Physiology and Pharmacology of the Bladder

  • Karl-Erik Andersson
Part of the Springer Specialist Surgery Series book series (SPECIALIST)


The functions of the lower urinary tract (LUT) are to store and periodically release urine. These functions are dependent upon a complex interplay between the central and peripheral nervous systems and local regulatory factors.1 The neural circuitry that controls these interactions is complex and involves pathways at many levels of the brain, the spinal cord, and the peripheral nervous system, and it is mediated by multiple neurotransmitters. Micturition is under voluntary control and depends on learned behavior that develops during maturation of the nervous system. Normal micturition requires coordination of the activity of the bladder and urethra with that of urethral striated muscle, and depends on the integration of pontine centers and autonomic and somatic efferent mechanisms within the lumbosacral spinal cord (see Fowler et al.2).


Muscarinic Receptor Lower Urinary Tract Nicotinic Receptor Detrusor Overactivity Human Bladder 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84(3):935-986PubMedCrossRefGoogle Scholar
  2. 2.
    Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008;9(6):453-466PubMedCrossRefGoogle Scholar
  3. 3.
    Zinner NR, Koke SC, Viktrup L. Pharmacotherapy for stress urinary incontinence: present and future options. Drugs. 2004;64(14):1503-1516PubMedCrossRefGoogle Scholar
  4. 4.
    Andersson K-E, Chapple CR, Cardozo L, Cruz F, Hashim H, Michel MC, Tannenbaum C, Wein AJ. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A eds. Incontinence. 4th International Consultation on Incontinence. Plymouth: Plymbridge Distributors; 2009Google Scholar
  5. 5.
    Lincoln J, Burnstock, G. Autonomic innervation of the urinary bladder and urethra. In: Maggi CA, ed. The Autonomic Nervous System. Vol. 6, Nervous Control of the Urogenital System. London: Harwood Academic Publisher; 1993:33–68, chap. 2Google Scholar
  6. 6.
    Zagorodnyuk VP, Costa M, Brookes SJ. Major classes of sensory neurons to the urinary bladder. Auton Neurosci. 2006;126–127:390-397PubMedCrossRefGoogle Scholar
  7. 7.
    Zagorodnyuk VP, Gibbins IL, Costa M, Brookes SJ, Gregory SJ. Properties of the major classes of mechanoreceptors in the guinea pig bladder. J Physiol. 2007; 585:147-163PubMedCrossRefGoogle Scholar
  8. 8.
    Iggo A. Tension receptors in the stomach and the urinary bladder. J Physiol. 1955;128:593-607PubMedGoogle Scholar
  9. 9.
    Kuru M. Nervous control of micturition. Physiol Rev. 1965;45:425-494PubMedGoogle Scholar
  10. 10.
    de Groat WC, Booth AM, Yoshimura N. Neurophysiology of micturition and its modification in animal models of human disease. In: Maggi CA, ed. Nervous Control of the Urogenital System. London: Harwood Academic; 1993:227-290Google Scholar
  11. 11.
    Häbler HJ, Jänig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol. 1990;425:545-562PubMedGoogle Scholar
  12. 12.
    Fall M, Lindstrom S, Mazieres L. A bladder-to-bladder cooling reflex in the cat. J Physiol. 1990;427:281-300PubMedGoogle Scholar
  13. 13.
    Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev. December 2004; 56(4):581-631PubMedCrossRefGoogle Scholar
  14. 14.
    Burnstock G. Purinergic signalling in lower urinary tract. In: Abbracchio MP, Williams MP, eds. Purinergic and Pyrimidinergic Signalling I Molecular, Nervous and Urogenitary System Function. Berlin: Springer; 2001:151, 423–515Google Scholar
  15. 15.
    Thor KB, Donatucci C. Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women. J Urol. 2004;172(1):27-33PubMedCrossRefGoogle Scholar
  16. 16.
    Yoshimura N, Kaiho Y, Miyazato M, et al. Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol. 2008; 377(4–6):437-448PubMedCrossRefGoogle Scholar
  17. 17.
    Andersson K-E. Bladder activation: afferent mechanisms. Urology. 2002;59(5 Suppl 1):43-50PubMedCrossRefGoogle Scholar
  18. 18.
    Birder LA, Kanai AJ, de Groat WC, et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA. 6, 2001;98(23):13396-13401PubMedCrossRefGoogle Scholar
  19. 19.
    Birder LA, Nakamura Y, Kiss S, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci. 2002;5(9):856-860PubMedCrossRefGoogle Scholar
  20. 20.
    Sui GP, Rothery S, Dupont E, Fry CH, Severs NJ. Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int. 2002;90(1):118-129PubMedCrossRefGoogle Scholar
  21. 21.
    Sui GP, Wu C, Fry CH. Electrical characteristics of suburothelial cells isolated from the human bladder. J Urol. 2004;171(2 Pt 1):938-943PubMedCrossRefGoogle Scholar
  22. 22.
    Birder and de Groat, 2007 (Birder LA, de Groat WC. Mechanisms of disease: involvement of the urothelium in bladder dysfunction., Nat Clin Pract Urol. 2007 Jan;4(1):46-54)PubMedCrossRefGoogle Scholar
  23. 23.
    Pandita RK, Andersson KE. Intravesical adenosine triphosphate stimulates the micturition reflex in awake, freely moving rats. J Urol. 2002;168(3):1230-1234PubMedCrossRefGoogle Scholar
  24. 24.
    Cockayne DA, Hamilton SG, Zhu QM, et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000;407(6807): 1011-1015PubMedCrossRefGoogle Scholar
  25. 25.
    Vlaskovska M, Kasakov L, Rong W, et al. P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci. 2001;21(15):5670-5677PubMedGoogle Scholar
  26. 26.
    Fovaeus M, Fujiwara M, Hogestatt ED, Persson K, Andersson KE. A non-nitrergic smooth muscle relaxant factor released from rat urinary bladder by muscarinic receptor stimulation. J Urol. 1999;161(2): 649-653PubMedCrossRefGoogle Scholar
  27. 27.
    Hawthorn MH, Chapple CR, Cock M, Chess-Williams R. Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br J Pharmacol. 2000;129(3):416-419PubMedCrossRefGoogle Scholar
  28. 28.
    Hashitani H, Brading AF, Suzuki H. Correlation between spontaneous electrical, calcium and mechanical activity in detrusor smooth muscle of the guinea-pig bladder. Br J Pharmacol. 2004;141(1):183-193PubMedCrossRefGoogle Scholar
  29. 29.
    Drake MJ, Mills IW, Gillespie JI. Model of peripheral autonomous modules and a myovesical plexus in normal and overactive bladder function. Lancet. 2001; 358(9279):401-403PubMedCrossRefGoogle Scholar
  30. 30.
    Gillespie JI. A developing view of the origins of urgency: the importance of animal models. BJU Int. 2005;96 (Suppl 1):22-28PubMedCrossRefGoogle Scholar
  31. 31.
    Kinder RB, Mundy AR. Pathophysiology of idiopathic detrusor instability and detrusor hyper-reflexia. An in vitro study of human detrusor muscle. Br J Urol. 1987;60(6):509-515PubMedCrossRefGoogle Scholar
  32. 32.
    Brading AF. A myogenic basis for the overactive bladder. Urology. 1997;50(6A Suppl):57-67; discussion 68-73PubMedCrossRefGoogle Scholar
  33. 33.
    Mills IW, Greenland JE, McMurray G, et al. Studies of the pathophysiology of idiopathic detrusor instability: the physiological properties of the detrusor smooth muscle and its pattern of innervation. J Urol. 2000; 163:646-651PubMedCrossRefGoogle Scholar
  34. 34.
    Turner WH, Brading AF. Smooth muscle of the bladder in the normal and the diseased state: pathophysiology, diagnosis and treatment. Pharmacol Ther. 1997; 75(2):77-110PubMedCrossRefGoogle Scholar
  35. 35.
    Stevens LA, Chapple CR, Chess-Williams R. Human idiopathic and neurogenic overactive bladders and the role of M2 muscarinic receptors in contraction. Eur Urol. 2007;52(2):531-538PubMedCrossRefGoogle Scholar
  36. 36.
    Wu C, Sui GP, Fry CH. Purinergic regulation of guinea pig suburothelial myofibroblasts. J Physiol. 2004;559 (Pt 1):231-243PubMedCrossRefGoogle Scholar
  37. 37.
    Fry CH, Sui GP, Kanai AJ, Wu C. The function of suburothelial myofibroblasts in the bladder. Neurourol Urodyn. 2007;26(6 Suppl):914-919PubMedCrossRefGoogle Scholar
  38. 38.
    Ikeda Y, Kanai A. Urotheliogenic modulation of intrinsic activity in spinal cord-transected rat bladders: role of mucosal muscarinic receptors. Am J Physiol Ren Physiol. 2008;295(2):F454-F461CrossRefGoogle Scholar
  39. 39.
    Sui GP, Wu C, Roosen A, Ikeda Y, Kanai AJ, Fry CH. Modulation of bladder myofibroblast activity: implications for bladder function. Am J Physiol Ren Physiol. 2008;295(3):F688-F697CrossRefGoogle Scholar
  40. 40.
    Gillespie JI, van Koeveringe GA, de Wachter SG, de Vente J. On the origins of the sensory output from the bladder: the concept of afferent noise. BJU Int. 2009;103(10):1324-1333PubMedCrossRefGoogle Scholar
  41. 41.
    Caulfield MP, Birdsall NJM. International Union of Pharmacology: XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998;50: 279-290PubMedGoogle Scholar
  42. 42.
    Sigala S, Mirabella G, Peroni A, et al. Differential gene expression of cholinergic muscarinic receptor subtypes in male and female normal human urinary bladder. Urology. 2002;60(4):719-725PubMedCrossRefGoogle Scholar
  43. 43.
    Bschleipfer T, Schukowski K, Weidner W, et al. Expression and distribution of cholinergic receptors in the human urothelium. Life Sci. 2007;80(24–25):2303-2307PubMedCrossRefGoogle Scholar
  44. 44.
    Yamaguchi O, Shishido K, Tamura K, et al. Evaluation of mRNAs encoding muscarinicreceptor subtypes in human detrusor muscle. J Urol. 1996;156:1208-1213PubMedCrossRefGoogle Scholar
  45. 45.
    Eglen RM, Hegde SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev. 1996;48:531-565PubMedGoogle Scholar
  46. 46.
    Hegde SS, Eglen RM. Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Life Sci. 1999;64(6–7):419-428PubMedCrossRefGoogle Scholar
  47. 47.
    Chess-Williams R. Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol. 2002;22(3):133-145PubMedCrossRefGoogle Scholar
  48. 48.
    Giglio D, Tobin G. Muscarinic receptor subtypes in the lower urinary tract. Pharmacology. 2009;83(5): 259-269PubMedCrossRefGoogle Scholar
  49. 49.
    Schneider T, Fetscher C, Krege S, Michel MC. Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther. June 2004;309(3):1148-1153PubMedCrossRefGoogle Scholar
  50. 50.
    Jezior JR, Brady JD, Rosenstein DI, McCammon KA, Miner AS, Ratz PH. Dependency of detrusor contractions on calcium sensitization and calcium entry through LOE-908-sensitive channels. Br J Pharmacol. 2001;134(1):78-87PubMedCrossRefGoogle Scholar
  51. 51.
    Wibberley A, Chen Z, Hu E, Hieble JP, Westfall TD. Expression and functional role of Rho-kinase in rat urinary bladder smooth muscle. Br J Pharmacol. 2003; 138(5):757-766PubMedCrossRefGoogle Scholar
  52. 52.
    Andersson K-E. Detrusor contraction – focus on muscarinic receptors. Scand J Urol Nephrol Suppl. 2004;215: 54-57PubMedCrossRefGoogle Scholar
  53. 53.
    Hegde SS, Choppin A, Bonhaus D, et al. Functional role of M-2 and M-3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol. 1997;120:1409-1418PubMedCrossRefGoogle Scholar
  54. 54.
    Kotlikoff MI, Dhulipala P, Wang YX. M2 signaling in smooth muscle cells. Life Sci. 1999;64(6–7):437-442PubMedCrossRefGoogle Scholar
  55. 55.
    Nakamura T, Kimura J, Yamaguchi O. Muscarinic M2 receptors inhibit Ca2+-activated K+ channels in rat bladder smooth muscle. Int J Urol. 2002;9(12):689-696PubMedCrossRefGoogle Scholar
  56. 56.
    Bonev AD, Nelson MT. Muscarinic inhibition of ATP-sensitive K+ channels by protein kinase C in urinary bladder smooth muscle. Am J Physiol. 1993;265(6 Pt 1):C1723-C1728PubMedGoogle Scholar
  57. 57.
    Braverman AS, Luthin GR, Ruggieri MR. M2 muscarinic receptor contributes to contraction of the denervated rat urinary bladder. Am J Physiol. 1998;275: R1654-R1660PubMedGoogle Scholar
  58. 58.
    Braverman A, Legos J, Young W, Luthin G, Ruggieri M. M2 receptors in genito-urinary smooth muscle pathology. Life Sci. 1999;64:429-436PubMedCrossRefGoogle Scholar
  59. 59.
    Braverman AS, Tallarida RJ, Ruggieri MR Sr. Interaction between muscarinic receptor subtype signal transduction pathways mediating bladder contraction. Am J Physiol Regul Integr Comp Physiol. September 2002; 283(3):R663-R668PubMedGoogle Scholar
  60. 60.
    Braverman AS, Ruggieri MR Sr. Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol Regul Integr Comp Physiol. 2003;285(3):R701-R708PubMedGoogle Scholar
  61. 61.
    Pontari MA, Braverman AS, Ruggieri MR Sr. The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction. Am J Physiol Regul Integr Comp Physiol. 2004;286(5):R874-R880PubMedCrossRefGoogle Scholar
  62. 62.
    D’Agostino G, Bolognesi ML, Lucchelli A, et al. Prejunctional muscarinic inhibitory control of acetylcholine release in the human isolated detrusor: involvement of the M4 receptor subtype. Br J Pharmacol. 2000;129(3):493-500PubMedCrossRefGoogle Scholar
  63. 63.
    Somogyi GT, de Groat WC. Function, signal transduction mechanisms and plasticity of presynaptic muscarinic receptors in the urinary bladder. Life Sci. 1999; 64(6–7):411-418PubMedCrossRefGoogle Scholar
  64. 64.
    Somogyi GT, Zernova GV, Yoshiyama M, Rocha JN, Smith CP, de Groat WC. Change in muscarinic modulation of transmitter release in the rat urinary bladder after spinal cord injury. Neurochem Int. 2003;43(1):73-77PubMedCrossRefGoogle Scholar
  65. 65.
    Tyagi S, Tyagi P, Van-le S, Yoshimura N, Chancellor MB, de Miguel F. Qualitative and quantitative expression profile of muscarinic receptors in human urothelium and detrusor. J Urol. 2006;176(4 Pt 1):1673-1678PubMedCrossRefGoogle Scholar
  66. 66.
    Mansfield KJ, Liu L, Mitchelson FJ, Moore KH, Millard RJ, Burcher E. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radiolig-and binding and quantitative competitive RT-PCR: changes in ageing. Br J Pharmacol. 2005;144(8):1089-1099PubMedCrossRefGoogle Scholar
  67. 67.
    Mukerji G, Yiangou Y, Grogono J, et al. Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol. 2006; 176(1):367-373PubMedCrossRefGoogle Scholar
  68. 68.
    Grol S, Essers PB, van Koeveringe GA, Martinez-Martinez P, de Vente J, Gillespie JI. M(3) muscarinic receptor expression on suburothelial interstitial cells. BJU Int. 11, 2009 [Epub ahead of print]Google Scholar
  69. 69.
    Wakabayashi Y, Tomoyoshi T, Fujimiya M, Arai R, Maeda T. Substance P-containing axon terminals in the mucosa of the human urinary bladder: pre-embedding immunohistochemistry using cryostat sections for electron microscopy. Histochemistry. 1993;100(6):401-407PubMedCrossRefGoogle Scholar
  70. 70.
    Persson K, Alm P, Johansson K, Larsson B, Andersson KE. Co-existence of nitrergic, peptidergic and acetylcholine esterase-positive nerves in the pig lower urinary tract. J Auton Nerv Syst. 1995;52(2–3):225-236PubMedCrossRefGoogle Scholar
  71. 71.
    Gabella G, Davis C. Distribution of afferent axons in the bladder of rats. J Neurocytol. 1998;27(3):141-155PubMedCrossRefGoogle Scholar
  72. 72.
    Ferguson DR, Kennedy I, Burton TJ. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes–a possible sensory mechanism? J Physiol. 1997;505(Pt 2):503-511PubMedCrossRefGoogle Scholar
  73. 73.
    Birder LA, Barrick SR, Roppolo JR, et al. Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium. Am J Physiol Ren Physiol. 2003;285(3):F423-F429Google Scholar
  74. 74.
    Kullmann FA, Artim DE, Birder LA, de Groat WC. Activation of muscarinic receptors in rat bladder sensory pathways alters reflex bladder activity. J Neurosci. 2008;28(8):1977-1987PubMedCrossRefGoogle Scholar
  75. 75.
    Yoshida M, Inadome A, Maeda Y, et al. Non-neuronal cholinergic system in human bladder urothelium. Urology. 2006;67(2):425-430PubMedCrossRefGoogle Scholar
  76. 76.
    Hanna-Mitchell AT, Beckel JM, Barbadora S, Kanai AJ, de Groat WC, Birder LA. Non-neuronal acetylcholine and urinary bladder urothelium. Life Sci. 2007;80(24–25): 2298-2302PubMedCrossRefGoogle Scholar
  77. 77.
    Beckel JM, Kanai A, Lee SJ, de Groat WC, Birder LA. Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells. Am J Physiol Ren Physiol. 2006;290(1):F103-F110CrossRefGoogle Scholar
  78. 78.
    Malloy BJ, Price DT, Price RR, et al. Alpha1-adrenergic receptor subtypes in human detrusor. J Urol. 1998; 160:937-943PubMedCrossRefGoogle Scholar
  79. 79.
    Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol. 2006;147(Suppl 2):S88-S119PubMedCrossRefGoogle Scholar
  80. 80.
    Andersson KE, Gratzke C. Pharmacology of alpha1-adrenoceptor antagonists in the lower urinary tract and central nervous system. Nat Clin Pract Urol. 2007; 4(7):368-378PubMedCrossRefGoogle Scholar
  81. 81.
    Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol. 2003;170(2 Pt 1):649-653PubMedCrossRefGoogle Scholar
  82. 82.
    Bouchelouche K, Andersen L, Alvarez S, Nordling J, Bouchelouche P. Increased contractile response to phenylephrine in detrusor of patients with bladder outlet obstruction: effect of the alpha1A and alpha1D-adrenergic receptor antagonist tamsulosin. J Urol. 2005;173(2):657-661PubMedCrossRefGoogle Scholar
  83. 83.
    Das AK, Leggett RE, Whitbeck C, et al. Effect of doxazosin on rat urinary bladder function after partial outlet obstruction. Neurourol Urodyn. 2002;21:160-166PubMedCrossRefGoogle Scholar
  84. 84.
    Andersson K-E. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev. 1993;45:253-308Google Scholar
  85. 85.
    Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S. Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedebergs Arch Pharmacol. 2008;377(4–6):473-481PubMedCrossRefGoogle Scholar
  86. 86.
    Badawi JK, Seja T, Uecelehan H, et al. Relaxation of human detrusor muscle by selective beta-2 and beta-3 agonists and endogenous catecholamines. Urology. 2007;69(4):785-790PubMedCrossRefGoogle Scholar
  87. 87.
    Leon LA, Hoffman BE, Gardner SD, et al. Effects of the beta 3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2- (3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1, 3-benzodioxole-2, 2-dicarboxylate (CL-316243) on bladder micturition reflex in spontaneously hypertensive rats. J Pharmacol Exp Ther. 2008;326(1):178-185PubMedCrossRefGoogle Scholar
  88. 88.
    Biers SM, Reynard JM, Brading AF. The effects of a new selective beta3-adrenoceptor agonist (GW427353) on spontaneous activity and detrusor relaxation in human bladder. BJU Int. 2006;98(6):1310-1314PubMedCrossRefGoogle Scholar
  89. 89.
    Andersson K-E. Pathways for relaxation of detrusor smooth muscle. In: Baskin LS, Hayward SW, eds. Advances in Bladder Research. New York: Kluwer Academic/Plenum; 1999:241-252Google Scholar
  90. 90.
    Uchida H, Shishido K, Nomiya M, Yamaguchi O. Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur J Pharmacol. 22, 2005;518(2–3):195-202PubMedCrossRefGoogle Scholar
  91. 91.
    Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC. Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 2008; 377(4–6):449-462PubMedCrossRefGoogle Scholar
  92. 92.
    Takemoto J, Masumiya H, Nunoki K, et al. Potentiation of potassium currents by beta-adrenoceptor agonists in human urinary bladder smooth muscle cells: a possible electrical mechanism of relaxation. Pharmacology. 2008;81(3):251-258PubMedCrossRefGoogle Scholar
  93. 93.
    Hristov KL, Cui X, Brown SM, Liu L, Kellett WF, Petkov GV. Stimulation of beta3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+-activated K+ channels. Am J Physiol Cell Physiol. 2008;295(5):C1344-C1353 [Epub September 17, 2008]PubMedCrossRefGoogle Scholar
  94. 94.
    Fujimura T, Tamura K, Tsutsumi T, et al. Expression and possible functional role of the beta3-adrenoceptor in human and rat detrusor muscle. J Urol. 1999;161(2):680-685PubMedCrossRefGoogle Scholar
  95. 95.
    Woods M, Carson N, Norton NW, Sheldon JH, Argentieri TM. Efficacy of the beta3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat. J Urol. 2001;166(3):1142-1147PubMedCrossRefGoogle Scholar
  96. 96.
    Takeda H, Yamazaki Y, Igawa Y, et al. Effects of beta(3)-adrenoceptor stimulation on prostaglandin E(2)-induced bladder hyperactivity and on the cardiovascular system in conscious rats. Neurourol Urodyn. 2002; 21(6):558-565PubMedCrossRefGoogle Scholar
  97. 97.
    Kaidoh K, Igawa Y, Takeda H, et al. Effects of selective beta2 and beta3-adrenoceptor agonists on detrusor hyperreflexia in conscious cerebral infarcted rats. J Urol. 2002;168(3):1247-1252PubMedCrossRefGoogle Scholar
  98. 98.
    Hicks A, McCafferty GP, Riedel E, et al. GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. J Pharmacol Exp Ther. 2007;323(1):202-209PubMedCrossRefGoogle Scholar
  99. 99.
    Colli E, Digesu GA, Olivieri L. Overactive bladder treatments in early phase clinical trials. Expert Opin Investig Drugs. 2007;16(7):999-1007PubMedCrossRefGoogle Scholar
  100. 100.
    Takasu T, Ukai M, Sato S, et al. Effect of (R)-2- (2-aminothiazol-4-yl)-4’- {2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther. 2007;321(2):642-647 [Epub February 9, 2007]PubMedCrossRefGoogle Scholar
  101. 101.
    Chapple CR, Yamaguchi O, Ridder A, et al. Clinical proof of concept study (Blossom) shows novel B3 adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl. 2008;7(3):239. abstract 674Google Scholar
  102. 102.
    Everaerts W, Gevaert T, Nilius B, De Ridder D. On the origin of bladder sensing: Tr(i)ps in urology. Neurourol Urodyn. 2008;27(4):264-273PubMedCrossRefGoogle Scholar
  103. 103.
    Birder LA, de Groat WC. Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat Clin Pract Urol. 2007;4(1):46-54PubMedCrossRefGoogle Scholar
  104. 104.
    Ishizuka O, Mattiasson A, Andersson K-E. Urodynamic effects of intravesical resiniferatoxin and capsaicin in conscious rats with and without outflow obstruction. J Urol. 1995;154:611-616PubMedCrossRefGoogle Scholar
  105. 105.
    Ishizuka O, Mattiasson A, Andersson KE. Effects of neurokinin receptor antagonists on L-dopa induced bladder hyperactivity in normal conscious rats. J Urol. 1995;154(4):1548-1551PubMedCrossRefGoogle Scholar
  106. 106.
    Szallazi A, Blumberg PM. Vanilloid receptors: new insights enhance potential as a therapeutic target. Pain. 1996;68(2–3):195-208CrossRefGoogle Scholar
  107. 107.
    Kuo H-C. Inhibitory effect of capsaicin on detrusor contractility: further study in the presence of ganglionic blocker and neurokinin receptor antagonist in the rat urinary bladder. Urol Int. 1997;59:95-101PubMedCrossRefGoogle Scholar
  108. 108.
    Andersson KE, Uckert S, Stief C, Hedlund P. Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS. Neurourol Urodyn. 2007;26(6 Suppl):928-933PubMedCrossRefGoogle Scholar
  109. 109.
    Truss MC, Stief CG, Uckert S, et al. Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J Urol. 2001; 19:344-350PubMedCrossRefGoogle Scholar
  110. 110.
    Longhurst PA, Briscoe JA, Rosenberg DJ, Leggett RE. The role of cyclic nucleotides in guinea-pig bladder contractility. Br J Pharmacol. 1997;121(8):1665-1672PubMedCrossRefGoogle Scholar
  111. 111.
    Kaiho Y, Nishiguchi J, Kwon DD, et al. The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction. BJU Int. 2008;101(5):615-620PubMedCrossRefGoogle Scholar
  112. 112.
    Nishiguchi J, Kwon DD, Kaiho Y, et al. Suppression of detrusor overactivity in rats with bladder outlet obstruction by a type 4 phosphodiesterase inhibitor. BJU Int. 2007;99(3):680-686PubMedCrossRefGoogle Scholar
  113. 113.
    Giembycz MA. Life after PDE4: overcoming adverse events with dual-specificity phosphodiesterase inhibitors. Curr Opin Pharmacol. 2005;5(3):238-244PubMedCrossRefGoogle Scholar
  114. 114.
    Sairam K, Kulinskaya E, McNicholas TA, Boustead GB, Hanbury DC. Sildenafil influences lower urinary tract symptoms. BJU Int. 2002;90(9):836-839PubMedCrossRefGoogle Scholar
  115. 115.
    McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177(4):1401-1407PubMedCrossRefGoogle Scholar
  116. 116.
    McVary KT, Monnig W, Camps JL Jr, Young JM, Tseng LJ, van den Ende G. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol. 2007;177(3):1071-1077PubMedCrossRefGoogle Scholar
  117. 117.
    Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2008;53(6):1236-1244PubMedCrossRefGoogle Scholar
  118. 118.
    de Groat WC, Yoshimura N. Pharmacology of the lower urinary tract. Annu Rev Pharmacol Toxicol. 2001;41:691-721PubMedCrossRefGoogle Scholar
  119. 119.
    Murray KH, Feneley RC. Endorphins-a role in lower urinary tract function? The effect of opioid blockade on the detrusor and urethral sphincter mechanisms. Br J Urol. 1982;54(6):638-640PubMedCrossRefGoogle Scholar
  120. 120.
    Dray A, Nunan L, Wire W. Naloxonazine and opioid-induced inhibition of reflex urinary bladder contractions. Neuropharmacology. 1987;26(1):67-74PubMedCrossRefGoogle Scholar
  121. 121.
    Herman RM, Wainberg MC, delGiudice PF, Willscher MK. The effect of a low dose of intrathecal morphine on impaired micturition reflexes in human subjects with spinal cord lesions. Anesthesiology. 1988; 69(3):313-318PubMedCrossRefGoogle Scholar
  122. 122.
    Kieffer BL. Opioids: first lessons from knockout mice. Trends Pharmacol Sci. 1999;20(1):19-26PubMedCrossRefGoogle Scholar
  123. 123.
    Raffa RB, Friderichs E. The basic science aspect on tramadol hydrochloride. Pain Rev. 1996;3:249-271Google Scholar
  124. 124.
    Pandita RK, Pehrson R, Christoph T, Friderichs E, Andersson KE. Actions of tramadol on micturition in awake, freely moving rats. Br J Pharmacol. 2003; 139(4):741-748PubMedCrossRefGoogle Scholar
  125. 125.
    Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study. Br J Clin Pharmacol. 2006;61(4): 456-463PubMedCrossRefGoogle Scholar
  126. 126.
    Ranson RN, Dodds AL, Smith MJ, Santer RM, Watson AH. Age-associated changes in the monoaminergic innervation of rat lumbosacral spinal cord. Brain Res. 16, 2003;972(1–2):149-158PubMedCrossRefGoogle Scholar
  127. 127.
    Thor KB, Blitz-Siebert A, Helke CJ. Autoradiographic localization of 5hydroxytryptamine1A, 5-hydroxytryptamine1B and 5-hydroxytryptamine1C/2 binding sites in the rat spinal cord. Neuroscience. 1993;5(1):235-252PubMedCrossRefGoogle Scholar
  128. 128.
    de Groat WC. Influence of central serotonergic mechanisms on lower urinary tract function. Urology. 2002;59(5 Suppl 1):30-36PubMedGoogle Scholar
  129. 129.
    McMahon SB, Spillane K. Brain stem influences on the parasympathetic supply to the urinary bladder of the cat. Brain Res. 25, 1982;234(2):237-249PubMedCrossRefGoogle Scholar
  130. 130.
    Sugaya K, Ogawa Y, Hatano T, Koyama Y, Miyazato T, Oda M. Evidence for involvement of the subcoeruleus nucleus and nucleus raphe magnus in urine storage and penile erection in decerebrate rats. J Urol. 1998;159(6):2172-2176PubMedCrossRefGoogle Scholar
  131. 131.
    Katofiasc MA, Nissen J, Audia JE, et al. Comparison of the effects of serotonin selective norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats. Life Sci. 2002;71(11):1227PubMedCrossRefGoogle Scholar
  132. 132.
    Thor K, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther. 1995;274(2):1014PubMedGoogle Scholar
  133. 133.
    Fraser MO, Chancellor MB. Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence. BJU Int. 2003;91(8):743PubMedCrossRefGoogle Scholar
  134. 134.
    Steers WD, Herschorn S, Kreder KJ, et al. Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int. 2007;100(2):337PubMedCrossRefGoogle Scholar
  135. 135.
    Chebib M, Johnston GAR. The ‘ABC’ of GABA receptors: a brief review. Clin Exp Pharmacol Physiol. 1999;26(11):937-940PubMedCrossRefGoogle Scholar
  136. 136.
    Igawa Y, Mattiasson A, Andersson KE. Effects of GABA-receptor stimulation and blockade on micturition in normal rats and rats with bladder outflow obstruction. J Urol. 1993;150(2 Pt 1):537-542PubMedGoogle Scholar
  137. 137.
    Pehrson R, Lehmann A, Andersson KE. Effects of gamma-aminobutyrate B receptor modulation on normal micturition and oxyhemoglobin induced detrusor overactivity in female rats. J Urol. 2002; 168(6):2700-2705PubMedCrossRefGoogle Scholar
  138. 138.
    Maggi CA, Santicioli P, Giuliani S, et al. The effects of baclofen on spinal and supraspinal micturition reflexes in rats. Naunyn Schmiedebergs Arch Pharmacol. 1987;336(2):197-203PubMedCrossRefGoogle Scholar
  139. 139.
    Malcangio M, Bowery NG. GABA and its receptors in the spinal cord. Trends Pharm Sci. 1996;17(12):457-462PubMedCrossRefGoogle Scholar
  140. 140.
    Coggeshall RE, Carlton SM. Receptor localization in the mammalian dorsal horn and primary afferent neurons. Brain Res Brain Res Rev. 1997;24(1):28-66PubMedCrossRefGoogle Scholar
  141. 141.
    Taylor MC, Bates CP. A double-blind crossover trial of baclofen–a new treatment for the unstable bladder syndrome. Br J Urol. 1979;51(6):504-505PubMedCrossRefGoogle Scholar
  142. 142.
    Maneuf YP, Gonzalez MI, Sutton KS, Chung FZ, Pinnock RD, Lee K. Cellular and molecular action of the putative GABA-mimetic, gabapentin. Cell Mol Life Sci. 2003;60(4):742-750PubMedCrossRefGoogle Scholar
  143. 143.
    Carbone A, Palleschi G, Conte A, Bova G, Iacovelli E, Bettolo RM. Gabapentin treatment of neurogenic overactive bladder. Clin Neuropharmacol. 2006;29(4):206-214.PubMedCrossRefGoogle Scholar
  144. 144.
    Kim YT, Kwon DD, Kim J, Kim DK, Lee JY, Chancellor MB. Gabapentin for overactive bladder and nocturia after anticholinergic failure. Int Braz J Urol. 2004; 30(4):275-278PubMedCrossRefGoogle Scholar
  145. 145.
    Lecci A, Maggi CA. Tachykinins as modulators of the micturition reflex in the central and peripheral nervous system. Regul Pept. 15, 2001;101(1–3):1-18PubMedCrossRefGoogle Scholar
  146. 146.
    Saffroy M, Torrens Y, Glowinski J, Beaujouan JC. Autoradiographic distribution of tachykinin NK2 binding sites in the rat brain: comparison with NK1 and NK3 binding sites. Neuroscience. 2003;116(3):761-773PubMedCrossRefGoogle Scholar
  147. 147.
    Covenas R, Martin F, Belda M, et al. Mapping of neurokinin-like immunoreactivity in the human brainstem. BMC Neurosci. 2003;4(1):3PubMedCrossRefGoogle Scholar
  148. 148.
    Ishizuka O, Igawa Y, Lecci A, Maggi CA, Mattiasson A, Andersson KE. Role of intrathecal tachykinins for micturition in unanaesthetized rats with and without bladder outlet obstruction. Br J Pharmacol. 1994;113(1):111-116PubMedGoogle Scholar
  149. 149.
    Seki S, Erickson KA, Seki M, et al. Elimination of rat spinal neurons expressing neurokinin 1 receptors reduces bladder overactivity and spinal c-fos expression induced by bladder irritation. Am J Physiol Ren Physiol. March 2005;288(3):F466-F473CrossRefGoogle Scholar
  150. 150.
    Massaro AM, Lenz KL. Aprepitant: a novel antiemetic for chemotherapy-induced nausea and vomiting. Ann Pharmacother. 2005;39(1):77-85PubMedGoogle Scholar
  151. 151.
    Green SA, Alon A, Ianus J, McNaughton KS, Tozzi CA, Reiss TF. Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol. 2006;176(6 Pt 1):2535-2540PubMedCrossRefGoogle Scholar
  152. 152.
    Gillespie JI. The autonomous bladder: a view of the origin of bladder overactivity and sensory urge. BJU Int. 2004;93(4):478-483PubMedCrossRefGoogle Scholar
  153. 153.
    Gillespie JI. Phosphodiesterase-linked inhibition of nonmicturition activity in the isolated bladder. BJU Int. 2004;93(9):1325-1332PubMedCrossRefGoogle Scholar

Copyright information

© Springer London 2011

Authors and Affiliations

  • Karl-Erik Andersson
    • 1
  1. 1.Institute for Regenerative MedicineWake Forest University Medical SchoolWinston SalemUSA

Personalised recommendations