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

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 β-adrenoceptors, in most species involving a strong β3-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 β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder

Pre-contraction with the thromboxane-mimetic U46619 enhances P2X receptor-mediated contractions in isolated porcine splenic artery

We have previously demonstrated that the thromboxane-mimetic U46619 enhances α2-adrenoceptor-mediated contractions through increased activation of extracellular signal-regulated kinase (ERK). In this study, we determined whether U46619 also enhances P2X-mediated contractions through the same pathway. Segments of porcine splenic artery were mounted in isolated tissue baths. Tissues were pre-contracted with U46619 to 10–20% of the response to 60 mM KCl prior to addition of α,β-methylene ATP (P2X receptor agonist). The effect of inhibition of ERK activation with the mitogen-activated protein (MAP)/ERK kinase inhibitor PD98059 (50 μM), Rho kinase inhibition with Y27632 (10 μM), p38 MAP kinase with SB203580 (10 μM) or l-type calcium channels with nifedipine (1 μM) on both the direct and enhanced contractions was then determined. U46619 enhanced the contractions to α,β-methylene ATP. Although PD98059 inhibited the direct contractions to α,β-methylene ATP, it had no effect on the U46619-enhanced contractions. Similarly, Y27632 and SB203580 inhibited the direct contractions to α,β-methylene ATP, but had no effect on the enhanced contractions. Nifedipine inhibited the responses to α,β-methylene ATP in the absence and presence of U46619. This study demonstrates that pre-contraction with U46619 enhances P2X-mediated contractions in the porcine splenic artery through a mechanism independent of ERK, Rho kinase and p38 MAP kinase. Further studies are required to determine the exact mechanism involved