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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 BKCa channel inhibitors iberiotoxin (30 nM) and charybdotoxin (30 nM) on isoproterenol-induced relaxation of rat urinary bladder. Taken from (Frazier et al. 2005)
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Fig5: Effects of the BKCa channel inhibitors iberiotoxin (30 nM) and charybdotoxin (30 nM) on isoproterenol-induced relaxation of rat urinary bladder. Taken from (Frazier et al. 2005)

Mentions: In guinea pig bladder, stimulation of β-AR activates BKCa channels via Ca2+-sensitive mechanisms by means of increase of Ca2+ influx and Ca2+ sparks (Petkov and Nelson 2005). Some investigators have demonstrated the involvement of BKCa channels in β-AR-mediated bladder relaxation using BKCa channel inhibitors such as iberiotoxin and charybdotoxin in rats (Frazier et al. 2005; Uchida et al. 2005) and guinea pigs (Kobayashi et al. 2000; Petkov and Nelson 2005). Studies in rats have demonstrated that the role of BKCa channels in β-AR-mediated relaxation may depend on the experimental conditions, i.e., being considerable in the presence of KCl-induced tone but absent in the presence of passive tension only (Fig. 5; Frazier et al. 2005; Uchida et al. 2005). While a study in guinea pigs has reported that β-AR relaxation is mediated by facilitation of BKCa channels following the activation of cAMP/PKA pathways (Kobayashi et al. 2000), studies in rats do not support the idea of a concomitant involvement of BKCa channels and the cAMP/PKA pathway (Frazier et al. 2005; Uchida et al. 2005).Fig. 5


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 BKCa channel inhibitors iberiotoxin (30 nM) and charybdotoxin (30 nM) on isoproterenol-induced relaxation of rat urinary bladder. Taken from (Frazier et al. 2005)
© Copyright Policy
Related In: Results  -  Collection

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

Fig5: Effects of the BKCa channel inhibitors iberiotoxin (30 nM) and charybdotoxin (30 nM) on isoproterenol-induced relaxation of rat urinary bladder. Taken from (Frazier et al. 2005)
Mentions: In guinea pig bladder, stimulation of β-AR activates BKCa channels via Ca2+-sensitive mechanisms by means of increase of Ca2+ influx and Ca2+ sparks (Petkov and Nelson 2005). Some investigators have demonstrated the involvement of BKCa channels in β-AR-mediated bladder relaxation using BKCa channel inhibitors such as iberiotoxin and charybdotoxin in rats (Frazier et al. 2005; Uchida et al. 2005) and guinea pigs (Kobayashi et al. 2000; Petkov and Nelson 2005). Studies in rats have demonstrated that the role of BKCa channels in β-AR-mediated relaxation may depend on the experimental conditions, i.e., being considerable in the presence of KCl-induced tone but absent in the presence of passive tension only (Fig. 5; Frazier et al. 2005; Uchida et al. 2005). While a study in guinea pigs has reported that β-AR relaxation is mediated by facilitation of BKCa channels following the activation of cAMP/PKA pathways (Kobayashi et al. 2000), studies in rats do not support the idea of a concomitant involvement of BKCa channels and the cAMP/PKA pathway (Frazier et al. 2005; Uchida et al. 2005).Fig. 5

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