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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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Related in: MedlinePlus

Effect of the adenylyl cyclase inhibitor SQ 22,536 (1 μM) and the protein kinase A inhibitor H7 (10 μM) on isoproterenol-induced relaxation of rat urinary bladder. Taken from (Frazier et al. 2005)
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Fig4: Effect of the adenylyl cyclase inhibitor SQ 22,536 (1 μM) and the protein kinase A inhibitor H7 (10 μM) on isoproterenol-induced relaxation of rat urinary bladder. Taken from (Frazier et al. 2005)

Mentions: To test the role of cAMP formation and PKA in bladder relaxation, three studies have recently been reported from rat bladder. In one study using the β2-agonist clenbuterol against field stimulation-induced tone, a PKA inhibitor was reported to block relaxation while not affecting the field stimulation-induced contraction (Hudman et al. 2000). Two other studies investigated used isoprenaline as the agonist (one additionally included a β3-selective agonist) against the effects of isoprenaline on both passive tension and KCl-induced tone (Fig. 4; Frazier et al. 2005; Uchida et al. 2005). Both studies have used adenylyl cyclase inhibitors such as SQ 22,536 and Rp-cAMPs and also PKA inhibitors such as H7 and H89. While their quantitative findings differ slightly, they both show that cAMP formation does not contribute to relaxation against KCl-induced tone. While some contribution exists for relaxation against passive tension, even under those conditions, it may account for only a minor part of the response. One of the studies additionally demonstrates that a guanylyl cyclase also is not involved to a major extent (Frazier et al. 2005). These findings indicate that the cAMP/PKA pathway may contribute to bladder relaxation by a β2-AR, but less, if at all, to that induced by a β3-selective or a non-selective agonist. The latter findings are in line with recent data from various other types of smooth muscle which have indicated that various types of K+ channels may be more important in β-AR-mediated relaxation than cAMP (Ferro 2006).Fig. 4


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)

Effect of the adenylyl cyclase inhibitor SQ 22,536 (1 μM) and the protein kinase A inhibitor H7 (10 μM) 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

Fig4: Effect of the adenylyl cyclase inhibitor SQ 22,536 (1 μM) and the protein kinase A inhibitor H7 (10 μM) on isoproterenol-induced relaxation of rat urinary bladder. Taken from (Frazier et al. 2005)
Mentions: To test the role of cAMP formation and PKA in bladder relaxation, three studies have recently been reported from rat bladder. In one study using the β2-agonist clenbuterol against field stimulation-induced tone, a PKA inhibitor was reported to block relaxation while not affecting the field stimulation-induced contraction (Hudman et al. 2000). Two other studies investigated used isoprenaline as the agonist (one additionally included a β3-selective agonist) against the effects of isoprenaline on both passive tension and KCl-induced tone (Fig. 4; Frazier et al. 2005; Uchida et al. 2005). Both studies have used adenylyl cyclase inhibitors such as SQ 22,536 and Rp-cAMPs and also PKA inhibitors such as H7 and H89. While their quantitative findings differ slightly, they both show that cAMP formation does not contribute to relaxation against KCl-induced tone. While some contribution exists for relaxation against passive tension, even under those conditions, it may account for only a minor part of the response. One of the studies additionally demonstrates that a guanylyl cyclase also is not involved to a major extent (Frazier et al. 2005). These findings indicate that the cAMP/PKA pathway may contribute to bladder relaxation by a β2-AR, but less, if at all, to that induced by a β3-selective or a non-selective agonist. The latter findings are in line with recent data from various other types of smooth muscle which have indicated that various types of K+ channels may be more important in β-AR-mediated relaxation than cAMP (Ferro 2006).Fig. 4

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