Common theme for drugs effective in overactive bladder treatment: inhibition of afferent signaling from the bladder

Brandy Hood, Karl-Erik Andersson, Brandy Hood, Karl-Erik Andersson

Abstract

The overactive bladder syndrome and detrusor overactivity are conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are still first-line treatment. These drugs often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium/suburothelium, the autonomous detrusor muscle activity during bladder filling and the diversity of nerve transmitters involved has sparked interest in both peripheral and central modulation of overactive bladder syndrome/detrusor overactivity pathophysiology. Three drugs recently approved for treatment of overactive bladder syndrome/detrusor overactivity (mirabegron, tadalafil and onabotulinum toxin A), representing different pharmacological mechanisms; that is, β-adrenoceptor agonism, phosphodiesterase type 5 inhibition, and inhibition of nerve release of efferent and afferent transmitters, all seem to have one effect in common: inhibition of the afferent nervous activity generated by the bladder during filling. In the present review, the different mechanisms forming the pharmacological basis for the use of these drugs are discussed.

© 2012 The Japanese Urological Association.

Figures

Fig. 1
Fig. 1
Pathophysiology of the OAB. In the bladder, increased afferent activity generated in the detrusor or mucosa through different mechanisms initiate involuntary detrusor contractions. Such contractions can be initiated independently of changes in afferent activity by changes in the CNS.

References

    1. Kanai A, Andersson KE. Bladder afferent signaling: recent findings. J. Urol. 2010;183:1288–1295.
    1. Andersson KE. Antimuscarinic mechanisms and the overactive detrusor: an update. Eur. Urol. 2011;59:377–386.
    1. de Groat WC. A neurologic basis for the overactive bladder. Urology. 1997;50:36–52.
    1. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol. Rev. 2004;84:935–986.
    1. Gillespie JI. The autonomous bladder: a view of the origin of bladder overactivity and sensory urge. BJU Int. 2004;93:478–483.
    1. 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;103:1324–1333.
    1. Birder LA, de Groat WC. Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat. Clin. Pract. Urol. 2007;4:46–54.
    1. Birder LA. Urothelial signaling. Handb. Exp. Pharmacol. 2011;202:207–231.
    1. Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and β-adrenoreceptor subtypes and their functional roles in human normal and obstructed bladders. J. Urol. 2003;170(2 Pt 1):649–653.
    1. Michel MC, Vrydag W. Alpha1-, alpha2- and β-adrenoreceptors in the urinary bladder, urethra and prostate. Br. J. Pharmacol. 2006;147(Suppl 2):S88.
    1. Igawa Y, Aizawa N, Homma Y. β3-adrenoreceptor agonists: possible role in the treatment of overactive bladder. Korean J. Urol. 2010;51:811–818.
    1. Iggo A. Tension receptors in the stomach and the urinary bladder. J. Physiol. 1955;128:593–607.
    1. 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;98:1310–1314.
    1. Aizawa N, Igawa Y, Nishizawa O, Wyndaele JJ. Effects of CL316,243, a β3 adrenoreceptor agonist, and intravesical prostaglandin E2 on the primary bladder afferent activity of the rat. Neurourol. Urodyn. 2010;29:771–776.
    1. Gillespie JI, Palea S, Guilloteau V, Guerard M, Lluel P, Korstanje C. Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3) -adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int. 2012;110(2 Pt B):E132–142.
    1. Kanai A, Wyndaele J, Andersson KE, et al. Researching bladder afferents – determining the effects of β3-adrenergic receptor agonists and botulinum toxin type-A. Neurourol. Urodyn. 2011;30:684–691.
    1. Kullmann FA, Downs TR, Artim DE, et al. Urothelial β-3 adrenergic receptors in the rat bladder. Neurourol. Urodyn. 2011;30:144–150.
    1. Limberg BJ, Andersson KE, Aura Kullmann F, Burmur G, de Groat WE, Rosenbaum J. S. β-Adrenergic receptor subtype expression in myocyte and non-myocyte cells in human female bladder. Cell Tissue Res. 2010;342:295–306.
    1. Birder LA, Apodaca G, de Groat WC, Kanai AJ. Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am. J. Physiol. 1998;275:F226–229.
    1. Murakami S, Chapple CR, Akino H, Sellers DJ, Chess-Williams R. The role of the urothelium in mediating bladder responses to isoprenaline. BJU Int. 2007;99:669–673.
    1. Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S. Expression and functional role of β-adrenoreceptors in the human urinary bladder urothelium. Naunyn. Schmiedebergs Arch. Pharmacol. 2008;377:473–481.
    1. Chapple CR, Yamaguchi O, Ridder A, et al. Clinical proof of concept study (Blossom) shows novel β3 adrenoreceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur. Urol. Suppl. 2008;7:239. (abstract 674)
    1. Chapple C, Wyndaele JJ, van Kerrebroeck P, Radziszewski P, Dvorak V. Dose ranging study of once-daily mirabegron (YM178), a novel selective β3 adrenoreceptor agonist, in patients with overactive bladder (OAB) Eur. Urol. Suppl. 2010;9:249. (abstract 774)
    1. Nitti V, Herschorn S, Auerbach S, Ayers M, Lee M, Martin N. The efficacy and safety of mirabegron in patients with overactive bladder syndrome – results from a North American Phase III trial. Eur. Urol. Suppl. 2011;10:278. (abstract 885)
    1. Khullar V, Cabronero J, Strömberg P, et al. The efficacy and tolerability of mirabegron in patients with overactive bladder – results from a European-Australian Phase III trial. Eur. Urol. Suppl. 2011;10:278. (abstract 886)
    1. Uckert S, Stief CG. Treatment of erectile dysfunction and lower urinary tract symptoms by phosphodiesterase inhibitors. Handb. Exp. Pharmacol. 2011;204:307–322.
    1. Andersson KE, de Groat WC, McVary KT, et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol. Urodyn. 2011;30:292–301.
    1. Andersson KE, Uckert S, Stief C, Hedlund P. Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS. Neurourol. Urodyn. 2007;26(6 Suppl):928–933.
    1. Fibbi B, Morelli A, Vignozzi L, et al. Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract. J. Sex. Med. 2010;7:59–69.
    1. Dmochowski R, Roehrborn C, Klise S, Xu L, Kaminetsky J, Kraus S. Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-week clinical trial. J. Urol. 2010;183:1092–1097.
    1. Oger S, Behr-Roussel D, Gorny D, et al. Signalling pathways involved in sildenafil-induced relaxation of human bladder dome smooth muscle. Br. J. Pharmacol. 2010;160:1135–1143.
    1. Uckert S, Sormes M, Kedia G, et al. Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue. Urology. 2008;71:526–530.
    1. Werkström V, Svensson A, Andersson KE, Hedlund P. Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects. BJU Int. 2006;98:414–423.
    1. Kedia GT, Sonnenberg JE, Kuczyk MA, Uckert S. In vitro functional responses of isolated human urethral tissue to phosphodiesterase (PDE) inhibitors. Eur. Urol. Suppl. 2011;10:291–292. (abstract 931)
    1. Caremel R, Oger-Roussel S, Behr-Roussel D, Grise P, Giuliano FA. Nitric oxide/cyclic guanosine monophosphate signaling mediates an inhibitory action on sensory pathways of the micturition reflex in the rat. Eur. Urol. 2010;58:616–625.
    1. Persson K, Igawa Y, Mattiasson A, Andersson KE. Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro. Br. J. Pharmacol. 1992;107:178–184.
    1. Pandita RK, Mizusawa H, Andersson KE. Intravesical oxyhemoglobin initiates bladder overactivity in conscious, normal rats. J. Urol. 2000;164:545–550.
    1. Sesatomi K, Hiragata S, Miyazato M, Chancellor M, Morris S, Yoshimura N. Nitric oxide-mediated suppression of detrusor overactivity by arginase inhibitor in rats with chronic spinal cord injury. Urology. 2008;72:696–700.
    1. Artim DE, Kullman FA, Daughtery SL, Wu H, de Groat WC. Activation of the nitric oxide-cGMP pathway reduces phasic contractions in neonatal rat bladder strips via protein kinase G. Am. J. Physiol. Renal Physiol. 2009;297:F333–340.
    1. Yoshimura N, Skei S, de Groat WC. Nitric oxide modulates Ca(2+) channels in dorsal root ganglion neurons innervating rat urinary bladder. J. Neurophysiol. 2001;86:304–311.
    1. Kanai A, Zabbarova I, Oefelein M, Radziszewski P, Ikeda Y, Andersson KE. Mechanisms of action of botulinum neurotoxins, β3-adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI-RS 2011. Neurourol. Urodyn. 2012;31:300–308.
    1. Sculptoreanu A, de Groat WC. Neurokinins enhance excitability in capsaicin-responsive DRG neurons. Exp. Neurol. 2007;205:92–100.
    1. Sculptoreanu A, Artim DE, de Groat WC. Neurokinins inhibit low threshold inactivating K+ currents in capsaicin responsive DRG neurons. Exp. Neurol. 2009;219:562–573.
    1. Behr-Roussel D, Oger S, Caisey S, et al. Vardenafil decrease bladder afferent nerve activity unanesthetized, decerebrate, spinal cord-injured rats. Eur. Urol. 2011;59:272–279.
    1. Minegawa T, Aizawa N, Igawa Y, et al. Inhibitory effects of phosphodiesterase 5 inhibitor, tadalafil, on mechanosensitive bladder afferent nerve activities of the rat and on acrolien-induced hyperactivity of these nerves. BJU Int. 2012;110:E259–266.
    1. Aizawa N, Igawa Y, Nishizawa O, et al. Effects of nitric oxide on the primary bladder afferent activities of the rat with and without intravesical acrolein treatment. Eur. Urol. 2011;59:264–271.
    1. Nomiya M, Burmeister DM, Sawada N, et al. Prophylactic effect of tadalafil on bladder function in a rat model of chronic bladder ischemia. J. Urol. 2012 doi: .
    1. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J. Urol. 2007;177:1401–1407.
    1. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J. Urol. 2008;180:1228–1234.
    1. Roehrborn CG, Kaminetsky JC, Auerbach SM, et al. Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int. 2010;105:502–507.
    1. 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;53:1236–1244.
    1. Martínez-Salamanca JI, Carballido J, Eardley I, et al. Phosphodiesterase type 5 inhibitors in the management of non-neurogenic male lower urinary tract symptoms: critical analysis of current evidence. Eur. Urol. 2011;60:527–535.
    1. Humeau Y, Doussau F, Grant NJ, Poulain B. How botulinum and tetanus neurotoxins block neurotransmitter release. Biochimie. 2000;82:427–446.
    1. Chancellor MB, Fowler CJ, Apostolidis A, et al. Drug Insight: biological effects of botulinum toxin A in the lower urinary tract. Nat. Clin. Pract. Urol. 2008;5:319–328.
    1. Coelho A, Cruz F, Cruz CD, Avelino A. Spread of onabotulinumtoxinA after bladder injection. Experimental study using the distribution of cleaved SNAP-25 as the marker of the toxin action. Eur. Urol. 2012;61:1178–1184.
    1. Ikeda Y, Zabbarova I, Birder L, et al. Botulinum neurotoxin serotype A suppresses neurotransmitter release from afferent as well as efferent nerves in the urinary bladder. Eur. Urol. 2012 doi: .
    1. Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology. 2005;26:785–793.
    1. Rapp DE, Turk KW, Bales GT, Cook SP. Botulinum toxin type A inhibits calcitonin gen-related peptide release from isolated rat bladder. J. Urol. 2006;175:1138–1142.
    1. Meng J, Wang J, Lawrence G, Dolly JO. Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J. Cell Sci. 2007;120(Pt 16):2864–2874.
    1. Lucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int. 2008;101:366–370.
    1. Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem. Int. 2004;45:987–993.
    1. Smith CP, Gangiano DA, Munoz A, et al. Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem. Int. 2008;52:1068–1075.
    1. Apostolidis A, Popta R, Yiangou Y, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J. Urol. 2005;174:977–982. discussion 982–3.
    1. Datta SN, Roosen A, Oullen A, et al. Immunohistochemial exression of muscarinic receptors in the urothelium and suburothelium of neurogenic and idiopathic overactive human bladders, and changes with botulinum neurotoxin administration. J. Urol. 2010;184:2578–2585.
    1. Mangera A, Andersson KE, Apostolidis A, et al. Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA) Eur. Urol. 2011;60:784–795.
    1. Sahai A, Khan MS, Dasgupta P. Efficacy of botulinum toxin A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J. Urol. 2007;177:2231–2236.
    1. Brubaker L, Richter HE, Visco A, et al. Refractory idiopathic urge urinary incontinence and botulinum A injection. J. Urol. 2008;180:217–222.
    1. Tincello DG, Kenyon S, Abrams KR, et al. Botulinum toxin A versus placebo for refractory detrusor overactivity in women: a randomized blinded placebo-controlled trial of 240 women (the RELAX study) Eur. Urol. 2012;62:507–514.
    1. Rovner E, Kennelly M, Schulte-Baukloh H, Zhou J, Haag-Molkenteller C, Dasgupta P. Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder. Neurourol. Urodyn. 2011;30:556–562.
    1. Kanagarajah P, Ayyathurai R, Caruso DJ, Gomez C, Gousse AE. Role of botulinum toxin-A in refractory idiopathic overactive bladder patients without detrusor overactivity. Int. Urol. Nephrol. 2012;44:91–97.
    1. Dmochowski R, Chapple C, Nitti VW, et al. Efficacy and safety of onabotulinumtoxin A for idiopathic overactive bladder: a double-blind, placebo controlled, randomized, dose ranging trial. J. Urol. 2010;184:2416–2422.

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