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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 Ca2+ channel inhibitor nifedipine and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various nifedipine concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, ***p < 0.001 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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Fig3: Effects of the Ca2+ channel inhibitor nifedipine and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various nifedipine concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, ***p < 0.001 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: The group of voltage-operated Ca2+ channels contains several types, among which, the L-type appears most relevant and has been most frequently studied with regard to the bladder. L-type Ca2+ channels can be inhibited by drugs such as nifedipine or diltiazem. Moreover, knockout mice have been generated, which lack a crucial subunit of L-type Ca2+ channels (Wegener et al. 2004). Various investigators have shown that L-type Ca2+ channel inhibitors reduce muscarinic-receptor-mediated detrusor contraction in rat (Schneider et al. 2004b), mouse (Wuest et al. 2007), rabbit (Zderic et al. 1994), pig (Buckner et al. 2002; Uchida et al. 1994; Wuest et al. 2007), and human (Fig. 3; Masters et al. 1999; Schneider et al. 2004a; Wuest et al. 2007). Interestingly, inhibition of bladder contraction was observed at inhibitor concentrations which are lower than those typically required to inhibit the contraction of vascular smooth muscle. Accordingly, knockout mice for the Cav1.2 L-type Ca2+ channel exhibited markedly reduced detrusor contraction in response to muscarinic agonists in vitro and also had dilated bladders in vivo (Wegener et al. 2004). While it has been proposed that Q-type voltage-operated Ca2+ channels may also contribute to bladder tone under some circumstances, N- and T-type Ca2+ channels apparently are not involved (Frew and Lundy 1995). Similarly, non-selective cation channels, Ca2+-activated Cl− channels, and Na+/Ca2+ exchanger do not play major role in Ca2+ influx in the bladder (Ganitkevich and Isenberg 1992; Nakayama and Brading 1993).Fig. 3


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 Ca2+ channel inhibitor nifedipine and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various nifedipine concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, ***p < 0.001 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

Fig3: Effects of the Ca2+ channel inhibitor nifedipine and its vehicle on carbachol-induced contraction. The upper panel shows carbachol concentration-response curves in the absence and presence of various nifedipine concentrations. The lower two panels show alterations of pEC50 and Emax relative to matched time controls. *p < 0.05, ***p < 0.001 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: The group of voltage-operated Ca2+ channels contains several types, among which, the L-type appears most relevant and has been most frequently studied with regard to the bladder. L-type Ca2+ channels can be inhibited by drugs such as nifedipine or diltiazem. Moreover, knockout mice have been generated, which lack a crucial subunit of L-type Ca2+ channels (Wegener et al. 2004). Various investigators have shown that L-type Ca2+ channel inhibitors reduce muscarinic-receptor-mediated detrusor contraction in rat (Schneider et al. 2004b), mouse (Wuest et al. 2007), rabbit (Zderic et al. 1994), pig (Buckner et al. 2002; Uchida et al. 1994; Wuest et al. 2007), and human (Fig. 3; Masters et al. 1999; Schneider et al. 2004a; Wuest et al. 2007). Interestingly, inhibition of bladder contraction was observed at inhibitor concentrations which are lower than those typically required to inhibit the contraction of vascular smooth muscle. Accordingly, knockout mice for the Cav1.2 L-type Ca2+ channel exhibited markedly reduced detrusor contraction in response to muscarinic agonists in vitro and also had dilated bladders in vivo (Wegener et al. 2004). While it has been proposed that Q-type voltage-operated Ca2+ channels may also contribute to bladder tone under some circumstances, N- and T-type Ca2+ channels apparently are not involved (Frew and Lundy 1995). Similarly, non-selective cation channels, Ca2+-activated Cl− channels, and Na+/Ca2+ exchanger do not play major role in Ca2+ influx in the bladder (Ganitkevich and Isenberg 1992; Nakayama and Brading 1993).Fig. 3

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