Aim

To examine function of both cholinergic (muscarinic) and TRPV1 receptors in human bladder urothelial (HBUC) from non-neurogenic overactive bladder (OAB) patients as compared to control subjects.



Methods

Primary HBUC cultures were derived from cystoscopic biopsies from OAB and control subjects. Muscarinic and TRPV1 function was assessed by acetylcholine (5 μm) or capsaicin (0.5 μm) evoked ATP release, measured by luciferase assay. Overall, expression of TRPV1 and muscarinic M3 receptors in bladder urothelial cells was accomplished using western immunoblotting.



Results

Our findings revealed that the response to acetylcholine in OAB HBUC cultures (which was blocked by the nonselective muscarinic antagonist, atropine methyl nitrate or AMN) was not significantly different than from controls. The acetylcholine M3 receptor was slightly decreased as compared to control. In contrast, OAB HBUC cultures exhibited a capsaicin hypersensitivity and augmented release of ATP (3.2 fold higher), which was blocked by the antagonist capsazepine. The increase in capsaicin sensitivity correlated with increased urothelial TRPV1 expression.



Conclusion

Though characterized in a small number of subjects, augmented release of urothelial-derived transmitters such as ATP could ‘amplify’ signalling between and within urothelial cells and nearby afferent nerves.

/pdf/alteration-in-trpv1-and-muscarinic-m3-receptor-expression-347wzhanmj.pdf

Alteration in TRPV1 and Muscarinic (M3) receptor expression and function in idiopathic overactive bladder urothelial cells

What's known on the subject? and What does the study add?



Recently, several studies have suggested that detrusor overactivity (DO) is the result of bladder ischaemia. Hypertension could affect pelvic arterial blood flow, resulting in loss of smooth muscle in the bladder with resultant loss of bladder compliance. Spontaneously hypertensive rats are considered a valuable tool for exploring the pathogenesis of DO. Some reports indicate that α1 adrenoceptor antagonists improve chronic ischaemia of the lower urinary tract in patients with LUTS, with concomitant improvement of their symptoms as well as improvement of DO through an increased bladder blood flow (BBF) in the rat with bladder outlet obstruction. However, the mechanism of improvement of silodosin on storage or irritative symptoms is not well investigated and is still unclear.



Silodosin prevents hypertension-related DO in the SHR via several possible mechanisms. One possible mechanism of the efficacy of silodosin to the DO includes the improvement of the BBF.



OBJECTIVE

• 
To investigate the effect of the α1A selective adrenoceptor antagonist, silodosin, on hypertension-related detrusor overactivity (DO) and its possible mechanism in spontaneously hypertensive rats (SHRs).





MATERIALS AND METHODS

• 
Twelve-week-old male SHRs received treatment with silodosin (100 µg/kg perorally) once daily for 6 weeks; vehicle-treated Wistar rats and vehicle-treated SHRs were used for our study.

• 
Six weeks after silodosin treatment, voiding functions were estimated by voiding behaviour and cystometric studies in all groups.

• 
The bladder blood flow was measured by the hydrogen clearance method, and tissue levels of nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) were measured by enzyme-linked immunosorbent assay (ELISA).

• 
Furthermore, the expressions of α1 adrenoceptor subtype mRNAs in the bladder were investigated by real-time PCR method.





RESULTS

• 
The SHRs showed significant increases in blood pressure, micturition frequency and tissue levels of NGF and CGRP in the bladder.

• 
Moreover, the SHRs showed significant decreases in bladder blood flow and single voided volume estimated by both voiding behaviour and cystometric studies compared with those in the Wistar rats.

• 
Six weeks of treatment with silodosin significantly ameliorated hypertension-related alterations of these variables with concomitant small changes of blood pressure.

• 
The expression levels of α1 adrenoceptor subtype mRNAs in the bladder were similar in all the groups and the rank order was α1A =α1D > α1B in all groups.

• 
However, there were no significant differences in the expressions of α1A adrenoceptor mRNAs between any groups.





CONCLUSION

• 
The data in the present study suggest that silodosin normalizes hypertension-related DO in SHRs, which could be related to its effect on the increased blood flow in the bladder.

Effect of silodosin on detrusor overactivity in the male spontaneously hypertensive rat

What's known on the subject? and What does the study add?

Hydroxyfasudil ameliorates bladder dysfunction in male spontaneously hypertensive rats.

Urinary biomarkers in women with refractory urgency urinary incontinence randomized to sacral neuromodulation versus onabotulinumtoxinA compared to controls

Overactive bladder syndrome (OAB) is highly prevalent bladder disorder in men and women. About 10-15% of the population suffers from urgency frequency with or without urgency urinary incontinence. It is estimated that 50-75% of patients with OAB may have urodynamic detrusor overactivity (DO). Urodynamic study invasive and most of the OAB patients might not accept it as a routine assessment. Therefore, a more objective and non-invasive test for diagnosis and assessing DO from OAB patients is needed. Recently, urinary nerve growth factor (NGF) has gained great interest in detecting DO in patients with OAB. Urinary NGF level was found to increase in OAB and urodynamic DO. Urinary NGF levels correlated with severity of OAB symptoms. Patients with either idiopathic or neurogenic DO may have increased urinary NGF levels. Urinary NGF levels have been shown to decrease in patients with patients with OAB and DO who have been well treated with antimuscarinics or botulinum toxin injection, but not in those with persistent OAB after treatment. Not all patients with OAB can have an elevated urinary NGF level; it may also be increased in patients with interstitial cystitis/painful bladder syndrome and other lower urinary tract diseases, suggesting urinary NGF expression could be a product of bladder inflammation and a limited specificity of urinary NGF for diagnosing DO. The source of urinary NGF has not yet been fully explored yet. Nevertheless, urinary NGF level is likely to be a promising biomarker for diagnosis of DO from OAB patients, to monitor therapeutic outcome and predict disease progression.

Promise of Urinary Nerve Growth Factor for Assessment of Overactive Bladder Syndrome.

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Promise of Urinary Nerve Growth Factor for Assessment of Overactive Bladder Syndrome.