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Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors.

Frazier EP, Peters SL, Braverman AS, Ruggieri MR, Michel MC - Naunyn Schmiedebergs Arch. Pharmacol. (2007)

Bottom Line: Nevertheless, cAMP apparently contributes in a minor way only to beta-adrenoceptor-mediated bladder relaxation.BKCa channels may play a greater role in beta-adrenoceptor-mediated bladder relaxation.We conclude that apart from muscarinic receptor antagonists and beta-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.

ABSTRACT
The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by beta-adrenoceptors, in most species involving a strong beta3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of beta-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to beta-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in beta-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and beta-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder.

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Effects of the Rho kinase inhibitor Y 27,632 and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various Y 27,632 concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, **p < 0.01 vs matching time controls in the presence of vehicle in a two-way analysis of variance followed by Dunnet post-tests. Taken from (Schneider et al. 2004a)
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Fig2: Effects of the Rho kinase inhibitor Y 27,632 and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various Y 27,632 concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, **p < 0.01 vs matching time controls in the presence of vehicle in a two-way analysis of variance followed by Dunnet post-tests. Taken from (Schneider et al. 2004a)

Mentions: Y-27,632, fasudil, and HA-1077 are ROCK inhibitors which are commonly used to assess the involvement of this kinase in biological responses. In the urinary bladder of humans (Fig. 2) and other mammals, Y-27,632, fasudil, and HA-1077 inhibit both phasic and sustained contraction induced by several stimuli including muscarinic receptor agonists (Braverman et al. 2006a; Fleichman et al. 2004; Jezior et al. 2001; Schneider et al. 2004a,b; Speich et al. 2005; Takahashi et al. 2004; Wibberley et al. 2003). Whereas all available studies indicate that ROCK inhibitors reduced potency of muscarinic receptor agonist carbachol in the bladder, results regarding the carbachol efficacy are conflicting (Braverman et al. 2006b; Fleichman et al. 2004; Schneider et al. 2004a, 2005; Takahashi et al. 2004). Based upon a reduction of the potency of M3-selective antagonist darifenacin in the presence of Y-27,632, it has been proposed that ROCK may have a specific role in the M2 receptor contribution to bladder tone (Braverman et al. 2006b). As the overall role of M2 receptors in bladder tone requires further clarification (Abrams et al. 2006; Hegde 2006), this proposal is awaiting confirmation by other investigators. In contrast to the consistently reported role of ROCK in muscarinic-receptor-mediated bladder contraction in vitro, ROCK inhibitors were reported not to affect physiological bladder contraction in vivo in healthy animals, but only under pathophysiological conditions (Rajasekaran et al. 2005). A possible role of ROCK in bladder dysfunction and its treatment has recently been reviewed (Peters et al. 2006).Fig. 2


Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors.

Frazier EP, Peters SL, Braverman AS, Ruggieri MR, Michel MC - Naunyn Schmiedebergs Arch. Pharmacol. (2007)

Effects of the Rho kinase inhibitor Y 27,632 and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various Y 27,632 concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, **p < 0.01 vs matching time controls in the presence of vehicle in a two-way analysis of variance followed by Dunnet post-tests. Taken from (Schneider et al. 2004a)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2480512&req=5

Fig2: Effects of the Rho kinase inhibitor Y 27,632 and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various Y 27,632 concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, **p < 0.01 vs matching time controls in the presence of vehicle in a two-way analysis of variance followed by Dunnet post-tests. Taken from (Schneider et al. 2004a)
Mentions: Y-27,632, fasudil, and HA-1077 are ROCK inhibitors which are commonly used to assess the involvement of this kinase in biological responses. In the urinary bladder of humans (Fig. 2) and other mammals, Y-27,632, fasudil, and HA-1077 inhibit both phasic and sustained contraction induced by several stimuli including muscarinic receptor agonists (Braverman et al. 2006a; Fleichman et al. 2004; Jezior et al. 2001; Schneider et al. 2004a,b; Speich et al. 2005; Takahashi et al. 2004; Wibberley et al. 2003). Whereas all available studies indicate that ROCK inhibitors reduced potency of muscarinic receptor agonist carbachol in the bladder, results regarding the carbachol efficacy are conflicting (Braverman et al. 2006b; Fleichman et al. 2004; Schneider et al. 2004a, 2005; Takahashi et al. 2004). Based upon a reduction of the potency of M3-selective antagonist darifenacin in the presence of Y-27,632, it has been proposed that ROCK may have a specific role in the M2 receptor contribution to bladder tone (Braverman et al. 2006b). As the overall role of M2 receptors in bladder tone requires further clarification (Abrams et al. 2006; Hegde 2006), this proposal is awaiting confirmation by other investigators. In contrast to the consistently reported role of ROCK in muscarinic-receptor-mediated bladder contraction in vitro, ROCK inhibitors were reported not to affect physiological bladder contraction in vivo in healthy animals, but only under pathophysiological conditions (Rajasekaran et al. 2005). A possible role of ROCK in bladder dysfunction and its treatment has recently been reviewed (Peters et al. 2006).Fig. 2

Bottom Line: Nevertheless, cAMP apparently contributes in a minor way only to beta-adrenoceptor-mediated bladder relaxation.BKCa channels may play a greater role in beta-adrenoceptor-mediated bladder relaxation.We conclude that apart from muscarinic receptor antagonists and beta-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.

ABSTRACT
The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by beta-adrenoceptors, in most species involving a strong beta3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of beta-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to beta-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in beta-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and beta-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder.

Show MeSH
Related in: MedlinePlus