Acute radiation impacts contractility of guinea-pig bladder strips affecting mucosal-detrusor interactions

McDonnell, Bronagh; Buchanan, Paul; Prise, Kevin M.; McCloskey, Karen

doi:10.1371/journal.pone.0193923

Cited by 7 publications

(12 citation statements)

References 32 publications

(39 reference statements)

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“…No significant differences were found between 3–7 and 14 days SCT groups (unpaired t-test, p>0.05). Similar to previous studies (Ikeda and Kanai 2008; McDonnell et al 2018), strips without the mucosa, from both SI and SCT mice had on average lower levels of spontaneous activity than those of strips with the UT, although this did not reach statistical significance (compare black bars with gray bars in Fig. 4e, f; one way ANOVA followed by Tukey’s multiple comparisons test p>0.05 for all groups).…”

Section: Resultssupporting

confidence: 82%

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Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice

Kullmann

McDonnell

et al. 2018

Naunyn-Schmiedeberg's Arch Pharmacol

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Transient receptor potential cation channel subfamily M member 4 (TRPM4) has been shown to play a key role in detrusor contractility under physiological conditions. In this study, we investigated the potential role of TRPM4 in detrusor overactivity following spinal cord transection (SCT) in mice. TRPM4 expression and function were evaluated in bladder tissue with or without the mucosa from spinal intact (SI) and SCT female mice (T8-T9 vertebra; 1-28 days post SCT) using PCR, western blot, immunohistochemistry, and muscle strip contractility techniques. TRPM4 was expressed in the urothelium (UT) and detrusor smooth muscle (DSM) and was upregulated after SCT. Expression levels peaked 3-7 days post SCT in both the UT and DSM. Pharmacological block of TRPM4 with the antagonist, 9-Phenanthrol (30 μM) greatly reduced spontaneous phasic activity that developed after SCT, regardless of the presence or absence of the mucosa. Detrusor overactivity following spinal cord injury leads to incontinence and/or renal impairment and represents a major health problem for which current treatments are not satisfactory. Augmented TRPM4 expression in the bladder after chronic SCT supports the hypothesis that TRPM4 channels play a role in DSM overactivity following SCT. Inhibition of TRPM4 may be beneficial for improving detrusor overactivity in SCI.

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Section: Resultssupporting

confidence: 82%

“…were performed as previously described (Kullmann et al 2014; McDonnell et al 2018). Animals were deeply anesthetized with isoflurane (4%) and euthanized by exsanguination.…”

Section: Methodsmentioning

confidence: 99%

Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice

Kullmann

McDonnell

et al. 2018

Naunyn-Schmiedeberg's Arch Pharmacol

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“…The urothelial barrier consists of a protective mucin layer that contains negatively charged glycosaminoglycans, the main components of which are hyaluronic acid (HA) and chondroitin sulfate (CS) [5] . RT may impair the function of the urothelium because of fibrosis and nerve changes in bladder tissue, leading to an acute local inflammatory response and chronic lower urinary tract symptoms (LUTS), whether or not associated with gross haematuria and pain [6] , [7] .…”

Section: Introductionmentioning

confidence: 99%

Multicentre International Study for the Prevention with iAluRil of Radio-induced Cystitis (MISTIC): A Randomised Controlled Study

Redorta

Sanguedolce

Pardo

et al. 2021

European Urology Open Science

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Background Radiation-induced cystitis is a common side effect of radiotherapy (RT) to the pelvic area. Hyaluronic acid (HA) and chondroitin sulfate (CS) are components of the urothelial mucosa and positive results have been obtained for intravesical HA/CS instillations for the treatment of urinary tract infections and bladder pain syndrome. HA/CS may also have a protective effect against RT bladder toxicity. Objective To investigate whether HA and CS protect the urothelium during RT, alleviate lower urinary tract symptoms, and improve quality of life. Design, setting, and participants This multicentre randomised controlled trial was conducted across seven centres in four countries. Male patients aged ≥18 yr scheduled to undergo primary intensity-modulated radiotherapy for localised prostate cancer were enrolled. Intervention Patients were randomised to intravesical HA/CS plus an oral formulation of curcumin, quercetin, HA, and CS (group A) or no treatment (group B). Outcome measurements and statistical analysis The primary endpoint was absolute changes from baseline to follow-up in urinary domain scores for the Expanded Prostate Cancer Index Composite (EPIC), the International Consultation on Incontinence Questionnaire-Male Lower Urinary Tract Symptoms (ICIQ-MLUTS), and the EuroQol Group EQ-5D-5L questionnaire. Data analysis for efficacy and safety outcomes was performed using an intention-to-treat (ITT) approach; the ITT population was defined as all randomised patients. Results and limitations Of 57 patients screened, 49 were enrolled and randomly assigned to either active treatment (group A, n = 25) or the control (group B, n = 24). Three patients in the control group withdrew after randomisation. Changes from baseline to 12 mo were worse in the control group for subtotal scores for urinary symptoms and impact of symptoms on quality of life and for the total score ( p = 0.05, p = 0.003, and p = 0.008, respectively). There was a significant time × group interaction in favour of active treatment for the incontinence symptom score ( p = 0.011) and bother score ( p = 0.017). The absence of a sham procedure and/or placebo is the main limitation. Conclusions Our results suggest that intravesical HA/CS in combination with an oral formulation may reduce urinary symptoms and improve QoL at short-term (1 yr) follow-up. Patient summary We investigated whether hyaluronic acid (HA) and chondroitin sulfate (CS) have a protective effect against the bladder toxicity of radiotherapy for prostate cancer. HA/CS used for weekly bladder irrigation for 6 wk and given orally with curcumin and quercetin for 12 wk reduced urinary i...

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“…Many of the changes to bladder function are due to RT injury to the MPG. Ex vivo radiation of guinea pig mucosal‐free detrusor strips also demonstrated increased contraction to carbachol and ATP 14 . Preclinical studies looking at in vivo bladder RT for cystitis have shown at early time points that bladder frequency increased while voiding volume and bladder capacity was reduced in female mice and rats 15 .…”

Section: Discussionmentioning

confidence: 99%

“…Ex vivo radiation of guinea pig mucosal-free detrusor strips also demonstrated increased contraction to carbachol and ATP. 14 Preclinical studies looking at in vivo bladder RT for cystitis have shown at early time points that bladder frequency increased while voiding volume and bladder capacity was reduced in female mice and rats. 15 Another study irradiated male rats (single 10 Gy dose to pelvico-abdominal region) and examined the lamina propria and epithelial bladder layers.…”

Section: Discussionmentioning

confidence: 99%

Impact of prostatic radiation therapy on bladder contractility and innervation

Turner

Powers

Odom

et al. 2021

Neurourology and Urodynamics

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Aims: To determine the effect of prostatic radiation therapy (RT) on bladder contractility and morphology, and axon, or neuron profiles within the detrusor and major pelvic ganglia (MPG) in male rats. Methods: Male Sprague-Dawley rats (8 weeks) received a single dose of prostatic RT (0 or 22 Gy). Bladders and MPG were collected 2-and 10-weeks post-RT. Detrusor contractile responses to carbachol and electrical field stimulation (EFS) were measured. Bladders were stained with Masson's trichrome, and antibodies for nonspecific neuronal marker, cholinergic nerve marker choline acetyltransferase (ChAT), and alpha-smooth muscle actin.MPG gene expression was assessed by quantitative polymerase chain reaction for ubiquitin carboxy-terminal hydrolase L1 (Uchl1) and Chat. Results: At 2 weeks post-RT, bladder smooth muscle, detrusor cholinergic axon profiles, and MPG Chat gene expression were increased (p < .05), while carbachol and EFS-mediated contractions were decreased (p < .05). In contrast, at 10 weeks post-RT, nerve-mediated contractions were increased compared with control (p < .05), while bladder smooth muscle, detrusor cholinergic axon profiles, MPG Chat expression, and carbachol contractions had normalized. At both 2-and 10-weeks post-RT, there was no change in detrusor nonspecific axon profiles and MPG Uchl1 expression. Conclusion:In a rat model, RT of the prostate and MPG was associated with early changes in MPG Chat gene expression, and bladder cholinergic axon profiles and smooth muscle content which resolved over time. After RT recovery, bladder contractility decreased early and increased by 10 weeks. Longterm changes to the MPG and increased bladder cholinergic axons may contribute to RT-induced bladder dysfunction in prostate cancer survivors.

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Acute radiation impacts contractility of guinea-pig bladder strips affecting mucosal-detrusor interactions

Cited by 7 publications

References 32 publications

Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice

Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice

Multicentre International Study for the Prevention with iAluRil of Radio-induced Cystitis (MISTIC): A Randomised Controlled Study

Impact of prostatic radiation therapy on bladder contractility and innervation

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