scholarly journals Intravesical TRPV4 blockade reduces repeated variate stress-induced bladder dysfunction by increasing bladder capacity and decreasing voiding frequency in male rats

2014 ◽  
Vol 307 (4) ◽  
pp. R471-R480 ◽  
Author(s):  
Liana Merrill ◽  
Margaret A. Vizzard
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Bladder Dysfunction ◽  
Bladder Capacity ◽  
Bladder Pain Syndrome ◽  
Male Rats ◽  
Bladder Function ◽  
Detrusor Smooth Muscle ◽  
Bladder Pain

Individuals with functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) often report symptom (e.g., urinary frequency) worsening due to stress. One member of the transient receptor potential ion channel vanilloid family, TRPV4, has recently been implicated in urinary bladder dysfunction disorders including OAB and IC/BPS. These studies address the role of TRPV4 in stress-induced bladder dysfunction using an animal model of stress in male rats. To induce stress, rats were exposed to 7 days of repeated variate stress (RVS). Quantitative PCR data demonstrated significant ( P ≤ 0.01) increases in TRPV4 transcript levels in urothelium but not detrusor smooth muscle. Western blot analyses of split urinary bladders (i.e., urothelium and detrusor) showed significant ( P ≤ 0.01) increases in TRPV4 protein expression levels in urothelial tissues but not detrusor smooth muscle. We previously showed that RVS produces bladder dysfunction characterized by decreased bladder capacity and increased voiding frequency. The functional role of TRPV4 in RVS-induced bladder dysfunction was evaluated using continuous, open outlet intravesical infusion of saline in conjunction with administration of a TRPV4 agonist, GSK1016790A (3 μM), a TRPV4 antagonist, HC067047 (1 μM), or vehicle (0.1% DMSO in saline) in control and RVS-treated rats. Bladder capacity, void volume, and intercontraction interval significantly decreased following intravesical instillation of GSK1016790A in control rats and significantly ( P ≤ 0.01) increased following administration of HC067047 in RVS-treated rats. These results demonstrate increased TRPV4 expression in the urothelium following RVS and that TRPV4 blockade ameliorates RVS-induced bladder dysfunction consistent with the role of TRPV4 as a promising target for bladder function disorders.

scholarly journals Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

2016 ◽  
Vol 310 (7) ◽  
pp. C600-C611 ◽  
Author(s):  
Kiril L. Hristov ◽  
Amy C. Smith ◽  
Shankar P. Parajuli ◽  
John Malysz ◽  
Eric S. Rovner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Single Cells ◽  
Receptor Potential ◽  
Detrusor Smooth Muscle ◽  
Rt Pcr ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Trpm4 Channel

Transient receptor potential melastatin 4 (TRPM4) channels are Ca2+-activated nonselective cation channels that have been recently identified as regulators of detrusor smooth muscle (DSM) function in rodents. However, their expression and function in human DSM remain unexplored. We provide insights into the functional role of TRPM4 channels in human DSM under physiological conditions. We used a multidisciplinary experimental approach, including RT-PCR, Western blotting, immunohistochemistry and immunocytochemistry, patch-clamp electrophysiology, and functional studies of DSM contractility. DSM samples were obtained from patients without preoperative overactive bladder symptoms. RT-PCR detected mRNA transcripts for TRPM4 channels in human DSM whole tissue and freshly isolated single cells. Western blotting and immunohistochemistry with confocal microscopy revealed TRPM4 protein expression in human DSM. Immunocytochemistry further detected TRPM4 protein expression in DSM single cells. Patch-clamp experiments showed that 9-phenanthrol, a selective TRPM4 channel inhibitor, significantly decreased the transient inward cation currents and voltage step-induced whole cell currents in freshly isolated human DSM cells. In current-clamp mode, 9-phenanthrol hyperpolarized the human DSM cell membrane potential. Furthermore, 9-phenanthrol attenuated the spontaneous phasic, carbachol-induced and nerve-evoked contractions in human DSM isolated strips. Significant species-related differences in TRPM4 channel activity between human, rat, and guinea pig DSM were revealed, suggesting a more prominent physiological role for the TRPM4 channel in the regulation of DSM function in humans than in rodents. In conclusion, TRPM4 channels regulate human DSM excitability and contractility and are critical determinants of human urinary bladder function. Thus, TRPM4 channels could represent promising novel targets for the pharmacological or genetic control of overactive bladder.

scholarly journals Optogenetic silencing of primary afferents reduces evoked and ongoing bladder pain

2017 ◽  
Author(s):  
Vijay K. Samineni ◽  
Aaron D. Mickle ◽  
Jangyeol Yoon ◽  
Jose G. Grajales-Reyes ◽  
Melanie Pullen ◽  
...  
Keyword(s):  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Bladder Function ◽  
Optoelectronic System ◽  
Sensory Afferents ◽  
Bladder Pain ◽  
Before And After ◽  
Visceromotor Response ◽  
Cutaneous Hypersensitivity

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) suffer from chronic pain that severely affects quality of life. Although the underlying pathophysiology is not well understood, inhibition of bladder sensory afferents temporarily relieves pain. Here, we explored the possibility that optogenetic inhibition of bladder sensory afferents could be used to modulate bladder pain. Specifically, we chose to study the role of Nav1.8+ sensory afferents before and after induction of a mouse model of bladder pain. The light-activated inhibitory proton pump Archaerhodopsin (Arch) was expressed under control of the Nav1.8+ promoter to selectively silence these neurons. Optically silencing Nav1.8+ afferents significantly blunted the evoked visceromotor response to bladder distension and led to small but significant changes in bladder function. To study of the role of these fibers in freely behaving mice, we developed a fully implantable, flexible, wirelessly powered optoelectronic system for the long-term manipulation of bladder afferent expressed opsins. We found that optogenetic inhibition of Nav1.8+ fibers reduced both ongoing pain and evoked cutaneous hypersensitivity in the context of cystitis, but had no effect in uninjured, naïve mice. These results suggest that selective optogenetic silencing of bladder afferents may represent a potential future therapeutic strategy for the treatment of bladder pain.

scholarly journals The Value of Cystoscopy in the Assessment of Interstitial Cystitis/Bladder Pain Syndrome

2021 ◽  
Vol 6 (2) ◽  
pp. 198-204
Author(s):  
R. F. Sholan
Keyword(s):  
Interstitial Cystitis ◽  
Pain Syndrome ◽  
Bladder Capacity ◽  
Bladder Pain Syndrome ◽  
Bladder Pain ◽  
Painful Bladder ◽  
Diagnostic Role ◽  
Mucosal Bleeding ◽  
Degree Of Severity

Background. There are significant differences in the diagnosis of interstitial cystitis/painful bladder syndrome (IC/ BPS), in particular, controversy regarding the diagnostic role of cystoscopy or hydrodistension cystoscopy.The aim of the study was to evaluate the results of cystoscopy with hydrodistension in women with IC/BPS.Materials and methods. The study involved 126 women with IC/BPS, mean age – 46.7 ± 14.0 years. The duration of the disease was 6.0 ± 2.8 years. Questionnaires PUF, VAS, USS, and potassium test were used. Cystoscopy and urinary bladder hydrodistension were performed.Results. The sum of points on the PUF scale was 8.14 ± 1.76, on the VAS scale – 5.45 ± 0.93, on the USS scale – 2.63 ± 0.91. A positive potassium test was detected in 91.3 % of cases, the sensitivity of the test was 86.5 %, the specificity – 84.6 %. The anatomical bladder capacity was 308.0 ± 77.5 ml. The average indicator of maximum bladder filling in women with mild pain was higher than in moderate and severe pain by 30.9 % (p < 0.05) and 53.0 % (p < 0.01), respectively. In 11.9 % of cases, polyps were detected at the external opening of the urethra. During cystoscopy, diffuse mucosal bleeding was detected in 39.8 % of cases, diffuse submucosal bleeding – in 21.4 %, rare glomerulations – in 14.3 %, Gunner’s lesions in 12.7 % of cases. After hydrodistension, the changes were more often diffuse (n = 57). There was a significant relationship (r = –0.57, p < 0.01) between the maximum filling of the bladder and the degree of severity of mucosal abnormalities. The severity of changes in the mucous membrane of the bladder positively correlated with the sum of points on the PUF questionnaire (r = +0.61, p = 0.003), on the VAS questionnaire (r = +0.59, p = 0.008) and according to the USS questionnaire (r = +0.66, p = 0.005).Conclusion. Cystoscopy can be used to examine IC/BPS in accordance with the recommendations of international societies. The obtained data can help to improve the effectiveness of IC/PBS diagnostics. 

scholarly journals Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

2013 ◽  
Vol 305 (2) ◽  
pp. R147-R156 ◽  
Author(s):  
Liana Merrill ◽  
Susan Malley ◽  
Margaret A. Vizzard
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Urinary Bladder ◽  
Body Weight Gain ◽  
Bladder Pain Syndrome ◽  
Male Rats ◽  
Bladder Function ◽  
Bladder Pain ◽  
Nerve Growth ◽  
Induced Changes

Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were significantly ( P ≤ 0.01) attenuated by day 5 of RVS, and adrenal weight was significantly ( P ≤ 0.05) increased. Histamine, MPO, NGF, and CXCL12 protein expression was significantly ( P ≤ 0.01) increased in the urinary bladder after RVS. Somatic sensitivity of the hindpaw and pelvic regions was significantly ( P ≤ 0.01) increased at all monofilament forces tested (0.1–4 g) after RVS. Intercontraction interval, infused volume, and void volume were significantly ( P ≤ 0.01) decreased after RVS. These studies demonstrate increased voiding frequency, histamine, MPO, NGF, and CXCL12 bladder content and somatic sensitivity after RVS suggesting an inflammatory component to stress-induced changes in bladder function and somatic sensitivity.

Role of capacitative Ca2+ entry in bronchial contraction and remodeling

2002 ◽  
Vol 92 (4) ◽  
pp. 1594-1602 ◽  
Author(s):  
Michele Sweeney ◽  
Sharon S. McDaniel ◽  
Oleksandr Platoshyn ◽  
Shen Zhang ◽  
Ying Yu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Bronchial Hyperresponsiveness ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Wall Thickening ◽  
Bronchial Wall ◽  
Intracellular Ca ◽  
Transient Receptor

Asthma is characterized by airway inflammation, bronchial hyperresponsiveness, and airway obstruction by bronchospasm and bronchial wall thickening due to smooth muscle hypertrophy. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) may serve as a shared signal transduction element that causes bronchial constriction and bronchial wall thickening in asthma. In this study, we examined whether capacitative Ca2+ entry (CCE) induced by depletion of intracellular Ca2+ stores was involved in agonist-mediated bronchial constriction and bronchial smooth muscle cell (BSMC) proliferation. In isolated bronchial rings, acetylcholine (ACh) induced a transient contraction in the absence of extracellular Ca2+ because of Ca2+ release from intracellular Ca2+ stores. Restoration of extracellular Ca2+in the presence of atropine, an M-receptor blocker, induced a further contraction that was apparently caused by a rise in [Ca2+]cyt due to CCE. In single BSMC, amplitudes of the store depletion-activated currents ( I SOC) and CCE were both enhanced when the cells proliferate, whereas chelation of extracellular Ca2+ with EGTA significantly inhibited the cell growth in the presence of serum. Furthermore, the mRNA expression of TRPC1, a transient receptor potential channel gene, was much greater in proliferating BSMC than in growth-arrested cells. Blockade of the store-operated Ca2+channels by Ni2+ decreased I SOC and CCE and markedly attenuated BSMC proliferation. These results suggest that upregulated TRPC1 expression, increased I SOC, enhanced CCE, and elevated [Ca2+]cyt may play important roles in mediating bronchial constriction and BSMC proliferation.

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