Urinary Tract pp 319-344

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 2011)

Muscarinic Acetylcholine Receptors in the Urinary Tract



Muscarinic receptors comprise five cloned subtypes, encoded by five distinct genes, which correspond to pharmacologically defined receptors (M1–M5). They belong to the family of G-protein-coupled receptors and couple differentially to the G-proteins. Preferentially, the inhibitory muscarinic M2 and M4 receptors couple to Gi/o, whereas the excitatory muscarinic M1, M3, and M5 receptors preferentially couple to Gq/11. In general, muscarinic M1, M3, and M5 receptors increase intracellular calcium by mobilizing phosphoinositides that generate inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol (DAG), whereas M2 and M4 receptors are negatively coupled to adenylyl cyclase. Muscarinic receptors are distributed to all parts of the lower urinary tract. The clinical use of antimuscarinic drugs in the treatment of detrusor overactivity and the overactive bladder syndrome has focused interest on the muscarinic receptors not only of the detrusor, but also of other components of the bladder wall, and these have been widely studied. However, the muscarinic receptors in the urethra, prostate, and ureter, and the effects they mediate in the normal state and in different urinary tract pathologies, have so far not been well characterized. In this review, the expression of and the functional effects mediated by muscarinic receptors in the bladder, urethra, prostate, and ureters, under normal conditions and in different pathologies, are discussed.


Bladder Cholinergic nerves Muscarinic receptor agonist Muscarinic receptor antagonist Prostate Ureter Urethra 


  1. Abrams P, Andersson KE (2007) Muscarinic receptor antagonists for overactive bladder. BJU Int 100(5):987–1006PubMedCrossRefGoogle Scholar
  2. Alberts P (1995) Classification of the presynaptic muscarinic receptor subtype that regulates 3H-acetylcholine secretion in the guinea pig urinary bladder in vitro. J Pharmacol Exp Ther 274(1):458–468PubMedGoogle Scholar
  3. An JY, Yun HS, Lee YP, Yang SJ, Shim JO, Jeong JH, Shin CY, Kim JH, Kim DS, Sohn UD (2002) The intracellular pathway of the acetylcholine-induced contraction in cat detrusor muscle cells. Br J Pharmacol 137(7):1001–1010PubMedCrossRefGoogle Scholar
  4. Andersson KE (1993) Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 45(3):253–308Google Scholar
  5. Andersson KE (2004a) Antimuscarinics for treatment of overactive bladder. Lancet Neurol 3(1):46–53PubMedCrossRefGoogle Scholar
  6. Andersson K-E (2004b) Detrusor contraction – focus on muscarinic receptors. Scand J Urol Nephrol Suppl 215:54–57PubMedCrossRefGoogle Scholar
  7. Andersson KE, Wein AJ (2004) Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev 56(4):581–631PubMedCrossRefGoogle Scholar
  8. Andersson KE, Persson CG, Alm P, Kullander S, Ulmsten U (1978) Effects of acetylcholine, noradrenaline, and prostaglandins on the isolated, perfused human fetal urethra. Acta Physiol Scand 104(4):394–401PubMedCrossRefGoogle Scholar
  9. Andersson KE, Holmquist F, Fovaeus M, Hedlund H, Sundler R (1991) Muscarinic receptor stimulation of phosphoinositide hydrolysis in the human isolated urinary bladder. J Urol 146(4):1156–1159PubMedGoogle Scholar
  10. Andersson K-E, Chapple CR, Cardozo L et al (2009) Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A (eds) Incontinence, 4th international consultation on incontinence. Plymouth. Plymbridge Distributors Ltd, Plymouth, UK, pp 631–699Google Scholar
  11. Anisuzzaman AS, Morishima S, Suzuki F, Tanaka T, Yoshiki H, Sathi ZS, Akino H, Yokoyama O, Muramatsu I (2008) Assessment of muscarinic receptor subtypes in human and rat lower urinary tract by tissue segment binding assay. J Pharmacol Sci 106(2):271–279PubMedCrossRefGoogle Scholar
  12. Arrighi S, Bosi G, Cremonesi F, Domeneghini C (2008) Immunohistochemical study of the pre- and postnatal innervation of the dog lower urinary tract: morphological aspects at the basis of the consolidation of the micturition reflex. Vet Res Commun 32(4):291–304PubMedCrossRefGoogle Scholar
  13. Arvidsson U, Riedl M, Elde R, Meister B (1997) Vesicular acetylcholine transporter (VAChT) protein: a novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J Comp Neurol 378(4):454–467PubMedCrossRefGoogle Scholar
  14. Barendrecht MM, Oelke M, Laguna MP, Michel MC (2007) Is the use of parasympathomimetics for treating an underactive urinary bladder evidence-based? BJU Int 99(4):749–752PubMedCrossRefGoogle Scholar
  15. 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(5):1833–1839PubMedCrossRefGoogle Scholar
  16. Blanco M, Robinson MJ (2004) Muscarinic M3 acetylcholine receptor immunostaining in paraffin-embedded normal and neoplastic prostatic gland tissue. Ann Diagn Pathol 8(6):333–336PubMedCrossRefGoogle Scholar
  17. Bonev AD, Nelson MT (1993) Muscarinic inhibition of ATP-sensitive K+ channels by protein kinase C in urinary bladder smooth muscle. Am J Physiol 265(6 Pt 1):C1623–C1628Google Scholar
  18. Braverman AS, Ruggieri MR Sr (2003) Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol Regul Integr Comp Physiol 285(3):R701–R708PubMedGoogle Scholar
  19. Braverman AS, Luthin GR, Ruggieri MR (1998) M2 muscarinic receptor contributes to contraction of the denervated rat urinary bladder. Am J Physiol 275:R1654–R1660PubMedGoogle Scholar
  20. Braverman A, Legos J, Young W, Luthin G, Ruggieri M (1999) M2 receptors in genito-urinary smooth muscle pathology. Life Sci 64:429–436PubMedCrossRefGoogle Scholar
  21. Braverman AS, Tallarida RJ, Ruggieri MR Sr (2002) Interaction between muscarinic receptor subtype signal transduction pathways mediating bladder contraction. Am J Physiol Regul Integr Comp Physiol 283(3):R663–R668PubMedGoogle Scholar
  22. Bschleipfer T, Schukowski K, Weidner W, Grando SA, Schwantes U, Kummer W, Lips KS (2007) Expression and distribution of cholinergic receptors in the human urothelium. Life Sci 80(24–25):2303–2307PubMedCrossRefGoogle Scholar
  23. Caine M, Raz S, Zeigler M (1975) Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 47(2):193–202PubMedCrossRefGoogle Scholar
  24. Caulfield MP, Birdsall NJM (1998) International Union of Pharmacology: XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290PubMedGoogle Scholar
  25. Chapple CR, Crowe R, Gilpin SA, Gosling J, Burnstock G (1991) The innervation of the human prostate gland – the changes associated with benign enlargement. J Urol 146(6):1637–1644PubMedGoogle Scholar
  26. Chapple C, Khullar V, Gabriel Z, Dooley JA (2005) The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 48(1):5–26PubMedCrossRefGoogle Scholar
  27. Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D (2008) The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 54(3):543–562PubMedCrossRefGoogle Scholar
  28. Charlton RG, Morley AR, Chambers P, Gillespie JI (1999) Focal changes in nerve, muscle and connective tissue in normal and unstable human bladder. BJU Int 84(9):953–960PubMedCrossRefGoogle Scholar
  29. Cheng JT, Yu BC, Tong YC (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):1–5PubMedCrossRefGoogle Scholar
  30. Chess-Williams R (2002) Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol 22(3):133–145PubMedCrossRefGoogle Scholar
  31. D’Agostino G, Barbieri A, Chiossa E, Tonini M (1997) M4 muscarinic autoreceptor-mediated inhibition of -3H-acetylcholine release in the rat isolated urinary bladder. J Pharmacol Exp Ther 283(2):750–756PubMedGoogle Scholar
  32. D’Agostino G, Bolognesi ML, Lucchelli A, Vicini D, Balestra B, Spelta V, Melchiorre C, Tonini M (2000) Prejunctional muscarinic inhibitory control of acetylcholine release in the human isolated detrusor: involvement of the M4 receptor subtype. Br J Pharmacol 129(3):493–500PubMedCrossRefGoogle Scholar
  33. Dass N, McMurray G, Greenland JE, Brading AF (2001) Morphological aspects of the female pig bladder neck and urethra: quantitative analysis using computer assisted 3-dimensional reconstructions. J Urol 165(4):1294–1299PubMedCrossRefGoogle Scholar
  34. De Laet K, De Wachter S, Wyndaele JJ (2006) Systemic oxybutynin decreases afferent activity of the pelvic nerve of the rat: new insights into the working mechanism of antimuscarinics. Neurourol Urodyn 25(2):156–161PubMedCrossRefGoogle Scholar
  35. De Wachter S, Wyndaele JJ (2001) Does bladder tone influence sensation of filling and electro-sensation in the bladder? A blind controlled study in young healthy volunteers using bethanechol. J Urol 165(3):802–804PubMedCrossRefGoogle Scholar
  36. De Wachter S, Van Meel TD, Wyndaele JJ (2003) Study of the afferent nervous system and its evaluation in women with impaired detrusor contractility treated with bethanechol. Urology 62(1):54–58PubMedCrossRefGoogle Scholar
  37. Dixon JS, Jen PY, Gosling JA (2000) The distribution of vesicular acetylcholine transporter in the human male genitourinary organs and its co-localization with neuropeptide Y and nitric oxide synthase. Neurourol Urodyn 19(2):185–194PubMedCrossRefGoogle Scholar
  38. Eglen RM, Hegde SS, Watson N (1996) Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 48:531–565PubMedGoogle Scholar
  39. Ehlert FJ, Griffin MT, Abe DM, Vo TH, Taketo MM, Manabe T, Matsui M (2005) The M 2 muscarinic receptor mediates contraction through indirect mechanisms in mouse urinary bladder. J Pharmacol Exp Ther 313:368–378PubMedCrossRefGoogle Scholar
  40. Ek A, Alm P, Andersson KE, Persson CG (1977) Adrenergic and cholinergic nerves of the human urethra and urinary bladder. A histochemical study. Acta Physiol Scand 3:345–352CrossRefGoogle Scholar
  41. Ek A, Andersson KE, Ulmsten U (1978) The effects of norephedrine and bethanechol on the human urethral closure pressure profile. Scand J Urol Nephrol 12(2):97–104PubMedCrossRefGoogle Scholar
  42. el-Salmy S, Downie JW, Awad SA (1985) Bladder and urethral function and supersensitivity to subcutaneously administered bethanechol in cats with chronic cauda equina lesions. J Urol 134(5):1011–1018PubMedGoogle Scholar
  43. Finkbeiner AE (1985) Is bethanechol chloride clinically effective in promoting bladder emptying? A literature review. J Urol 134(3):443–449PubMedGoogle Scholar
  44. Finney SM, Andersson KE, Gillespie JI, Stewart LH (2006) Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions? BJU Int 98(3):503–507PubMedCrossRefGoogle Scholar
  45. Frazier EP, Braverman AS, Peters SLM, Michel MC, Ruggieri MR Sr (2007) Does phospholipase C mediate muscarinic receptor-induced rat urinary bladder contraction? J Pharmacol Exp Ther 322:998–1002PubMedCrossRefGoogle Scholar
  46. German K, Bedwani J, Davies J, Brading AF, Stephenson TP (1995) Physiological and morphometric studies into the pathophysiology of detrusor hyperreflexia in neuropathic patients. J Urol 153:1678–1683PubMedCrossRefGoogle Scholar
  47. Giglio D, Tobin G (2009) Muscarinic receptor subtypes in the lower urinary tract. Pharmacology 83(5):259–269PubMedCrossRefGoogle Scholar
  48. Giglio D, Ryberg AT, To K, Delbro DS, Tobin G (2005) Altered muscarinic receptor subtype expression and functional responses in cyclophosphamide induced cystitis in rats. Auton Neurosci 122(1–2):9–20PubMedCrossRefGoogle Scholar
  49. Goepel M, Gronewald A, Krege S, Michel MC (1998) Muscarinic receptor subtypes in porcine detrusor: comparison with humans and regulation by bladder augmentation. Urol Res 26:149–154PubMedCrossRefGoogle Scholar
  50. Gosling JA, Gilpin SA, Dixon JS, Gilpin CJ (1986) Decrease in the autonomic innervation of human detrusor muscle in outflow obstruction. J Urol 136:501–504PubMedGoogle Scholar
  51. Grol S, Essers PB, van Koeveringe GA, Martinez-Martinez P, de Vente J, Gillespie JI (2009) M(3) muscarinic receptor expression on suburothelial interstitial cells. BJU Int 104(3):398–405PubMedCrossRefGoogle Scholar
  52. Guay DR (2003) Clinical pharmacokinetics of drugs used to treat urge incontinence. Clin Pharmacokinet 42(14):1243–1285PubMedCrossRefGoogle Scholar
  53. Gudermann T, Kalkbrenner F, Schultz G (1996) Diversity and selectivity of receptor-G protein interaction. Annu Rev Pharmacol Toxicol 36:429–459PubMedGoogle Scholar
  54. Gup DI, Baumann M, Lepor H, Shapiro E (1989a) Muscarinic cholinergic receptors in normal pediatric and myelodysplastic bladders. J Urol 142(2 Pt 2):595–599, discussion 603–605PubMedGoogle Scholar
  55. Gup DI, Shapiro E, Baumann M, Lepor H (1989b) Contractile properties of human prostate adenomas and the development of infravesical obstruction. Prostate 15(2):105–114PubMedCrossRefGoogle Scholar
  56. Gup DI, Shapiro E, Baumann M, Lepor H (1990) Autonomic receptors in human prostate adenomas. J Urol 143(1):179–185PubMedGoogle Scholar
  57. Harrison SCV, Hunnam GR, Farman P, Doyle PT (1987) Bladder instability and denervation in patients with bladder outflow obstruction. Br J Urol 60:519–522PubMedCrossRefGoogle Scholar
  58. Harriss DR, Marsh KA, Birmingham AT, Hill SJ (1995) Expression of muscarinic M3-receptors coupled to inositol phospholipid hydrolysis in human detrusor cultured smooth muscle cells. J Urol 154(3):1241–1245PubMedCrossRefGoogle Scholar
  59. Hashitani H, Suzuki H (1996) Altered electrical properties of bladder smooth muscle in streptozotocin-induced diabetic rats. Br J Urol 77(6):798–804PubMedGoogle Scholar
  60. Hawthorn MH, Chapple CR, Cock M, Chess-Williams R (2000) Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br J Pharmacol 129(3):416–419PubMedCrossRefGoogle Scholar
  61. Hedlund H, Andersson KE (1988) Effects of prazosin and carbachol in patients with benign prostatic obstruction. Scand J Urol Nephrol 22(1):19–22PubMedGoogle Scholar
  62. Hedlund H, Andersson KE, Larsson B (1985) α-adrenoceptors and muscarinic receptors in the isolated human prostate. J Urol 134(6):1291–1298PubMedGoogle Scholar
  63. Hedlund P, Ekström P, Larsson B, Alm P, Andersson KE (1997) Heme oxygenase and NO-synthase in the human prostate – relation to adrenergic, cholinergic and peptide-containing nerves. J Auton Nerv Syst 63(3):115–126PubMedCrossRefGoogle Scholar
  64. Hegde SS, Eglen RM (1999) Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Life Sci 64(6–7):419–428PubMedCrossRefGoogle Scholar
  65. Hegde SS, Choppin A, Bonhaus D et al (1997) Functional role of M-2 and M-3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol 120:1409–1418PubMedCrossRefGoogle Scholar
  66. Herbison P, Hay-Smith J, Ellis G, Moore K (2003) Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. Br Med J 326:841–844CrossRefGoogle Scholar
  67. Hernández M, Símonsen U, Prieto D, Rivera L, García P, Ordaz E, García-Sacristán A (1993) Different muscarinic receptor subtypes mediating the phasic activity and basal tone of pig isolated intravesical ureter. Br J Pharmacol 110(4):1413–1420PubMedGoogle Scholar
  68. Hernández M, García-Sacristán A, Orensanz LM (1995) Muscarinic binding sites of the pig intravesical ureter. J Auton Pharmacol 15(5):351–359PubMedCrossRefGoogle Scholar
  69. Igawa Y, Zhang X, Nishizawa O, Umeda M, Iwata A, Taketo MM, Manabe T, Matsui M, Andersson KE (2004) Cystometric findings in mice lacking muscarinic M 2 or M 3 receptors. J Urol 172:2460–2464PubMedCrossRefGoogle Scholar
  70. Iijima K, De Wachter S, Wyndaele JJ (2007) Effects of the M3 receptor selective muscarinic antagonist darifenacin on bladder afferent activity of the rat pelvic nerve. Eur Urol 52(3):842–847PubMedCrossRefGoogle Scholar
  71. Ikeda Y, Birder L, Buffington C, Roppolo J, Kanai A (2009) Mucosal muscarinic receptors enhance bladder activity in cats with feline interstitial cystitis. J Urol 181(3):1415–1422PubMedCrossRefGoogle Scholar
  72. Inadome A, Yoshida M, Takahashi W, Yono M, Seshita H, Miyamoto Y, Kawano T, Ueda S (1998) Prejunctional muscarinic receptors modulating acetylcholine release in rabbit detrusor smooth muscles. Urol Int 61(3):135–141PubMedCrossRefGoogle Scholar
  73. James S, Chapple CR, Phillips MI, Greengrass PM, Davey MJ, Turner-Warwick RT, Milroy EJ, Burnstock G (1989) Autoradiographic analysis of alpha-adrenoceptors and muscarinic cholinergic receptors in the hyperplastic human prostate. J Urol 142(2 Pt 1):438–444PubMedGoogle Scholar
  74. Jezior JR, Brady JD, Rosenstein DI, McCammon KA, Miner AS, Ratz PH (2001) Dependency of detrusor contractions on calcium sensitization and calcium entry through LOE-908-sensitive channels. Br J Pharmacol 134(1):78–87PubMedCrossRefGoogle Scholar
  75. Johns A (1983) Alpha- and beta-adrenergic and muscarinic cholinergic binding sites in the bladder and urethra of the rabbit. Can J Physiol Pharmacol 61(1):61–66PubMedGoogle Scholar
  76. Jositsch G, Papadakis T, Haberberger RV, Wolff M, Wess J, Kummer W (2009) Suitability of muscarinic acetylcholine receptor antibodies for immunohistochemistry evaluated on tissue sections of receptor gene-deficient mice. Naunyn Schmiedebergs Arch Pharmacol 379(4):389–395PubMedCrossRefGoogle Scholar
  77. Kaplan SA, Te AE, Blaivas JG (1995) Urodynamic findings in patients with diabetic cystopathy. J Urol 153:342–344PubMedCrossRefGoogle Scholar
  78. Kester RR, Mooppan UM, Gousse AE, Alver JE, Gintautas J, Gulmi FA, Abadir AR, Kim H (2003) Pharmacological characterization of isolated human prostate. J Urol 170(3):1032–1038PubMedCrossRefGoogle Scholar
  79. Kinder RB, Mundy AR (1987) Pathophysiology of idiopathic detrusor instability and detrusor hyper-reflexia. An in vitro study of human detrusor muscle. Br J Urol 60(6):509–515PubMedCrossRefGoogle Scholar
  80. Koraitim MM (2008) The male urethral sphincter complex revisited: an anatomical concept and its physiological correlate. J Urol 179(5):1683–1689PubMedCrossRefGoogle Scholar
  81. Kotlikoff MI, Dhulipala P, Wang YX (1999) M2 signaling in smooth muscle cells. Life Sci 64(6–7):437–442PubMedCrossRefGoogle Scholar
  82. Krichevsky VP, Pagala MK, Vaydovsky I, Damer V, Wise GJ (1999) Function of M3 muscarinic receptors in the rat urinary bladder following partial outlet obstruction. J Urol 161(5):1644–1650PubMedCrossRefGoogle Scholar
  83. Latifpour J, Gousse A, Kondo S, Morita T, Weiss RM (1989) Effects of experimental diabetes on biochemical and functional characteristics of bladder muscarinic receptors. J Pharmacol Exp Ther 248:81–88PubMedGoogle Scholar
  84. Lepor H, Kuhar MJ (1984) Characterization and localization of the muscarinic cholinergic receptor in human prostatic tissue. J Urol 132(2):397–402PubMedGoogle Scholar
  85. Lincoln J, Burnstock G (1993) Autonomic innervation of the urinary bladder and urethra. In: Maggi CA (ed) The autonomic nervous system, vol 6, Nervous control of the urogenital system, Chapter 2. Harwood Academic, London, pp 33–68Google Scholar
  86. Long S, Nergårdh A (1978) Autonomic receptor functions of the human ureter: an in vitro study. Scand J Urol Nephrol 12(1):23–26PubMedGoogle Scholar
  87. Mansfield KJ, Liu L, Mitchelson FJ, Moore KH, Millard RJ, Burcher E (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(8):1089–1099PubMedCrossRefGoogle Scholar
  88. Mansfield KJ, Liu L, Moore KH, Vaux KJ, Millard RJ, Burcher E (2007) Molecular characterization of M2 and M3 muscarinic receptor expression in bladder from women with refractory idiopathic detrusor overactivity. BJU Int 99(6):1433–1438PubMedCrossRefGoogle Scholar
  89. Mansfield KJ, Chandran JJ, Vaux KJ, Millard RJ, Christopoulos A, Mitchelson FJ, Burcher E (2009) Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa. J Pharmacol Exp Ther 328(3):893–899PubMedCrossRefGoogle Scholar
  90. Matsui M, Motomura D, Fujikawa T, Jiang J, Takahashi S, Manabe T, Taketo MM (2002) Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J Neurosci 22(24):10627–10632PubMedGoogle Scholar
  91. Mattiasson A, Andersson KE, Sjögren C (1984) Adrenoceptors and cholinoceptors controlling noradrenaline release from adrenergic nerves in the urethra of rabbit and man. J Urol 131(6):1190–1195PubMedGoogle Scholar
  92. Mattiasson A, Andersson KE, Andersson PO, Larsson B, Sjögren C, Uvelius B (1990) Nerve-mediated functions in the circular and longitudinal muscle layers of the proximal female rabbit urethra. J Urol 143(1):155–160PubMedGoogle Scholar
  93. Michel MC, Hegde SS (2006) Treatment of the overactive bladder syndrome with muscarinic receptor antagonists: a matter of metabolites? Naunyn Schmiedebergs Arch Pharmacol 374(2):79–85PubMedCrossRefGoogle Scholar
  94. Michel MC, Wieland T, Tsujimoto G (2009) How reliable are G-protein-coupled receptor antibodies? Naunyn Schmiedebergs Arch Pharmacol 379(4):385–388PubMedCrossRefGoogle Scholar
  95. Mills IW, Greenland JE, McMurray G, McCoy R, Ho KHT, Noble JG, Brading AF (2000) Studies of the pathophysiology of idiopathic detrusor instability: the physiological properties of the detrusor smooth muscle and its pattern of innervation. J Urol 163:646–651PubMedCrossRefGoogle Scholar
  96. Mimata H, Wheeler MA, Fukomoto Y, Takigawa H, Nishimoto T, Weiss RM, Latifpour J (1995) Enhancement of muscarinic receptor-coupled phosphatidyl inositol hydrolysis in diabetic bladder. Mol Cell Biochem 152:71–76PubMedGoogle Scholar
  97. Mukerji G, Yiangou Y, Grogono J, Underwood J, Agarwal SK, Khullar V, Anand P (2006) Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol 176(1):367–373PubMedCrossRefGoogle Scholar
  98. Mutoh S, Latifpour J, Saito M, Weiss RM (1997) Evidence for the presence of regional differences in the subtype specificity of muscarinic receptors in rabbit lower urinary tract. J Urol 157(2):717–721PubMedCrossRefGoogle Scholar
  99. Nagahama K, Tsujii T, Morita T, Azuma H, Oshima H (1998) Differences between proximal and distal portions of the male rabbit posterior urethra in the physiological role of muscarinic cholinergic receptors. Br J Pharmacol 124(6):1175–1180PubMedCrossRefGoogle Scholar
  100. Nakamura T, Kimura J, Yamaguchi O (2002) Muscarinic M2 receptors inhibit Ca2+-activated K+ channels in rat bladder smooth muscle. Int J Urol 9(12):689–696PubMedCrossRefGoogle Scholar
  101. Nemeth L, O’Briain DS, Puri P (2001) Demonstration of neuronal networks in the human upper urinary tract using confocal laser scanning microscopy. J Urol 166(1):255–258PubMedCrossRefGoogle Scholar
  102. Novara G, Galfano A, Secco S, D’Elia C, Cavalleri S, Ficarra V, Artibani W (2008) A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Eur Urol 54(4):740–763PubMedCrossRefGoogle Scholar
  103. Obara K, Arai K, Miyajima N, Hatano A, Tomita Y, Takahashi K (2000) Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells. Urol Res 28(3):196–200PubMedCrossRefGoogle Scholar
  104. Pandita RK, Fujiwara M, Alm P, Andersson KE (2000) Cystometric evaluation of bladder function in non-anesthetized mice with and without bladder outlet obstruction. J Urol 164(4):1385–1389PubMedCrossRefGoogle Scholar
  105. Persson CG, Andersson KE (1976) Adrenoceptor and cholinoceptor mediated effects in the isolated urethra of cat and guinea-pig. Clin Exp Pharmacol Physiol 3(5):415–426PubMedCrossRefGoogle Scholar
  106. Persson K, Alm P, Johansson K, Larsson B, Andersson KE (1995) Co-existence of nitrergic, peptidergic and acetylcholine esterase-positive nerves in the pig lower urinary tract. J Auton Nerv Syst 52(2–3):225–236PubMedCrossRefGoogle Scholar
  107. Persson K, Johansson K, Alm P, Larsson B, Andersson KE (1997) Morphological and functional evidence against a sensory and sympathetic origin of nitric oxide synthase-containing nerves in the rat lower urinary tract. Neuroscience 77(1):271–281PubMedCrossRefGoogle Scholar
  108. Pradidarcheep W, Labruyere WT, Dabhoiwala NF, Lamers WH (2008) Lack of specificity of commercially available antisera: better specifications needed. J Histochem Cytochem 56:1099–1111PubMedCrossRefGoogle Scholar
  109. Pradidarcheep W, Stallen J, Labruyere WT, Dabhoiwala NF, Michel MC, Lamers WH (2009) Lack of specificity of commercially available antisera against muscarinic and adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol 379:397–402PubMedCrossRefGoogle Scholar
  110. Prieto D, Simonsen U, Martín J, Hernández M, Rivera L, Lema L, García P, García-Sacristán A (1994) Histochemical and functional evidence for a cholinergic innervation of the equine ureter. J Auton Nerv Syst 47(3):159–170PubMedCrossRefGoogle Scholar
  111. Rayford W, Noble MJ, Austenfeld MA, Weigel J, Mebust WK, Shah GV (1997) Muscarinic cholinergic receptors promote growth of human prostate cancer cells. Prostate 30(3):160–166PubMedCrossRefGoogle Scholar
  112. Restorick JM, Mundy AR (1989) The density of cholinergic and alpha and beta adrenergic receptors in the normal and hyper-reflexic human detrusor. Br J Urol 63(1):32–35PubMedCrossRefGoogle Scholar
  113. Riedl CR, Stephen RL, Daha LK, Knoll M, Plas E, Pflüger H (2000) Electromotive administration of intravesical bethanechol and the clinical impact on acontractile detrusor management: introduction of a new test. J Urol 164(6):2108–2111PubMedCrossRefGoogle Scholar
  114. Roden DM (2004) Drug-induced prolongation of the QT interval. N Engl J Med 350(10):1013–1022PubMedCrossRefGoogle Scholar
  115. Rolle U, Chertin B, Nemeth L, Puri P (2002) Demonstration of nitrergic and cholinergic innervation in whole-mount preparations of rabbit, pig, and human upper urinary tract. Pediatr Surg Int 18(5–6):315–318PubMedCrossRefGoogle Scholar
  116. Rolle U, Brylla E, Tillig B, Chertin B, Cascio S, Puri P (2008) Demonstration of intrinsic innervation of the guinea pig upper urinary tract using whole-mount preparation. Neurourol Urodyn 27(4):341–347PubMedCrossRefGoogle Scholar
  117. Roosen A, Wu C, Sui GP, Fry CH (2008) Synergistic effects in neuromuscular activation and calcium-sensitization in the bladder trigone. BJU Int 101(5):610–614PubMedCrossRefGoogle Scholar
  118. Ruggieri MR Sr, Braverman AS (2006) Regulation of bladder muscarinic receptor subtypes by experimental pathologies. Auton Autacoid Pharmacol 26(3):311–325PubMedCrossRefGoogle Scholar
  119. Ruggieri MR, Colton MD, Wang P, Wang J, Smyth RJ, Pontari MA, Luthin GR (1995) Human prostate muscarinic receptor subtypes. J Pharmacol Exp Ther 274(2):976–982PubMedGoogle Scholar
  120. Sakamoto K, Suri D, Rajasekaran M (2006) Characterization of muscarinic receptor subtypes in human ureter. J Endourol 20(11):939–942PubMedCrossRefGoogle Scholar
  121. Schneider T, Fetscher C, Krege S, Michel MC (2004a) Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther 309(3):1148–1153PubMedCrossRefGoogle Scholar
  122. Schneider T, Hein P, Michel MC (2004b) Signal transduction underlying carbachol-induced contraction of rat urinary bladder. I. Phospholipases and Ca2+ sources. J Pharmacol Exp Ther 308(1):47–53PubMedCrossRefGoogle Scholar
  123. Schulman CC (1975) Ultrastructural evidence for adrenergic and cholinergic innervation of the human ureter. J Urol 113(6):765–771PubMedGoogle Scholar
  124. Sibley GN (1984) A comparison of spontaneous and nerve-mediated activity in bladder muscle from man, pig and rabbit. J Physiol 354:431–443PubMedGoogle Scholar
  125. Sibley GNA (1987) The physiological response of the detrusor muscle to experimental bladder outflow obstruction in the pig. Br J Urol 60:332–336PubMedCrossRefGoogle Scholar
  126. Sigala S, Mirabella G, Peroni A, Pezzotti G, Simeone C, Spano P, Cunico SC (2002) Differential gene expression of cholinergic muscarinic receptor subtypes in male and female normal human urinary bladder. Urology 60(4):719–725PubMedCrossRefGoogle Scholar
  127. Sjögren C, Andersson KE, Husted S, Mattiasson A, Moller-Madsen B (1982) Atropine resistance of transmurally stimulated isolated human bladder muscle. J Urol 128(6):1368–1371PubMedGoogle Scholar
  128. Somogyi GT, de Groat WC (1992) Evidence for inhibitory nicotinic and facilitatory muscarinic receptors in cholinergic nerve terminals of the rat urinary bladder. J Auton Nerv Syst 37(2):89–97PubMedCrossRefGoogle Scholar
  129. Somogyi GT, de Groat WC (1999) Function, signal transduction mechanisms and plasticity of presynaptic muscarinic receptors in the urinary bladder. Life Sci 64(6–7):411–418PubMedCrossRefGoogle Scholar
  130. Somogyi GT, Zernova GV, Yoshiyama M, Rocha JN, Smith CP, de Groat WC (2003) Change in muscarinic modulation of transmitter release in the rat urinary bladder after spinal cord injury. Neurochem Int 43(1):73–77PubMedCrossRefGoogle Scholar
  131. Speakman MJ, Brading AF, Gilpin CJ, DixonJS GSA, Gosling J (1987) Bladder outflow obstruction – a cause of denervation supersensitivity. J Urol 138:1461–1466PubMedGoogle Scholar
  132. Speakman MJ, Walmsley D, Brading AF (1988) An in vitro pharmacological study of the human trigone – a site of non-adrenergic, non-cholinergic neurotransmission. Br J Urol 61(4):304–309PubMedCrossRefGoogle Scholar
  133. Stevens LA, Sellers DJ, McKay NG, Chapple CR, Chess-Williams R (2006) Muscarinic receptor function, density and G-protein coupling in the overactive diabetic rat bladder. Auton Autacoid Pharmacol 26(3):303–309PubMedCrossRefGoogle Scholar
  134. Stevens LA, Chapple CR, Chess-Williams R (2007) Human idiopathic and neurogenic overactive bladders and the role of M2 muscarinic receptors in contraction. Eur Urol 52(2):531–538PubMedCrossRefGoogle Scholar
  135. Tagliani M, Candura SM, Di Nucci A, Franceschetti 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(6):750–755PubMedCrossRefGoogle Scholar
  136. Taki N, Taniguchi T, Okada K, Moriyama N, Muramatsu I (1999) Evidence for predominant mediation of alpha1-adrenoceptor in the tonus of entire urethra of women. J Urol 162(5):1829–1832PubMedCrossRefGoogle Scholar
  137. Taylor JA III, Kuchel GA (2006) Detrusor underactivity: clinical features and pathogenesis of an underdiagnosed geriatric condition. J Am Geriatr Soc 54(12):1920–1932PubMedCrossRefGoogle Scholar
  138. Tobin G, Sjögren C (1995) In vivo and in vitro effects of muscarinic receptor antagonists on contractions and release of [ 3 H]acetylcholine in the rabbit urinary bladder. Eur J Pharmacol 281:1–8PubMedCrossRefGoogle Scholar
  139. Tomiyama Y, Wanajo I, Yamazaki Y, Murakami M, Kojima M, Shibata N (2003) Functional muscarinic cholinoceptors in the isolated canine ureter. Naunyn Schmiedebergs Arch Pharmacol 367(4):348–352PubMedCrossRefGoogle Scholar
  140. Tomiyama Y, Wanajo I, Yamazaki Y, Kojima M, Shibata N (2004) Effects of cholinergic drugs on ureteral function in anesthetized dogs. J Urol 172(4 Pt 1):1520–1523PubMedCrossRefGoogle Scholar
  141. Tong YC, Cheng JT, Hsu CT (2006) Alterations of M(2)-muscarinic receptor protein and mRNA expression in the urothelium and muscle layer of the streptozotocin-induced diabetic rat urinary bladder. Neurosci Lett 406(3):216–221PubMedCrossRefGoogle Scholar
  142. Turner WH, Brading AF (1997) Smooth muscle of the bladder in the normal and the diseased state: pathophysiology, diagnosis and treatment. Pharmacol Ther 75(2):77–110PubMedCrossRefGoogle Scholar
  143. Twiddy DA, Downie JW, Awad SA (1980) Response of the bladder to bethanechol after acute spinal cord transection in cats. J Pharmacol Exp Ther 215(2):500–506PubMedGoogle Scholar
  144. Tyagi S, Tyagi P, Van-le S, Yoshimura N, Chancellor MB, de Miguel F (2006) Qualitative and quantitative expression profile of muscarinic receptors in human urothelium and detrusor. J Urol 176(4 Pt 1):1673–1678PubMedCrossRefGoogle Scholar
  145. Ulmsten U, Andersson KE (1977) The effects of emeprone on intravesical and intra-urethral pressure in women with urgency incontinence. Scand J Urol Nephrol 11(2):103–109PubMedCrossRefGoogle Scholar
  146. van Koppen CJ, Kaiser B (2003) Regulation of muscarinic acetylcholine receptor signaling. Pharmacol Ther 98(2):197–220PubMedCrossRefGoogle Scholar
  147. Wang P, Luthin GR, Ruggieri MR (1995) Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther 273:959–966PubMedGoogle Scholar
  148. Werner ME, Knorn AM, Meredith AL, Aldrich RW, Nelson MT (2007) Frequency encoding of cholinergic- and purinergic-mediated signaling to mouse urinary bladder smooth muscle: modulation by BK channels. Am J Physiol Regul Integr Comp Physiol 292(1):R616–R624PubMedGoogle Scholar
  149. Wibberley A, Chen Z, Hu E, Hieble JP, Westfall TD (2003) Expression and functional role of Rho-kinase in rat urinary bladder smooth muscle. Br J Pharmacol 138(5):757–766PubMedCrossRefGoogle Scholar
  150. Witte LP, Chapple CR, de la Rosette JJ, Michel MC (2008) Cholinergic innervation and muscarinic receptors in the human prostate. Eur Urol 54(2):326–334PubMedCrossRefGoogle Scholar
  151. Wu G, Bogatkevich GS, Mukhin YV, Benovic JL, Hildebrandt JD, Lanier SM (2000) Identification of Gβγ binding sites in the third intracellular loop of the M 3 -muscarinic receptor and their role in receptor regulation. J Biol Chem 275:9026–9034PubMedCrossRefGoogle Scholar
  152. Yamaguchi O, Shishido K, Tamura K et al (1996) Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J Urol 156:1208–1213PubMedCrossRefGoogle Scholar
  153. Yamamoto M, Unno T, Matsuyama H, Kohda M, Masuda N, Nishimura M, Ishii T, Komori S (2008) Two types of cation channel activated by stimulation of muscarinic receptors in guinea-pig urinary bladder smooth muscle. J Pharmacol Sci 108(3):248–257PubMedCrossRefGoogle Scholar
  154. Yamanishi T, Chapple CR, Yasuda K, Chess-Williams R (2000) The role of M2 -muscarinic receptors in mediating contraction of the pig urinary bladder in vitro. Br J Pharmacol 131:1482–1488PubMedCrossRefGoogle Scholar
  155. Yokoyama O, Nagano K, Kawaguchi K, Hisazumi H (1991) The response of the detrusor muscle to acetylcholine in patients with infravesical obstruction. Urol Res 19:117–121PubMedCrossRefGoogle Scholar
  156. Yoshida M, Miyamae K, Iwashita H, Otani M, Inadome A (2004) Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology 63(3 Suppl 1):17–23PubMedCrossRefGoogle Scholar
  157. Yoshida M, Inadome A, Maeda Y, Satoji Y, Masunaga K, Sugiyama Y, Murakami S (2006) Non-neuronal cholinergic system in human bladder urothelium. Urology 67(2):425–430PubMedCrossRefGoogle Scholar
  158. Yoshida M, Masunaga K, Satoji Y, Maeda Y, Nagata T, Inadome A (2008) Basic and clinical aspects of non-neuronal acetylcholine: expression of non-neuronal acetylcholine in urothelium and its clinical significance. J Pharmacol Sci 106(2):193–198PubMedCrossRefGoogle Scholar
  159. Yoshimura N, Kaiho Y, Miyazato M, Yunoki T, Tai C, Chancellor MB, Tyagi P (2008) Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol 377(4–6):437–448PubMedCrossRefGoogle Scholar
  160. Zhou H, Meyer A, Starke K, Gomeza J, Wess J, Trendelenburg AU (2002) Heterogeneity of release-inhibiting muscarinic autoreceptors in heart atria and urinary bladder: a study with M(2)- and M(4)-receptor-deficient mice. Naunyn Schmiedebergs Arch Pharmacol 365(2):112–122PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Institute for Regenerative MedicineWake Forest University School of MedicineWinston SalemUSA

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