Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity

Deruyver, Yves; Weyne, Emmanuel; Dewulf, Karel; Rietjens, Roma; Pinto, Shirly; Ranst, Nele Van; Franken, Jan; Vanneste, Matthias; Albersen, Maarten; Gevaert, Thomas; Vennekens, Rudi; Ridder, Dirk De; Voets, Thomas; Everaerts, Wouter

doi:10.1016/j.eururo.2018.05.020

Cited by 45 publications

(42 citation statements)

References 24 publications

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“…Intravesical instillation of GSK1016790, a TRPV4 agonist, induces bladder hyperactivity by reducing the threshold for bladder afferents activation . More recently, in a pelvic nerve injury rat model that exhibits phenotypic characteristics of UAB, TRPV4 agonist instillation improved the bladder function by increasing voiding frequency and reducing the postvoid residual volume . Here, we showed that old mice exhibited a downregulation of TRPV4 in the urothelium (but not in DSM and urethra), which may contribute to impaired bladder reflex.…”

Section: Discussionmentioning

confidence: 61%

“…24 More recently, in a pelvic nerve injury rat model that exhibits phenotypic characteristics of UAB, TRPV4 agonist instillation improved the bladder function by increasing voiding frequency and reducing the postvoid residual volume. 25 Here, we showed that old mice exhibited a downregulation of TRPV4 in the urothelium (but not in DSM and urethra), which may contribute to impaired bladder reflex. TRPV4 may, therefore, play an important role in the physiopathology of UAB in aged individuals.…”

Section: Aging Induces Biochemical and Molecular Changes In Bladdermentioning

confidence: 67%

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Autonomic dysregulation at multiple sites is implicated in age‐associated underactive bladder in female mice

Oliveira

Alexandre

Bonilla-Becerra

et al. 2019

Neurourology and Urodynamics

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Aims To evaluate the functional and molecular alterations of contractile and relaxant machinery in the bladder and urethra that lead to the underactive bladder (UAB) in old female mice. Methods Female young (3‐months) and old (18‐months) C57BL/6 mice were used. Urodynamic was assessed in awake and anaesthetized mice. Electrical‐field stimulation (EFS) and concentration‐response curves to contractile and relaxing agents in isolated bladders and urethras were performed. Messenger RNA (mRNA) expressions of muscarinic, adrenergic, and transient receptor potential vanilloid‐4 (TRPV4), and of the enzymes tyrosine hydroxylase and neuronal nitric oxide synthase (nNOS) were determined. Bladder cyclic adenosine monophosphate (cAMP) levels were measured. Results Cystometry in old mice showed incapacity to produce bladder emptying. On filter paper, old mice showed reduced urinary spots. Compared to the young group, bladder contractions induced by EFS and carbachol were lower in old mice. The β3‐adrenoceptor agonist mirabegron promoted higher bladder relaxation and elevation of cAMP levels in old mice. In old mice urethras, the α1a‐adrenoceptor agonist phenylephrine produced higher contractions, but no differences were found for the NO donor sodium nitroprusside‐induced relaxations. In old mice, increased mRNA expressions of β3‐ and α1a‐adrenoceptors in bladder and urethra were found, respectively, whereas the muscarinic M2 and M3 receptors and β2‐adrenoceptors did not change between groups. Reduced mRNA expressions of tyrosine hydroxylase and nNOS were found in old mouse urethras. Additionally, TRPV4 expression was reduced in bladder urothelium from old mice. Conclusion Age‐associated mouse UAB is the result of autonomic dysfunction at multiple levels leading to the less sensitive and overrelaxed bladder, along with urethral hypercontractility.

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Section: Discussionmentioning

confidence: 61%

Section: Aging Induces Biochemical and Molecular Changes In Bladdermentioning

confidence: 67%

Autonomic dysregulation at multiple sites is implicated in age‐associated underactive bladder in female mice

Oliveira

Alexandre

Bonilla-Becerra

et al. 2019

Neurourology and Urodynamics

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“…67,68 The demonstration of TRRV4-mediated ATP release in native bladder tissue suggests that TRPV4 can influence the physiology of the bladder. 55,64-66 TRPV4 activation evoked sustained contractions in intact bladder strips of similar magnitude to those evoked by the cholinergic agonist carbachol.…”

Section: The Basic Mode Of Action and Functional Role Of Trpv4 Recementioning

confidence: 99%

“…Thus, these findings reveal that TRPV4 activity in DSM may indeed influence bladder pathologies associated with muscle over-activity or underactivity. 67,68 The demonstration of TRRV4-mediated ATP release in native bladder tissue suggests that TRPV4 can influence the physiology of the bladder. It is currently thought that the urothelium senses distension in the bladder during filling and communicates this to the underlying tissues by release of ATP as a chemical signal.…”

Section: The Basic Mode Of Action and Functional Role Of Trpv4 Recementioning

confidence: 99%

TRPV4 receptor as a functional sensory molecule in bladder urothelium: Stretch‐independent, tissue‐specific actions and pathological implications

Roberts

Sui

et al. 2019

FASEB j.

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The newly recognized sensory role of bladder urothelium has generated intense interest in identifying its novel sensory molecules. Sensory receptor TRPV4 may serve such function. However, specific and physiologically relevant tissue actions of TRPV4, stretch-independent responses, and underlying mechanisms are unknown and its role in human conditions has not been examined. Here we showed TRPV4 expression in guinea-pig urothelium, suburothelium, and bladder smooth muscle, with urothelial predominance. Selective TRPV4 activation without stretch evoked significant ATP release-key urothelial sensory process, from live mucosa tissue, full-thickness bladder but not smooth muscle, and sustained muscle contractions. ATP release was mediated by Ca 2+ -dependent, pannexin/connexin-conductive pathway involving protein tyrosine kinase, but independent from vesicular transport and chloride channels. TRPV4 activation generated greater Ca 2+ rise than purinergic activation in urothelial cells. There was intrinsic TRPV4 activity without exogeneous stimulus, causing ATP release. TRPV4 contributed to 50% stretch-induced ATP release. TRPV4 activation also triggered superoxide release. TRPV4 expression was increased with aging. Human bladder mucosa presented similarities to guinea pigs.Overactive bladders exhibited greater TRPV4-induced ATP release with age dependence. These data provide the first evidence in humans for the key functional role of TRPV4 in urothelium with specific mechanisms and identify TRPV4 up-regulation in aging and overactive bladders. K E Y W O R D S aging, ATP release, overactive bladders, TRPV4 receptor, urothelium 264 | ROBERTS ET al 2 | MATERIALS AND METHODS | Animal and human tissue preparationsYoung (2-5 months) and aging (24-36 months) male Dunkin-Hartley guinea pigs (GPs, B&K Universal) were maintained under standard feeding conditions and used for experiments. GPs between 2 and 5 months old are mature young adults,

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“…Clinically, NOUR without an identifiable cause, that is, no nerve/muscle disease or damage, is classified as idiopathic, which includes many NOUR patients with unidentified functional changes in the central nervous system. Although myogenic/neurogenic animal models can be produced by bladder ischemia or pelvic nerve injury, 8,9 a recent study 10 in cats successfully produced an animal model of NOUR without nerve/muscle injury by prolonged stimulation of somatic afferent axons in the tibial nerve. This cat model of NOUR was used in the current study to determine if stimulation of the superficial peroneal nerve can reverse NOUR elicited by prolonged tibial nerve stimulation (TNS).…”

Section: Introductionmentioning

confidence: 99%

Superficial peroneal neuromodulation of nonobstructive urinary retention in cats

Zhao

Chen

Guo

et al. 2020

Neurourology and Urodynamics

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Aims To determine if superficial peroneal nerve stimulation (SPNS) can improve nonobstructive urinary retention (NOUR). Methods In α‐chloralose anesthetized cats, NOUR was induced by repetitive application (4‐16 times) of 30‐minute tibial nerve stimulation (TNS: 5 Hz frequency, 0.2 ms pulse width) at 4 to 6 times threshold intensity (T) for inducing toe twitches. SPNS (1 Hz, 0.2 ms) at 2 to 4 times threshold intensity (T) for inducing posterior thigh muscle contractions was applied either continuously (SPNSc) during a cystometrogram (CMG) or during voiding (SPNSv) by a surgically implanted cuff electrode or by skin surface electrodes to determine if the stimulation reduced NOUR induced by prolonged TNS. Results During control CMGs, efficient (86.4% ± 5.5%) voiding occurred with a postvoid residual (PVR) volume equal to 14.9% ± 6.2% of control bladder capacity. NOUR elicited by prolonged TNS significantly (P < .05) increased bladder capacity to 168.6% ± 15.5% of control, reduced voiding efficiency to 30.4% ± 4.8%, and increased PVR to 109% ± 9.2% of control. Using the implanted cuff electrode, SPNSc and SPNSv significantly (P < .05) increased voiding efficiency to 66.7% ± 7.4% and 65.0% ± 5.9%, respectively, and reduced PVR to 52.2% ± 11.4% and 64.3% ± 11.6%, respectively. SPNSc but not SPNSv significantly (P < .05) reduced bladder capacity to 133.4% ± 15% of control. Transcutaneous SPNSv but not SPNSc also significantly (P < .05) reversed the TNS‐induced NOUR responses. Conclusions This study shows that SPNS is effective in reversing NOUR induced by prolonged TNS. Transcutaneous SPNS provides the opportunity to develop a noninvasive neuromodulation therapy for NOUR to treat more patients than current sacral neuromodulation therapy.

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Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity

Cited by 45 publications

References 24 publications

Autonomic dysregulation at multiple sites is implicated in age‐associated underactive bladder in female mice

Autonomic dysregulation at multiple sites is implicated in age‐associated underactive bladder in female mice

TRPV4 receptor as a functional sensory molecule in bladder urothelium: Stretch‐independent, tissue‐specific actions and pathological implications

Superficial peroneal neuromodulation of nonobstructive urinary retention in cats

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