Investigations into the presence of functional ß1, ß2 and ß3-adrenoceptors in urothelium and detrusor of human bladder

Tyagi, Pradeep; Thomas, Catherine A.; Yoshimura, Naoki; Chancellor, Michael B.

doi:10.1590/s1677-55382009000100012

Cited by 68 publications

(46 citation statements)

References 19 publications

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“…Moreover, solabegron also inhibited field stimulation-induced contraction, which was not mimicked by isoprenaline. In another study with human isolated detrusor strips, solabegron produced relaxation with an EC 50 of 1.9 nM with an efficacy similar to that of isoprenaline (Tyagi et al 2009). Within that study, both solabegron and isoprenaline also inhibited human detrusor tone induced by field stimulation.…”

Section: Isolated Tissue Studiesmentioning

confidence: 89%

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Igawa

Michel

2012

Naunyn-Schmiedeberg's Arch Pharmacol

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β 3 -Adrenoceptor agonists are an emerging drug class for the treatment of the overactive bladder syndrome, and clinical proof-of-concept data have been obtained for three representatives of this class, mirabegron, ritobegron, and solabegron. We review here the pharmacological profile of these three drugs and discuss the potential clinical relevance of differences between them. In the absence of direct comparative studies, it appears that all three are strong agonists selective for β 3 -vs. β 1 -and β 2 -adrenoceptors in studies with cloned receptor subtypes. The potency of these agonists may be species-dependent, with all three having high potency in the human detrusor. All three agonists were effective in one or more animal models of bladder dysfunction, which typically involved reductions of micturition frequency. Agonist doses effective for bladder function lowered blood pressure in some cases, but the relevance of this for clinical use is difficult to determine due to species differences in the importance of cardiovascular β 3 -adrenoceptors. While limited effects on other organ systems are expected for β 3 -adrenoceptor agonists, this requires further investigation.

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Section: Isolated Tissue Studiesmentioning

confidence: 89%

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Igawa

Michel

2012

Naunyn-Schmiedeberg's Arch Pharmacol

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“…It has been shown that urothelial-derived NO can be released in response to mechanical as well as chemical stimulation and may either facilitate or inhibit the activity of bladder afferent nerves conveying bladder sensation (18,42). In this regard, activation of urothelial receptors and release of inhibitory mediators may explain, in part, the mechanism of action for therapies (e.g., ␤ 3 -AR agonists) in treatment of bladder disorders such as the overactive bladder (OAB) (137,283,301).…”

Section: Urothelium-lamina Propria Interactionsmentioning

confidence: 99%

Urothelial Signaling

Birder

Andersson

2013

Physiological Reviews

390

362

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The urothelium, which lines the inner surface of the renal pelvis, the ureters, and the urinary bladder, not only forms a high-resistance barrier to ion, solute and water flux, and pathogens, but also functions as an integral part of a sensory web which receives, amplifies, and transmits information about its external milieu. Urothelial cells have the ability to sense changes in their extracellular environment, and respond to chemical, mechanical and thermal stimuli by releasing various factors such as ATP, nitric oxide, and acetylcholine. They express a variety of receptors and ion channels, including P2X3 purinergic receptors, nicotinic and muscarinic receptors, and TRP channels, which all have been implicated in urothelial-neuronal interactions, and involved in signals that via components in the underlying lamina propria, such as interstitial cells, can be amplified and conveyed to nerves, detrusor muscle cells, and ultimately the central nervous system. The specialized anatomy of the urothelium and underlying structures, and the possible communication mechanisms from urothelial cells to various cell types within the bladder wall are described. Changes in the urothelium/ lamina propria ("mucosa") produced by different bladder disorders are discussed, as well as the mucosa as a target for therapeutic interventions.

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“…Vesicular exocytosis is enhanced by cAMP in various cell types (7,13,19). Metabotropic receptors that regulate cAMP are found in urothelium: G-protein G s -or G i/o -coupled receptors, such as α 2 and β adrenergic (26,27,31) and muscarinic M2 and M4 (8,21,34) receptors. Furthermore, store-operated Ca 2+ entry specifically inhibited adenylyl cyclase type 6 (10,14).…”

Section: Adenylyl Cyclase-camp Pathway Did Not Cause Urothelial Atp Rmentioning

confidence: 99%

“…The adenylyl cyclase-cAMP pathway is upregulated by G s protein. In urinary bladder, β 1 -, β 2 -, and β 3 -adrenoceptors, which are G s -coupled-receptors, are expressed in urothelium (27,31). Among adrenoceptor subtypes in urothelium, α 1D is involved in the induction of ATP release (17), and β activation triggered a production and release of nitric oxide (5).…”

Section: Referencesmentioning

confidence: 99%

The regulation of distention-induced ATP release from urothelium by the adenylyl cyclase-cyclic AMP pathway

et al. 2012

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Distention of the bladder during urine storage induces ATP release from urothelium, thereby facilitating transmission of visceral sensory signals to afferent nerve fibers. An excess of urothelial ATP release was found in interstitial cystitis, a condition accompanied by hyperesthesia of the urinary bladder; it remains unclear which signals are involved in this upregulation. The present study demonstrated that the adenylyl cyclase pathway enhances distention-induced ATP release in mouse bladder. In the absence of distention, adenylyl cyclase activation by forskolin or cyclic AMP increases by rolipram did not induce significant ATP release. However, forskolin or rolipram significantly enhanced ATP release from urothelium by a physiologically normal urine storage pressure (5 cmH 2 O). Blockade of adenylyl cyclases did not alter pressure-induced ATP release in normal condition. Thus, the adenylyl cyclase-cAMP pathway might be activated in pathological conditions and cause an excess of ATP release.Recent studies revealed that urinary bladder epithelium (urothelium) functions as a visceral sensory organ as well as a barrier against urine (1, 3, 6). Distention of the bladder wall during urine storage causes a release of adenosine triphosphate (ATP) from the urothelium. Released ATP could act through the purinergic receptor P2X 3 , which is expressed on afferent nerve terminals in close proximity to urothelial cells. Studies using P2X 3 -deficient mice revealed that P2X 3 is essential for control of the urinary bladder volume reflex (11, 32); the pain response behavior was also reduced in these mice (11). These studies indicate that urothelial ATP release could play a key role in both volume-and noxious stimulus-evoked reflexes. In fact, an excess of urothelial ATP release was detected in interstitial cystitis or overactive bladder, conditions accompanied by visceral hyperesthesia leading to frequent urination or bladder pain (2, 28-30). However, the precise signaling cascade involved in the pathological increase of urothelial ATP release remains unknown. Identification of this signaling cascade may lead to improved strategies for clinical management of storage symptoms or bladder pain. Urothelial ATP release is mediated by various signal transduction pathways (24). In these, Ca 2+ plays an important role in the induction or regulation of ATP release. Urothelial ATP release was shown to be triggered by activation of transient receptor potential (TRP) V1 or TRPV4 (4,22,25), which are ion channels permeable to cations such as Ca 2+ . Knockout mice lacking TRPV1 or TRPV4 showed impairment of stretch-evoked increases in intracellular Ca 2+ and in ATP release from the urothelium (4, 15). Furthermore, Ca 2+ release from the endoplasmic reticulum (ER) is involved in induction of urothelial ATP release (23). On the other hand, store-operated Ca 2+ entry, which is driven by depletion of Ca 2+ stores in the ER, exerted an opposite, suppressive effect (23). Involvement of Ca 2+ implies that ATP

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Investigations into the presence of functional ß1, ß2 and ß3-adrenoceptors in urothelium and detrusor of human bladder

Cited by 68 publications

References 19 publications

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Urothelial Signaling

The regulation of distention-induced ATP release from urothelium by the adenylyl cyclase-cyclic AMP pathway

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