Female Urology/IncontinenceA Role for the P2X Receptor in Urinary Tract Physiology and in the Pathophysiology of Urinary Dysfunction
Introduction
Modern research techniques have yielded better insight into the neurogenic factors that contribute to the pathophysiology of urinary dysfunction, including overactive bladder (OAB) and interstitial cystitis (IC). In addition to a large body of investigation that has better defined the role of motor neuron dysfunction in OAB, increasing evidence suggests that sensory neuron dysfunction may also be involved in the pathophysiology OAB and, in addition, IC. Upregulation of neuropeptide binding sites within the bladder and afferent nerve stimulation by nerve growth factor are examples of phenomena that can occur with urinary dysfunction and suggest sensory neuron involvement [1], [2]. In addition, a class of ATP receptors, known as P2 receptors, may play critical roles in both sensory and motor functions in the bladder. Although these receptors function in normal bladder, they may be especially important in diseased bladder. As such, a basic understanding of P2 receptors and their involvement in the physiology of micturition, urinary dysfunction, and as a possible target of pharmacotherapy, is useful to the urologic community.
Section snippets
History of purinergic neurotransmission and the P2 receptor class
The early history of the P2X receptor in nerve signaling was based on investigation demonstrating that ATP was released from sensory nerves following antidromic stimulation. This raised the possibility that ATP might be involved in sensory neurotransmission [3]. Subsequently, a non-adrenergic, non-cholinergic (NANC) nervous supply to various viscera, including the urinary bladder, was identified [4]. These findings served as the foundation for subsequent research investigating the potential
The P2X receptor: sensory function
Experiments conducted over 25 years ago suggested a role for a P2 receptor in sensation. ATP induced pain in humans when injected subcutaneously [13]. At that time, the target receptor for ATP, and its location, were unknown. In the ensuing decades, evidence has accumulated suggesting P2X3 receptors on sensory neurons mediate much of this response. During the initial P2X3 gene cloning experiments, P2X3 mRNA was found exclusively within sensory neurons [10]. This finding renewed interest in P2X3
The P2X receptor: motor function
Research implicating the P2X receptor in the motor component of bladder function is based on early reports demonstrating a non-cholinergic component to motor neuron transmission in the mammalian bladder [30]. Subsequent studies provided evidence that this component might be mediated by extracellular ATP and the P2X receptor [31]. Electrophysiological evidence demonstrates that ATP is an excitatory transmitter in smooth muscle cells of guinea-pig, rabbit, and pig urinary bladders [32]. Both ATP
The P2X receptor and the pathophysiology of bladder dysfunction
Most of the research focusing on purinergic neurotransmission in pathophysiology of urinary dysfunction comes from the examination of OAB. Several studies suggest that P2X receptor expression and function change in patients with both IDO and neurogenic detrusor overactivity. Bayliss et al. [40] demonstrated non-cholinergic transmission in detrusor samples of patients with IDO. O’Reilly et al. [12] found an increased expression of the P2X2 subtype protein and mRNA in patients with IDO, and
Targeting the P2X receptor in the treatment of urologic disorders
Both the study and treatment of urinary dysfunction, including OAB and IC, remain difficult and the people afflicted are numerous. The prevalence of patients with symptoms of OAB in Europe and the United States is approximately 16% [49]. Although anticholinergic medication can improve symptoms of OAB, a recent review describes only a small statistical difference between drug and placebo treatments [50]. Likewise, IC has a prevalence of 60/100,000 cases in the U.S. and has a notoriously
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2016, Pharmacology and TherapeuticsCitation Excerpt :This could be relevant because the gold standard drugs in OAB treatment, muscarinic receptor antagonists, by definition can only inhibit signals coming from agonists at such receptors including the endogenous acetylcholine. Under pathophysiological conditions, several other mediators have been shown to contribute to the regulation of detrusor smooth muscle tone including ATP (Rapp et al., 2005; Burnstock, 2014) but also, particularly in the presence of inflammation, bradykinin, prostaglandin E2 or serotonin (Maggi, 1992; Meini et al., 1998; Cristofaro et al., 2007; Sand and Michel, 2014). These findings raised the possibility that on mechanistic grounds β3-adrenoceptor agonists may be more effective OAB treatments than muscarinic receptor antagonists.
The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease
2014, Current Opinion in PharmacologyCitation Excerpt :Muscarinic receptors are the primary mediator of urinary bladder contraction during physiological voiding but, in contrast to humans, non-cholinergic mediators can significantly contribute to bladder contraction in the healthy bladder of various animal species [32]. However, in both animals and humans, non-cholinergic mediators such as ATP or bradykinin become increasingly important under pathological conditions [33–35]. Despite the much greater expression of M2 than M3 receptors in the bladder of humans and most other mammalian species (see ‘Receptor expression patterns in airways and bladder’ section), the direct contractile effects of muscarinic agonists is mediated primarily if not exclusively by the minor population of M3 receptors [36].
Purinergic P2X <inf>3</inf> heteroreceptors enhance parasympathetic motor drive in isolated porcine detrusor, a reliable model for development of P2X selective blockers for detrusor hyperactivity
2012, Pharmacological ResearchCitation Excerpt :The relative importance of the purinergic component, however, is species dependent, being dominant in cat, mouse and rabbit, to moderate in guinea pig, rat and dog, to less pronounced in pig and humans [9]. Although negligible in normal human bladder [10], the role of ATP has recently attracted considerable attention in the pathophysiology of abnormal detrusors [11]. In fact, the purinergic component seems responsible for the increased atropine-resistance of parasympathetically-evoked contractions observed in aging [12] and in subjects with urological disease states such as obstructed bladder (OB) [10,13] and interstitial cystitis (IC) [14], or idiopathic detrusor overactivity (IDO) [15], where the magnitude is greatest [16].
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