P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin.
ABSTRACT 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.
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ABSTRACT: Purinergic signalling is involved in a number of physiological and pathophysiological activities in the lower urinary tract. In the bladder of laboratory animals there is parasympathetic excitatory cotransmission with the purinergic and cholinergic components being approximately equal, acting via P2X1 and muscarinic receptors, respectively. Purinergic mechanosensory transduction occurs where ATP, released from urothelial cells during distension of bladder and ureter, acts on P2X3 and P2X2/3 receptors on suburothelial sensory nerves to initiate the voiding reflex, via low threshold fibres, and nociception, via high threshold fibres. In human bladder the purinergic component of parasympathetic cotransmission is less than 3 %, but in pathological conditions, such as interstitial cystitis, obstructed and neuropathic bladder, the purinergic component is increased to 40 %. Other pathological conditions of the bladder have been shown to involve purinoceptor-mediated activities, including multiple sclerosis, ischaemia, diabetes, cancer and bacterial infections. In the ureter, P2X7 receptors have been implicated in inflammation and fibrosis. Purinergic therapeutic strategies are being explored that hopefully will be developed and bring benefit and relief to many patients with urinary tract disorders.Purinergic Signalling 11/2013; · 2.64 Impact Factor
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ABSTRACT: This article summarizes anatomical, neurophysiological, and pharmacological studies in humans and animals to provide insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract and alterations in these mechanisms in lower urinary tract dysfunction. The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Therefore, injury or diseases of the nervous system, as well as disorders of the peripheral organs, can produce lower urinary tract dysfunction, leading to lower urinary tract symptoms, including both storage and voiding symptoms, and pelvic pain. Neuroplasticity underlying pathological changes in lower urinary tract function is discussed.Korean journal of urology 02/2014; 55(2):81-90.
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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.AJP Renal Physiology 11/2013; · 4.42 Impact Factor