The ATP-gated purinergic receptor P2X3 is expressed by small diameter sensory neurons and has been identified in normal and neurogenic human bladder suburothelial fibres. Animal models have shown that ATP is released by the urothelium during bladder distension, suggesting a mechanosensory role for P2X3 receptors in normal bladder function. Successful treatment of spinal neurogenic detrusor overactivity (NDO) with intravesical resiniferatoxin (RTX), which partly acts on suburothelial C fibres, provides evidence for the emergence of a C fibre-mediated spinal reflex. The aim of this study was to investigate the possible role of P2X3-positive innervation in this pathological voiding reflex by comparing suburothelial P2X3 immunoreactivity of controls and in patients with NDO before and after intravesical RTX.
Bladder biopsies were obtained from 8 controls and 20 patients with refractory NDO enrolled in a trial of intravesical RTX. P2X3 nerve fibre density and intensity were studied in the specimens by immunohistochemistry.
P2X3-IR nerve fibres were significantly increased in patients with NDO compared to controls (p=0.014). Thirteen patients had pre- and post-RTX biopsies available for immunohistochemistry; 5 of them responded clinically and 8 were non-responders. In the 5 patients who responded to RTX, there was a significant decrease in P2X3-positive fibres (p=0.032), whereas in non-responders, P2X3-IR nerve fibre density did not change significantly.
In patients with NDO, the numbers of P2X3-IR nerve fibres were increased in the suburothelium. There was a significant decrease in P2X3 immunoreactivity in responders to RTX, indicating a potential pathophysiological role for the P2X3 expressing fibres.
"The subsequent identification of P2X3 receptors on suburothelial nerves, as well as the attenuation of afferent activity and urinary retention in mice lacking P2X3 receptors (14, 50), emphasized the importance of the urothelium as a structure that may specifically influence afferent activation and bladder function (4, 6, 42). Changes to urothelial receptor expression (3, 7, 9, 43) and ATP release (5, 27, 48) in tissues or cultured cells obtained from overactive bladders further demonstrated the pathological implications of this tissue, which may lead to specific drug targets for the management of overactive bladders. However, the functional pathways mediated by the various urothelial receptors (3, 7, 10, 12, 41) remain poorly understood. "
[Show abstract][Hide abstract] ABSTRACT: The urothelium is a newly-recognized sensory structure that detects bladder fullness. Pivotal to this sensory role is release of ATP from the urothelium. However, the routes for urothelial ATP release, its modulation by receptor-mediated pathways and the autocrine/paracrine role of ATP are poorly understood, especially in native tissue. We examined the action of key neurotransmitters - purinergic and muscarinic agonists on ATP release and its paracrine effect. Guinea-pig and human urothelial mucosae were mounted in a perfusion trough; superfusate ATP was measured using luciferin-luciferase assay and tissue contractions were recorded with a tension transducer. Intracellular calcium was measured in isolated urothelial cells with Fura-2. P2Y agonist UTP but not P2X agonist α,β-methylene-ATP, generated ATP release. Muscarinic agonist carbachol and M2-preferential agonist oxotremorine also generated ATP release, antagonized by M2-specific agent methoctramine. Agonist-evoked ATP release was accompanied by mucosal contractions. Urothelial ATP release was differentially mediated by intracellular calcium release, c-AMP, exocytosis or connexins. Urothelium-attached smooth muscle exhibited spontaneous contractions that were augmented by sub-threshold concentrations of carbachol which had little direct effect on smooth muscle. This activity was attenuated by desensitizing P2X receptors on the smooth muscle. Urothelial ATP release was increased in aging bladders. Purinergic and muscarinic agents produced similar effects in human urothelial tissue. This is the first demonstration of specific modulation of urothelial ATP release in native tissue by purinergic and muscarinic neurotransmitters via distinct mechanisms. Released ATP produces paracrine effects on underlying tissues. This process is altered during aging and has relevance to human bladder pathologies.
"Recently, neural P2X 3 receptors have been suggested to exert a prominent role in the control of bladder fullness sensation and efferent transmitter release in pathophysiological circumstances , in particular in human bladders with detrusor overactivity (DO) where an increase in P2X 3 receptor expression was observed too . Consequently, the blockade of these receptors might be clinically beneficial   , but the development of novel P2X 3 antagonists requires a first screening of their pharmacological activity in an animal model in which compelling evidence has surfaced that a dysregulation of the purinergic pathway promoting conditions of functional neurologic hyperactivity relates to motor (efferent) urologic abnormalities. "
[Show abstract][Hide abstract] ABSTRACT: Various forms of low urinary tract symptoms (LUTS) seem dependant upon dysregulation of the purinergic pathway which produces sensory- or motor-activated incontinence. A body of evidence in human urinary bladders supports a link between up-regulation of purinergic activity and the pathogenesis of detrusor instability. This study investigated the potential role of adenosine 5'-triphosphate (ATP) in the control of detrusor motor drive in a model of porcine urinary bladder. The involvement of ATP on excitatory activity was assessed by measuring neurally-evoked [(3)H]-acetylcholine (ACh) release and smooth muscle contraction in detrusor strips. Epithelium-deprived preparations were used to minimize the influence of non-neural sources of ACh and ATP on parasympathetic neurotransmission. ACh release and smooth muscle contractility were not significantly affected by neural ATP in normal detrusor, but markedly enhanced when ATP hydrolysis was reduced by ectoATPase inhibitors, as well as by α,β-methylene-ATP (ABMA), agonist resistant to ecto-enzymes degradation. Prejunctional P2X receptors located on cholinergic nerves are involved in such potentiating effect. These purinergic heteroreceptors were characterized as P2X(3) subunits by means of the putative antagonists: NF449 (P2X(1,3) selective), NF023 (P2X(1,3) selective), PPNDS (P2X(1) selective) and A-317491 (P2X(3) selective). In porcine detrusor, P2X(3) receptors are functionally expressed at neural site facilitating neurogenic ACh release. When purine breakdown is experimentally down-regulated to mimicking the impaired purinergic pathway observed in pathological human bladders, endogenous ATP can markedly enhance detrusor contractility through activation of these receptors. Since P2X(3) blockade represents a potential therapeutic approach for diseases of the urinary tract, isolated porcine detrusor represents a reliable model for development of novel selective P2X(3) antagonists beneficial in the treatment of detrusor hyperactivity.
Pharmacological Research 01/2012; 65(1):129-36. DOI:10.1016/j.phrs.2011.10.002 · 4.41 Impact Factor
"Studies in humans have revealed an increased density of TRPV1-and P2X 3 immunoreactivity as well as immunoreactivity to a panneuronal marker (PGP9.5) in suburothelial nerves and increased TRPV1-immunoreactivity in the basal layer of the urothelium in patients with neurogenic detrusor overactivity (NDO) (Apostolidis et al., 2005a; Brady et al., 2004a, 2004b). Treatment of NDO patients with intravesical capsaicin or another C-fiber neurotoxin, resiniferatoxin, produces symptomatic improvement in a subpopulation of these patients and reduces the density of TRPV1, P2X3 and PGP9.5 immunoreactive nerve fibers and urothelial TRPV1 immunoreactivity (Brady et al., 2004a, 2004b). Injections into the bladder wall of botulinum neurotoxin type A (BoNT/A), an agent that blocks the release of neurotransmitters from urothelial cells and from afferent and efferent nerves also reduces NDO (Apostolidis and Fowler, 2008; Popat et al., 2005; Schurch et al., 2007) and reduces the density of TRPV1-and P2X 3 -immunoreactive nerves (Apostolidis et al., 2005a, 2005b; Apostolidis and Fowler, 2008). "
[Show abstract][Hide abstract] ABSTRACT: The lower urinary tract has two main functions, storage and periodic expulsion of urine, that are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the external urethra sphincter). During urine storage the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure. During micturition the outlet relaxes and the bladder contracts to promote efficient release of urine. This reciprocal relationship between bladder and outlet is generated by reflex circuits some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However the bladder does not empty efficiently because coordination between the bladder and urethral outlet is lost. Studies in animals indicate that dysfunction of the lower urinary tract after spinal cord injury is dependent in part on plasticity of bladder afferent pathways as well as reorganization of synaptic connections in the spinal cord. Reflex plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and/or the peripheral target organs.
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