Bladder pain induced by prolonged peripheral alpha 1A adrenoceptor stimulation involves the enhancement of transient receptor potential vanilloid 1 activity and an increase of urothelial adenosine triphosphate release

Matos, Rita; Cordeiro, Miguel; Coelho, Ana; Ferreira, Sónia; Martins-Silva, Carlos; Igawa, Yasuhiko; Cruz, Francisco; Charrua, Ana

doi:10.1111/apha.12744

Cited by 15 publications

(15 citation statements)

References 58 publications

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“…NE containing nerves are found in the mucosa in close proximity to UTC, suggesting possible interactions between sympathetic fibers and UT. UTC express α‐AR and β‐AR . Our results show that stimulation of α‐ARs but not β‐ARs in cultured rat UTC resulted in ROS production (Figure D).…”

Section: Discussionmentioning

confidence: 67%

“…Our results show that stimulation of α‐ARs but not β‐ARs in cultured rat UTC resulted in ROS production (Figure D). Other studies have shown that exposure of cultured human UTC to the α‐AR agonist phenylephrine, results in increased ATP release in response to mechanical stimulation when compared to control cells and in the WAS rodent model an α1‐AR antagonist reversed bladder frequency, urinary NE excretion as well as changes in the morphology of the UT . Thus, urothelial α‐ARs seem to play significant roles in mediator release and oxidative stress, both of which can influence afferent nerve excitability and pain pathways.…”

Section: Discussionmentioning

confidence: 93%

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Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Kullmann

McDonnell

Wolf‐Johnston

et al. 2018

Neurourology and Urodynamics

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Aim Chronic stress exacerbates the symptoms of most pain disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). Abnormalities in urothelial cells (UTC) occur in this debilitating bladder condition. The sequence of events that might link stress (presumably through increased sympathetic nervous system‐SNS activity) to urothelial dysfunction are unknown. Since autonomic dysregulation, mitochondrial dysfunction, and oxidative stress all occur in chronic pain, we investigated whether chronic psychological stress initiated a cascade linking these three dysfunctions. Methods Adult female Wistar Kyoto rats were exposed to 10 days of water avoidance stress (WAS). Bladders were then harvested for Western blot and single cell imaging in UTC cultures. Results UTC from WAS rats exhibited depolarized mitochondria membrane potential (Ψm ∼30% more depolarized compared to control), activated AMPK and altered UT mitochondria bioenergetics. Expression of the fusion protein mitofusion‐2 (MFN‐2) was upregulated in the mucosa, suggesting mitochondrial structural changes consistent with altered cellular metabolism. Intracellular calcium levels were elevated in cultured WAS UTC, consistent with impaired cellular function. Stimulation of cultured UTC with alpha‐adrenergic (α‐AR) receptor agonists increased reactive oxidative species (ROS) production, suggesting a direct action of SNS activity on UTC. Treatment of rats with guanethidine to block SNS activity prevented most of WAS‐induced changes. Conclusions Chronic stress results in persistent sympathetically mediated effects that alter UTC mitochondrial function. This may impact the urothelial barrier and signaling, which contributes to bladder dysfunction and pain. This is the first demonstration, to our knowledge, of a potential autonomic mechanism directly linking stress to mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 93%

Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Kullmann

McDonnell

Wolf‐Johnston

et al. 2018

Neurourology and Urodynamics

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“…Birder et al (2002a) studied the TRPV1 channel in a TRPV1 knockout (À/À) mouse model and detected an increased bladder capacity and a decrease in ATP excretion during bladder distention, implying that the TRPV1 receptors may also regulate normal bladder filling mechanosignalling. Charrua et al confirmed these results by detecting an increase in urothelial ATP excretion after TRPV1 activation (Charrua et al 2009, Matos et al 2016. OAB is associated with Cfibre activation and bladder instillation with TRPV1 agonists like capsaicin or the superagonist resiniferatoxin has been clinically applied in humans to desensitize these normally silent nerves to reduce the symptoms of OAB.…”

Section: Mechanoreceptorsmentioning

confidence: 91%

“…, Matos et al . ). OAB is associated with C‐fibre activation and bladder instillation with TRPV1 agonists like capsaicin or the superagonist resiniferatoxin has been clinically applied in humans to desensitize these normally silent nerves to reduce the symptoms of OAB.…”

Section: Mechanosensationmentioning

confidence: 97%

Urothelium update: how the bladder mucosa measures bladder filling

2016

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“…Based on their results, Charrua et al [ 47 ] concluded that excessive adrenergic stimulation of the bladder may contribute to the pathophysiological mechanisms of BPS/IC. In a follow-up study, Matos et al [ 53 ] showed that phenylephrine-induced morphological bladder changes, bladder overactivity, and L6 spinal cord Fos expression, were reversed by the highly selective α 1A -AR antagonist, silodosin, but not by naftopidil, a relatively selective antagonist for α 1D -ARs. Prazosin (which blocks all subtypes of α 1 -ARs) had an intermediate effect.…”

Section: Reduction Of Sympathetic Overactivity and Stressmentioning

confidence: 99%

Current Pharmacologic Approaches in Painful Bladder Research: An Update

Andersson

Birder

2017

Int Neurourol J

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The symptoms of interstitial cystitis (IC)/bladder pain syndrome (BPS) may have multiple causes and involve many contributing factors. Traditional treatments (intravesical instillations) have had a primary focus on the bladder as origin of symptoms without adequately considering the potential influence of other local (pelvic) or systemic factors. Systemic pharmacological treatments have had modest success. A contributing factor to the low efficacy is the lack of phenotyping the patients. Individualized treatment based on is desirable, but further phenotype categorization is needed. There seems to be general agreement that IC is a unique disease and that BPS is a syndrome with multiple pathophysiologies, but this has so far not been not been well reflected in preclinical research with the aim of finding new pharmacological treatments. Current research approaches, including anti-nerve growth factor treatment, anti-tumor necrosis factor-α treatment, activation of SHIP1 (AQX-1125), and P2X3 receptor antagonists, and α1-adrenoceptor antagonists are potential systemic treatments, implying that not only the bladder is exposed to the administered drug, which may be beneficial if the IC/BPS is a bladder manifestation of a systemic disease, or negative (adverse effects) if it is a local bladder condition. Local treatment approaches such as the antagonism of Toll-like receptors (which still is only experimental) and intravesical liposomes (with positive proof-of-concept), may have the advantages of a low number of systemic adverse effects, but cannot be expected to have effects on symptoms generated outside the bladder. Assessment of which of the treatment approaches discussed in this review that can be developed into useful therapies requires further studies.

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Bladder pain induced by prolonged peripheral alpha 1A adrenoceptor stimulation involves the enhancement of transient receptor potential vanilloid 1 activity and an increase of urothelial adenosine triphosphate release

Abstract: This study suggests that the activation of peripheral alpha 1A adrenoceptors induces CVP, probably through its interaction with TRPV1 and ATP release.

Cited by 15 publications

References 58 publications

Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Urothelium update: how the bladder mucosa measures bladder filling

Current Pharmacologic Approaches in Painful Bladder Research: An Update

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