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Urothelium and Afferent Nerves: Role and Therapeutic Targets for OAB

Urothelium and Afferent Nerves: Role and Therapeutic Targets for OAB. Joon Chul Kim The Catholic University of Korea. Pathophysiology of OAB. Myogenic Neurogenic Autonomous bladder theory Urothelium and afferent nerve signaling Combination Unknown.

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Urothelium and Afferent Nerves: Role and Therapeutic Targets for OAB

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  1. Urotheliumand Afferent Nerves: Role and Therapeutic Targets for OAB Joon Chul Kim The Catholic University of Korea

  2. Pathophysiology of OAB • Myogenic • Neurogenic • Autonomous bladder theory • Urothelium and afferent nerve signaling • Combination • Unknown Ouslander J, N Eng J Med 2004;350(8):786-799

  3. Pathophysiology of OAB • Although the etiology of OAB is multifactorial, recent • studies have demonstrated that changes in afferent • signaling contribute to OAB symptom generation • Novel neuron-like properties of the bladder • epithelium generate increased afferent activity, which • leads ultimately the emergence of characteristic • symptoms of OAB

  4. Urine “Plastic” Blood Urothelium: more than just a barrier A Simple Barrier ?????......of course not!!! -urothelial cells are very active -receptors, secretory function, etc.

  5. Urothelium: no longer considered as a passive protecting barrier • Urothelial cells play an important role in modulation • of bladder activity by responding to local chemical • and mechanical stimuli and then sending chemical • signals to bladder afferent nerves, which then • convey information to the central nervous system • Urothelial cells express various “sensor molecules” • (receptors/ion channels)

  6. Urothelium has a neuron-like property • TRPV1 expression in urothelium Urothelial cells Urothelial tissues • Express nicotinic acetylcholine receptor 1 2 3 4 5 6 7 2 3 4  Kim JC, et al, J Urol, 2001;165(5Suppl):31,34 Birder LA, et al, Proc Natl Acad Sci USA, 2001;98:13396

  7. Urothelium has a neuron-like property • Release of neurotransmitters CAP: Capsaicin CPZ: Capsazepine NIC: Nicotine C6: Hexamethonium NO Concentration (uM) NO Concentration (uM) Kim JC, et al, J Urol, 2001;165(5Suppl):31,34 Cook and McCleskey, Nature, 2000;407:951

  8. Urothelialmuscarinic receptors could have a role • Recent evidence indicates that urothelial cells express muscarinic receptors, and urothelial/suburothelial muscarinic receptors have a potential role in micturition reflex Zarghooni S, et al, Life Sci 2007;80:2308 de Groat WC, Urology 2004;64(suppl 1):7

  9. Afferent innervation of urothelium Urothelium Urothelium Suburothelial neurons Detrusor Andersson KE, Urology, 2002;59:45

  10. Interaction among receptors, chemical mediators Yoshimura N, et al, Naunyn-Schmiedeberg’s Arch Pharmacol, 2008;377:437

  11. Role of interstitial cell (IC) • Urothelium and suburothelial space is important for sensing bladder fullness • Network as a functional • syncytium in close • association with the • suburothelial sensory • nerves and urothelium • Expression of TRPV1 and MR • on ICs Urothelium Chemical transmitters Sensory nerve Interstitial cell (myofibroblast) Spinal cord Electrical communication Smooth muscle

  12. Urothelium is intelligent • Urothelium directly communicates with suburothelial afferent • Urothelium may participate in sensory mechanisms by • responding to mechanical and chemical stimuli and in turn • release transmitters that can influence the excitability of adjacent • afferent nerves • Increased sensitivity of these afferents may lead to OAB

  13. Urothelial alterations in OAB • Several specific alterations in urothelial function and • ultrastructure have been demonstrated in OAB • - Increased expression of epithelial Na channel (ENaC) • - Stretch-evoked ATP release • - Increased expression of several receptors and • gap junction proteins • - Increased release of acetylcholine (Ach) • - Increased levels of prostaglandin (PG) and NGF

  14. ENaC is increased significantly in human obstructed bladders with DO Control BOO with DO beta ENaC gamma ENaC alpha ENaC Araki I, et al, Urology, 2004;64:1255

  15. ENaC is increased significantly in human obstructed bladders with DO • ENaC expression correlates significantly with storage • symptom scores Araki I, et al, Urology, 2004;64:1255

  16. Stretch-evoked ATP and Ach release from urothelium are enhanced SCI rat Release of Ach from urothelium Ach release increases with age Khera M, et al, Neurochem Int 2004;45:987 Yoshida M, et al. Urology, 2006;67:425

  17. Muscarinic and purinergic receptor in urothelium increased in overactivity Control BOO + DO M2 M3 CU: Control urothelium BU: BOO+DO urothelium CM: Control muscle BM: BOO+DO muscle P2X3 • Changes in urothelium receptor expression could have a role in mediating the afferent sensory responses in the urinary bladder Kim JC, et al, BJU Int, 2008;101:371

  18. Increased electrical coupling in detrusoroveractivity • Connexin 43 and connexin 26 have been • investigated for predominant gap junction protein • These proteins are differentially regulated during BOO • and contribute to the response of the bladder wall DO Control Cx43 β-actin UT UT sm sm * Cx43 Cx26 Li L, et al, Am J Physiol Cell Physiol, 2007;293:C1627 Haefliger JA, et al, Exp Cell Res, 2002;274:216

  19. Increased Cx26 and Cx43 in mucosal layer related to detrusor overactivity in patients with BOO due to BPH • Connexin 43 mRNAs • Connexin 26 mRNAs GAPDH GAPDH Cx43 Cx26 DO(+) DO(-) DO(+) DO(-) DO(+) DO(-) * * Relative density Relative density Cha SH & Kim JC, KJU, 2004;45:897

  20. Effects of connexin inhibitor on detrusor overactivity associated with BOO • Contraction interval • Western blotting Con BOO GA Oleamide † *,† Cx26 Contraction interval (min) * Cx43 †: p<0.05 as compared with BOO Kim JC, et al, Eur Urol 2006;5(suppl):297

  21. NGF in urothelium increased in bladder associated with detrusoroveractivity Overactive Urothelial layer * * Relative density NGF expressioninurothelium Kim JC, et al, BJU Int 2006;98:435 Kim JC, et al, Neurourol Urodyn, 2001;20(4):444

  22. Urothelium can release NGF, which can be detected in the urine • Urinary NGF concentration * * Male Female Urinary NGF concentration (pg/ml) Concentration (pg/ml) Kim JC, et al, Int J Urol 2005;12:875 Kim JC, et al, J Urol 2006;175:1773 Liu & Kuo, J Urol 2008;179:2270 Yokoyama T, et al, Neurourol Urodyn 2008;27:417

  23. Urothelium can release NGF and PG, which can be detected in the urine • Urinary PG concentration Urinary PGE2 concentration Urinary PGF2 concentration * * Concentration (ng/ml) Concentration (ng/ml) • Urinary levels of NGF and PG is significantly increased in patients • with OAB and these factor may be used as markers to evaluate • overactive bladder symptoms Kim JC, et al, Int J Urol 2005;12:875 Kim JC, et al, J Urol 2006;175:1773

  24. Alteration of bladder afferent pathways in OAB • Urothelial dysfunction that can increase the amount of urothelially released substances may lead to the changes in properties of bladder afferent pathways, resulting in increased OAB symptoms • In particular, C-fiber bladder afferents may be critical for symptom generation in pathologic states such as OAB

  25. Alteration of bladder afferent pathways in OAB • After neurologic or possibly inflammatory insult, C-fibers become the predominant reflex to the spinal tract • Considerable C-fiber upregulation in symptomatic subjects with neurogenic DO and BOO and in patients with BPH Ouslander JG, N Engl J Med 2004;350:786 Yoshimura N and Chancellor MB, J Urol 2002;168:1897 Hyrayama A, et al, Urology 2003;62:909

  26. Contribution of afferent hyperexcitability to the emergence of DO and OAB • Suppression of bladder afferent activity with BTX, which effectively treats DO, and reduces the expression of the capsaicin receptor (TRPV1) and ATP receptor (P2X3) Control : TRPV1-IR fibers DO After BTX Apostolidis A, et al, J Urol 2005;174:977

  27. Potential targets of receptor or ion channel inbladder afferent pathways • Overall, hyperexcitability of bladder afferent pathways, especially of the C-fiber population, • is likely to contribute to the emergence of OAB • symptoms • Therefore, therapies targeting receptors/ion channels expressed in C-fibers could be effective for reducing symptoms in OAB patients

  28. Potential targets of receptor or ion channel inbladder afferent pathways Yoshimura N, et al, Naunyn-Schmiedeberg’s Arch Pharmacol, 2008;377:437

  29. Conclusions • Recently, many evidences suggested the important • role of urothelium and afferent pathway in the • mechanism of OAB • New therapeutic targets at the levels of the urothelium • and afferent pathways are proposed • Development of several drugs with different • mechanisms will be promising in the near future

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