Abstract
The urothelium is a newly recognized sensory structure that detects bladder fullness. Pivotal to this sensory role is the 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 mucosa were mounted in a perfusion trough; superfusate ATP was measured using a luciferin-luciferase assay, and tissue contractions were recorded with a tension transducer. Intracellular Ca2+ was measured in isolated urothelial cells with fura-2. The P2Y agonist UTP but not the P2X agonist α,β-methylene-ATP generated ATP release. The muscarinic agonist carbachol and the M2-preferential agonist oxotremorine also generated ATP release, which was antagonized by the M2-specific agent methoctramine. Agonist-evoked ATP release was accompanied by mucosal contractions. Urothelial ATP release was differentially mediated by intracellular Ca2+ release, cAMP, exocytosis, or connexins. Urothelium-attached smooth muscle exhibited spontaneous contractions that were augmented by subthreshold concentrations of carbachol, which had little direct effect on smooth muscle. This activity was attenuated by desensitizing P2X receptors on 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.
Highlights
THE ROLE OF THE UROTHELIUM as a novel sensory structure has generated intense interest in recent years and may serve similar sensory and motor functions in other mucosa-lined visceral organs
Changes to urothelial receptor expression [3, 7, 9, 43] and Although UTP (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
In a subset of control experiments, the mucosa was further separated into uroepithelium and suburothelial layers, and total ATP released from each tissue layer was collected and measured in a static system
Summary
THE ROLE OF THE UROTHELIUM as a novel sensory structure has generated intense interest in recent years and may serve similar sensory and motor functions in other mucosa-lined visceral organs. Drugs currently used to manage the overactive bladder work better in the filling phase rather than the voiding phase of the micturition cycle [2] when the detrusor muscle is relaxed These drugs may influence a sensory pathway associated with bladder filling rather than the voiding phase of the micturition cycle when motor nerves contract detrusor smooth muscle. ATP released from the urothelium may have an autocrine function or may act in a local paracrine way to influence afferent nerve, interstitial cell, or detrusor smooth muscle function. This study aimed to 1) characterize ATP release and its modulation by purinergic and muscarinic receptor agonists, the major excitatory neurotransmitters, in intact guinea pig urothelial tissue and 2) explore its paracrine effect on smooth muscle function. Further aims were to determine if these processes were altered in the aging bladder and whether similar phenomena were present in the human bladder
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