Urothelium and afferent nerves role and therapeutic targets for oab
This presentation is the property of its rightful owner.
Sponsored Links
1 / 29

Urothelium and Afferent Nerves: Role and Therapeutic Targets for OAB PowerPoint PPT Presentation


  • 79 Views
  • Uploaded on
  • Presentation posted in: General

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.

Download Presentation

Urothelium and Afferent Nerves: Role and Therapeutic Targets for OAB

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Urothelium and afferent nerves role and therapeutic targets for oab

Urotheliumand Afferent Nerves: Role and Therapeutic Targets for OAB

Joon Chul Kim

The Catholic University of Korea


Pathophysiology of oab

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


Pathophysiology of oab1

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


Urothelium more than just a barrier

Urine

“Plastic”

Blood

Urothelium: more than just a barrier

A Simple Barrier ?????......of course not!!!

-urothelial cells are very active

-receptors, secretory function, etc.


Urothelium no longer considered as a passive protecting barrier

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)


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

Afferent innervation of urothelium

Urothelium

Urothelium

Suburothelial neurons

Detrusor

Andersson KE, Urology, 2002;59:45


Urothelium and afferent nerves role and therapeutic targets for oab

Interaction among receptors, chemical mediators

Yoshimura N, et al, Naunyn-Schmiedeberg’s Arch Pharmacol, 2008;377:437


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

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


Urothelium and afferent nerves role and therapeutic targets for oab

Potential targets of receptor or ion channel inbladder afferent pathways

Yoshimura N, et al, Naunyn-Schmiedeberg’s Arch Pharmacol, 2008;377:437


Urothelium and afferent nerves role and therapeutic targets for oab

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


  • Login