity. World J. Urol. 28:609–14 [Google Scholar]
  98. Fowler CJ, Griffiths D, de Groat WC. 98.  2008. The neural control of micturition. Nat. Rev. Neurosci. 9:453–66 [Google Scholar]
  99. Drake MJ, Tannenbaum C, Kanai AJ. 99.  2010. Potential insights into lower urinary function derived from CNS imaging. Neurourol. Urodyn. 29:629–33 [Google Scholar]
  100. Fowler CJ, Griffiths DJ. 100.  2010. A decade of functional brain imaging applied to bladder control. Neurourol. Urodyn. 29:49–55 [Google Scholar]
  101. Yoshimura N, Miyazoto M, Kitta T, Yoshikawa S. 101.  2014. Central nervous targets for the treatment of bladder dysfunction. Neurourol. Urodyn. 33:59–66 [Google Scholar]
  102. Michel MC, Radziszeswski P, Falconer C, Marschall-Kehrel D, Rundfeldt C, Vanhoutte F. 102.  2008. The centrally acting ion channel modulator flupirtine improves bladder function in animal models and patients with overactive bladder syndrome Presented at Int. Cont. Soc. 2008, Oct. 20–24, Cairo. http://www.icsoffice.org/Abstracts/Publish/46/000406.pdf [Google Scholar]
  103. Dale PR, Cernecka H, Schmidt M, Dowing M, Charlton SJ, Michel MC. 103.  2014. The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease. Curr. Opin. Pharmacol. 16:31–42 [Google Scholar]
  104. Somogyi GT, Tanowitz M, de Groat WC. 104.  1995. Prejunctional facilitatory α1-adrenoceptors in the rat urinary bladder. Br. J. Pharmacol. 114:1710–16 [Google Scholar]
  105. Szell EA, Yamamoto T, de Groat WC, Somogyi GT. 105.  2000. Smooth muscle and parasympathetic nerve terminals in the rat urinary bladder have different subtypes of α1 adrenoceptors. Br. J. Pharmacol. 130:1685–91 [Google Scholar]
  106. Messori E, Rizzi CA, Candura SM, Lucchelli A, Balestra B, Tonini M. 106.  1995. 5-Hydroxytryptamine receptors that facilitate excitatory neuromuscular transmission in the guinea-pig isolated detrusor muscle. Br. J. Pharmacol. 115:677–83 [Google Scholar]
  107. Candura SM, Messori E, Fraceschetti GP, D'Agostino G, Vicini D. 107.  et al. 1996. Neural 5-HT4 receptors in human isolated detrusor muscle: effects of indole, benzimidazolone and substituted benzamide agonists and antagonists. Br. J. Pharmacol. 118:1965–70 [Google Scholar]
  108. Chetty N, Coupar IM, Chess-Williams R, Kerr KP. 108.  2007. Demonstration of 5-HT3 receptor function and expression in the mouse bladder. Naunyn-Schmiedeberg's Arch. Pharmacol. 375:359–68 [Google Scholar]
  109. Tsurusaki M, Yoshida M, Akasu T, Nagatsu I. 109.  1990. α2-Adrenoceptors mediate the inhibition of cholinergic transmission in parasympathetic ganglia of the rabbit urinary bladder. Synapse 5:233–40 [Google Scholar]
  110. Zoubek J, Somogyi GT, de Groat WC. 110.  1993. A comparison of inhibitory effects of neuropeptide Y on rat urinary bladder, urethra, and vas deferens. Am. J. Physiol. Regul. Integr. Comp. Physiol. 265:R537–43 [Google Scholar]
  111. Tran LV, Somogyi GT, de Groat WC. 111.  1994. Inhibitory effect of neuropeptide Y on adrenergic and cholinergic transmission in rat urinary bladder and urethra. Am. J. Physiol. Regul. Integr. Comp. Physiol. 266:R1411–17 [Google Scholar]
  112. Davis B, Goepel M, Bein S, Chess-Williams R, Chapple CR, Michel MC. 112.  2000. Lack of neuropeptide Y receptor detection in human bladder and prostate. BJU Int. 85:918–24 [Google Scholar]
  113. Elbadawi A, Diokno AC, Millard RJ. 113.  1998. The aging bladder: morphology and urodynamics. World J. Urol. 16:Suppl. 1S10–34 [Google Scholar]
  114. Golbidi S, Laher I. 114.  2010. Bladder dysfunction in diabetes mellitus. Front. Pharmacol. 1:136 [Google Scholar]
  115. Grol S, Nile CJ, Martinez-Martinez P, van Koeveringe GA, de Wachter SGG. 115.  et al. 2011. M3 muscarinic receptor-like immunoreactivity in sham-operated and obstructed guinea pig bladders. J. Urol. 185:1959–66 [Google Scholar]
  116. Ochodnicky P, Uvelius B, Andersson K-E, Michel MC. 116.  2013. Autonomic nervous control of the urinary bladder. Acta Physiol. 207:16–33 [Google Scholar]
  117. Cumming JA, Chisholm GD. 117.  1992. Changes in detrusor innervation with relief of outflow tract obstruction. Br. J. Urol. 69:7–11 [Google Scholar]
  118. Chapple CR, Milner P, Moss HE, Burnstock G. 118.  1992. Loss of sensory neuropeptides in the obstructed human bladder. Br. J. Urol. 70:373–81 [Google Scholar]
  119. Nilvebrant L, Ekström J, Malmberg L. 119.  1986. Muscarinic receptor density in the rat urinary bladder after denervation, hypertrophy and urinary diversion. Acta Pharmacol. Toxicol. 59:306–14 [Google Scholar]
  120. Tuttle JB, Steers WD, Albo M, Nataluk E. 120.  1994. Neural input regulates tissue NGF and growth of the adult rat urinary bladder. J. Auton. Nerv. Syst. 49:147–48 [Google Scholar]
  121. Braverman AS, Luthin GR, Ruggieri MR. 121.  1998. M2 muscarinic receptor contributes to contraction of the denervated rat urinary bladder. Am. J. Physiol. Regul. Integr. Comp. Physiol. 275:R1654–60 [Google Scholar]
  122. Braverman AS, Ruggieri MR Sr. 122.  2003. Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285:R701–8 [Google Scholar]
  123. Vizzard MA. 123.  2000. Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction. Exp. Neurol. 161:273–84 [Google Scholar]
  124. Turner WH, Brading AF. 124.  1999. Smooth muscle of the bladder in the normal and the diseased state: pathophysiology, diagnosis and treatment. Pharmacol. Ther. 75:77–110 [Google Scholar]
  125. Yamaguchi O. 125.  2004. Response of bladder smooth muscle cells to obstruction: signal transduction and the role of mechanosensors. Urology 63:11–16 [Google Scholar]
  126. Fry CH, Skennerton D, Wood D, Wu C. 126.  2002. The cellular basis of contraction in human detrusor smooth muscle from patients with stable and unstable bladders. Urology 59:Suppl. 5A3–12 [Google Scholar]
  127. Fry CH, Sui GP, Severs NJ, Wu C. 127.  2004. Spontaneous activity and electrical coupling in human detrusor smooth muscle: implications for detrusor overactivity?. Urology 63:Suppl. 3A3–10 [Google Scholar]
  128. Roosen A, Chapple CR, Dmochowski RR, Fowler CJ, Gratzke C. 128.  et al. 2009. A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. Eur. Urol. 56:810–20 [Google Scholar]
  129. Hegde SS. 129.  2006. Muscarinic receptors in the bladder: from basic research to therapeutics. Br. J. Pharmacol. 147:S80–87 [Google Scholar]
  130. Braverman AS, Ruggieri MR Sr. 130.  2006. Muscarinic receptor transcript and protein density in hypertrophied and atrophied rat urinary bladder. Neurourol. Urodyn. 25:55–61 [Google Scholar]
  131. Peters SLM, Schmidt M, Michel MC. 131.  2006. Rho kinase: a target for treating urinary bladder dysfunction?. Trends Pharmacol. Sci. 27:492–97 [Google Scholar]
  132. Frazier EP, Peters SLM, Braverman AS, Ruggieri MR Sr, Michel MC. 132.  2008. Signal transduction underlying control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 377:449–62 [Google Scholar]
  133. Witte LPW, de Haas N, Mammen M, Stangeland EL, Steinfeld T. 133.  et al. 2011. Muscarinic receptor subtypes and signalling involved in the attenuation of isoprenaline-induced rat urinary bladder relaxation. Naunyn-Schmiedeberg's Arch. Pharmacol. 384:555–63 [Google Scholar]
  134. Johnston L, Carson C, Lyons AD, Davidson RA, McCloskey KD. 134.  2008. Cholinergic-induced Ca2+ signaling in interstitial cells of Cajal from the guinea pig bladder. Am. J. Physiol. Ren. Physiol. 294:F645–55 [Google Scholar]
  135. Michel MC, Vrydag W. 135.  2006. α1-, α2- and β-adrenoceptors in the urinary bladder, urethra and prostate. Br. J. Pharmacol. 147:S88–119 [Google Scholar]
  136. Igawa Y, Schneider T, Yamazaki Y, Tatemichi S, Homma Y. 136.  et al. 2012. Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322. Naunyn-Schmiedeberg's Arch. Pharmacol. 385:759–67 [Google Scholar]
  137. Levin RM, Levin SS, Zhao Y, Buttyan R. 137.  1997. Cellular and molecular aspects of bladder hypertrophy. Eur. Urol. 32:Suppl. 115–21 [Google Scholar]
  138. Levin RM, English M, Barretto M, Dubuc M, O'Connor L. 138.  et al. 2000. Normal detrusor is more sensitive than hypertrophied detrusor to in vitro ischemia followed by re-oxygenation. Neurourol. Urodyn. 19:701–12 [Google Scholar]
  139. Pessina F, Marazova K, Ninfali P, Avanzi L, Manfredini S, Sgaragli G. 139.  2004. In vitro neuroprotection by novel antioxidants in guinea-pig urinary bladder subjected to anoxia/reperfusion damage. Naunyn-Schmiedeberg's Arch. Pharmacol. 370:521–28 [Google Scholar]
  140. Yamaguchi O, Nomiya M, Andersson K-E. 140.  2014. Functional consequences of chronic bladder ischemia. Neurourol. Urodyn. 33:54–58 [Google Scholar]
  141. Ishida T, Shimoda N, Sato K, Ogawa O, Nishizawa O, Kato T. 141.  1999. Effects of ischemia on voiding function and nerve growth factor on the rat urinary bladder. Jpn. J. Urol. 90:564–71 [Google Scholar]
  142. Okutsu H, Matsumoto S, Hanai T, Noguchi Y, Fujiyasu N. 142.  et al. 2010. Effects of tamsulosin on bladder blood flow and bladder function in rats with bladder outlet obstruction. Urology 75:235–40 [Google Scholar]
  143. Inoue S, Saito M, Tsounapi P, Dimitriadis F, Ohmasa F. 143.  et al. 2012. Effect of silodosin on detrusor overactivity in the male spontaneously hypertensive rat. BJU Int. 110:E118–24 [Google Scholar]
  144. Sawada N, Nomiya M, Hood B, Koslov D, Zarifpour M, Andersson K-E. 144.  2013. Protective effect of a β3-adrenoceptor agonist on bladder function in a rat model of chronic bladder ischemia. Eur. Urol. 64:664–71 [Google Scholar]
  145. Yono M, Pouresmail M, Takahashi W, Flanagan JF, Weiss RM, Latifpour J. 145.  2005. Effect of insulin treatment on tissue size of the genitourinary tract in BB rats with spontaneously developed and streptozotocin-induced diabetes. Naunyn-Schmiedeberg's Arch. Pharmacol. 372:251–55 [Google Scholar]
  146. Panayi DC, Tekkis P, Fernando R, Hendricken C, Khullar V. 146.  2010. Ultrasound measurement of bladder wall thickness is associated with the overactive bladder syndrome. Neurourol. Urodyn. 29:1295–98 [Google Scholar]
  147. Myers JB, Dall'Era JE, Koul S, Kumar B, Khandrika L. 147.  et al. 2009. Biochemical alterations in partial bladder outlet obstruction in mice: up-regulation of the mitogen activated protein kinase pathway. J. Urol. 181:1926–32 [Google Scholar]
  148. Soler R, Andersson K-E, Chancellor MB, Chapple CR, de Groat WC. 148.  et al. 2013. Future direction in pharmacotherapy for non-neurogenic male lower urinary tract symptoms. Eur. Urol. 64:610–21 [Google Scholar]
  149. Ückert S, Oelke M. 149.  2011. Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction. Br. J. Clin. Pharmacol. 72:197–204 [Google Scholar]
  150. Leiria LO, Silva FH, Davel APC, Alexandre ED, Calixto MC. 150.  et al. 2014. The soluble guanylyl cyclase activator BAY 60-2770 ameliorates overactive bladder in obese mice. J. Urol. 191:539–47 [Google Scholar]
  151. Frias B, Charrua A, Avelino A, Michel MC, Cruz F, Cruz CD. 151.  2012. Transient receptor potential vanilloid 1 mediates nerve growth factor-induced bladder hyperactivity and noxious input. BJU Int. 110:E422–28 [Google Scholar]
  152. Franken J, Uvin P, de Ridder D, Voets T. 152.  2014. TRP channels in lower urinary tract dysfunction. Br. J. Pharmacol. 171:2537–51 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error