A Role for the P2X Receptor in Urinary Tract Physiology and in the Pathophysiology of Urinary Dysfunction

doi:10.1016/j.eururo.2005.04.019

European Urology

Volume 48, Issue 2, August 2005, Pages 303-308

https://doi.org/10.1016/j.eururo.2005.04.019 Get rights and content

Abstract

Objective:

We provide a historical perspective of the P2X receptor class in bladder physiology and the pathophysiology of urinary dysfunction.

Methods:

A literature search was performed using the MEDLINE database.

Results:

Evidence suggests that P2X receptors serve a combined function in sensory and motor activity of human bladder. P2X receptors mediate excitation of sensory neurons and evoke muscle contraction in response to ATP release. Anatomical and functional defects in the P2X receptor signaling are associated with a variety of urologic diseases.

Conclusion:

Current research underscores the importance of P2X receptors in urologic physiology. Potential applications exist in relation to the diagnosis and treatment of urinary dysfunction. However, the detailed mechanism of P2X receptor function in bladder physiology and in urinary tract disease remains unknown and warrants further investigation.

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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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.
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The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease
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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].
Muscarinic receptor antagonists and β-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and β-adrenoceptors are physiological antagonists for smooth muscle tone in airways and bladder. Muscarinic agonism may attenuate β-adrenoceptor-mediated relaxation more than other contractile stimuli. Chronic treatment with one drug class may regulate expression of the target receptor but also that of the opposing receptor. Prejunctional β₂-adrenoceptors can enhance neuronal acetylcholine release. Moreover, at least in the airways, muscarinic receptors and β-adrenoceptors are expressed in different locations, indicating that only a combined modulation of both systems may cause dilatation along the entire bronchial tree. While all of these factors contribute to a rationale for a combination of muscarinic receptor antagonists and β-adrenoceptor agonists, the full value of such combination as compared to monotherapy can only be determined in clinical studies.
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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 [³H]-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 P2X₃ subunits by means of the putative antagonists: NF449 (P2X_1,3 selective), NF023 (P2X_1,3 selective), PPNDS (P2X₁ selective) and A-317491 (P2X₃ selective). In porcine detrusor, P2X₃ 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 P2X₃ blockade represents a potential therapeutic approach for diseases of the urinary tract, isolated porcine detrusor represents a reliable model for development of novel selective P2X₃ antagonists beneficial in the treatment of detrusor hyperactivity.
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Tension recordings were made from strips of rabbit urethral smooth muscle. Recordings were made of membrane potential and ionic currents from freshly isolated smooth muscle cells and interstitial cells of Cajal using the patch clamp technique.
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Female Urology/IncontinenceA Role for the P2X Receptor in Urinary Tract Physiology and in the Pathophysiology of Urinary Dysfunction

Abstract

Objective:

Methods:

Results:

Conclusion:

Introduction

Section snippets

History of purinergic neurotransmission and the P2 receptor class

The P2X receptor: sensory function

The P2X receptor: motor function

The P2X receptor and the pathophysiology of bladder dysfunction

Targeting the P2X receptor in the treatment of urologic disorders

J Urol

Br J Anesth

J Urol

J Urol

Trends in Pharm Sci

Neurosci

J Urol

Autonomic neuroscience-basic and clinical

Autonomic neuroscience-basic and clinical

J Urol

J Urol

Urology

J Urol

Eur Urol

J Urol

J Urol

Eur J Pharmacol

High affinity binding sites for 3H Substance P in urinary bladders of cats with interstitial cystitis

J Urol

The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves

J Physiol

A basis for distinguishing two types of purinergic receptor

Subunit arrangement in P2X receptors

J Neurosci

Pharmacology of cloned P2X receptors

Annu Rev Pharmacol Toxicol

A new class of ligand-gated ion channel defined by P2X receptor for extracellular ATP

Nature

New structural motif for ligan-gated ion channels defined by an ionotropic ATP receptor

Nature

A P2X purinoceptor expressed by a subset of sensory neurons

Nature

Identification of algogenic substances in human erythrocytes

J Physiol

Female Urology/Incontinence
A Role for the P2X Receptor in Urinary Tract Physiology and in the Pathophysiology of Urinary Dysfunction