Vol 83, No 11 (2012)
ARTICLES
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Overactive bladder--a new insight into the pathogenesis of its idiopathic form

Łukasz Nowakowski, Beata Kulik-Rechberger, Andrzej Wróbel, Tomasz Rechberger
Ginekol Pol 2012;83(11).
Vol 83, No 11 (2012)
ARTICLES

Abstract

In the last few years cytokines have been shown to be the most important local cell signaling molecules, strongly involved in the pathogenesis of the overactive bladder symptoms. Proper bladder function is dependent on gap junction activity The main gap junction proteins which can be found in bladder smooth muscle are Connexin 43 (Cx43) and Connexin 45 (Cx45). Experimental studies focused on the influence of Basic Fibroblast Growth Factor on Connexin expression in bladder smooth muscle cells have shown an increased expression of Cx43, contrary to Cx45. Elevated level of Connexin 43 leads to overactivity of muscle fibers. It was also proved that expression of these proteins in tissues is modulated by cytokines. Regulation of the Cx43 promoter depends on an activating factor 1 (AP-1), cyclic monophosphate (cAMP) and retinoid concentration as well. AP-1 is induced by extracellular-signal-regulated kinases (ERK 1/2) through the activation of basic fibroblast growth factor (bFGF). Recent studies revealed that cytokine-induced modulation of gap junction plays an important role in the pathogenesis of OAB, whereas activation of sympathetic fibers via beta adrenoreceptors (beta-AR) causes relaxation of the bladder The beta-3 adrenoreceptors are divided into beta-1, beta-2, beta-3 subtypes. beta-3 adrenoreceptors have been found in fat and smooth muscle tissue. Density of beta-3 AR is very high in urinary bladder detrusor Activation of beta-3 AR leads to the relaxation of smooth muscle fibers during the filling phase and is cAMP-dependent. Missense mutation of this receptor subtype in the human bladder leading to the substitution of Tryptophan (Trp) by Arginine (Arg), occurs in about one-third of the world's population. Studies have shown that about 50% of women with Trp 64 Arg polymorphism have OAB symptoms. Higher concentration of beta3-AR with Trp 64 Arg polymorphism in bladders of women with diagnosed OAB is probably associated with a lower level of cAMP and weaker relaxation of the bladder smooth muscle. The role of the muscarinic receptors (M1-M5) in the pathogenesis of OAB has been widely described. Unfortunately due to lack of selective muscarinic ligands, the function of each subtype of the receptor has not been fully elucidated yet. A mouse model lacking one or more muscarinic receptors types has been constructed recently Animals were used to assess the real influence of various muscarinic receptors on bladder function. Studies have confirmed the importance of these receptors in the function of the urinary tract, offering a new insight in their mutual interactions and pathogenesis of OAB. Better understanding of these and new mechanisms may improve the process of diagnosis and treatment of the disease in the near future.

Abstract

In the last few years cytokines have been shown to be the most important local cell signaling molecules, strongly involved in the pathogenesis of the overactive bladder symptoms. Proper bladder function is dependent on gap junction activity The main gap junction proteins which can be found in bladder smooth muscle are Connexin 43 (Cx43) and Connexin 45 (Cx45). Experimental studies focused on the influence of Basic Fibroblast Growth Factor on Connexin expression in bladder smooth muscle cells have shown an increased expression of Cx43, contrary to Cx45. Elevated level of Connexin 43 leads to overactivity of muscle fibers. It was also proved that expression of these proteins in tissues is modulated by cytokines. Regulation of the Cx43 promoter depends on an activating factor 1 (AP-1), cyclic monophosphate (cAMP) and retinoid concentration as well. AP-1 is induced by extracellular-signal-regulated kinases (ERK 1/2) through the activation of basic fibroblast growth factor (bFGF). Recent studies revealed that cytokine-induced modulation of gap junction plays an important role in the pathogenesis of OAB, whereas activation of sympathetic fibers via beta adrenoreceptors (beta-AR) causes relaxation of the bladder The beta-3 adrenoreceptors are divided into beta-1, beta-2, beta-3 subtypes. beta-3 adrenoreceptors have been found in fat and smooth muscle tissue. Density of beta-3 AR is very high in urinary bladder detrusor Activation of beta-3 AR leads to the relaxation of smooth muscle fibers during the filling phase and is cAMP-dependent. Missense mutation of this receptor subtype in the human bladder leading to the substitution of Tryptophan (Trp) by Arginine (Arg), occurs in about one-third of the world's population. Studies have shown that about 50% of women with Trp 64 Arg polymorphism have OAB symptoms. Higher concentration of beta3-AR with Trp 64 Arg polymorphism in bladders of women with diagnosed OAB is probably associated with a lower level of cAMP and weaker relaxation of the bladder smooth muscle. The role of the muscarinic receptors (M1-M5) in the pathogenesis of OAB has been widely described. Unfortunately due to lack of selective muscarinic ligands, the function of each subtype of the receptor has not been fully elucidated yet. A mouse model lacking one or more muscarinic receptors types has been constructed recently Animals were used to assess the real influence of various muscarinic receptors on bladder function. Studies have confirmed the importance of these receptors in the function of the urinary tract, offering a new insight in their mutual interactions and pathogenesis of OAB. Better understanding of these and new mechanisms may improve the process of diagnosis and treatment of the disease in the near future.
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Keywords

animals, Connexin 43 - metabolism, Connexins - metabolism, Disease Models, animal, female, Fibroblast Growth Factors - metabolism, health status, humans, mice, Mitogen-Activated Protein Kinase 1 - metabolism, Mitogen-Activated Protein Kinase 3 - metabolism, receptors, Muscarinic - metabolism, Transcription Factor AP-1 - metabolism, Urinary bladder, Overactive - metabolism, Women' s Health

About this article
Title

Overactive bladder--a new insight into the pathogenesis of its idiopathic form

Journal

Ginekologia Polska

Issue

Vol 83, No 11 (2012)

Bibliographic record

Ginekol Pol 2012;83(11).

Keywords

animals
Connexin 43 - metabolism
Connexins - metabolism
Disease Models
animal
female
Fibroblast Growth Factors - metabolism
health status
humans
mice
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
receptors
Muscarinic - metabolism
Transcription Factor AP-1 - metabolism
Urinary bladder
Overactive - metabolism
Women's Health

Authors

Łukasz Nowakowski
Beata Kulik-Rechberger
Andrzej Wróbel
Tomasz Rechberger

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