Alterations in detrusor contractility in rat model of bladder cancer

Abstract

Urinary incontinence of idiopathic nature is a common complication of bladder cancer, yet, the mechanisms underlying changes in bladder contractility associated with cancer are not known. Here by using tensiometry on detrusor smooth muscle (DSM) strips from normal rats and rats with bladder cancer induced by known urothelial carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), we show that bladder cancer is associated with considerable changes in DSM contractility. These changes include: (1) decrease in the amplitude and frequency of spontaneous contractions, consistent with the decline of luminal pressures during filling, and detrusor underactivity; (2) diminution of parasympathetic DSM stimulation mainly at the expense of m-cholinergic excitatory transmission, suggestive of difficulty in bladder emptying and weakening of urine stream; (3) strengthening of TRPV1-dependent afferent limb of micturition reflex and TRPV1-mediated local contractility, promoting urge incontinence; (4) attenuation of stretch-dependent, TRPV4-mediated spontaneous contractility leading to overflow incontinence. These changes are consistent with the symptomatic of bladder dysfunction in bladder cancer patients. Considering that BBN-induced urothelial lesions in rodents largely resemble human urothelial lesions at least in their morphology, our studies establish for the first time underlying reasons for bladder dysfunction in bladder cancer.

DNA Methylome Changes of Muscle- and Neuronal-Related Processes Precede Bladder Cancer Invasiveness

“…The urinary bladder smooth muscle is excitable by multiple ion channels, primarily calcium channels like Cav1, Cacna1c, Atp2b4, and transient receptor potential (Trp) channels [43], many of which showed, in our study, changes in expression and methylation pattern in invasive tumors. Changes in bladder contractility is a known complication of BC, and alterations in detrusor contractility was found in the rat model of bladder cancer, confirming our findings and stressing the importance of neuro-muscle disturbances in BC [44].…”

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…These pathologies can be interconnected. As mentioned above, diabetes mellitus is a risk factor for bladder cancer prognosis [ 64 ], and urinary incontinence is a common complication of bladder cancer [ 133 ].…”

A novel prognostic model based on three integrin subunit genes-related signature for bladder cancer

“…Idiopathic urinary incontinence is a common complication of BLCA. Studies have shown that BLCA is associated with dramatic changes in the contractility of the smooth muscle of the detrusor ( 33 , 34 ). One of the features of cancers that occur in the bladder is that the tumor invades and crosses the biophysical barrier of the smooth muscle ( 35 ).…”