Mucosal modulation of contractility in bladder strips from normal and overactive rat models and the effect of botulinum toxin A on overactive bladder strips

Campbell, Patrick; McDonnell, Bronagh; Monaghan, Kevin; Baysting, L; Little, Oonagh; McCloskey, Karen

doi:10.1002/nau.23082

Cited by 5 publications

(6 citation statements)

References 26 publications

(63 reference statements)

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“…Radiation did not significantly affect spontaneous activity (AUC), amplitude or frequency in intact strips (both N = 17, n = 25, P>0.05, Fig 5B–5D ) or mucosa-free strips (both N = 7, n = 13). Consistent with other studies [ 21 ] spontaneous activity (AUC) in intact, non-irradiated strips (N = 17, n = 25) was larger than in mucosa-free strips (N = 7, n = 13, P<0.05) although phasic contraction amplitude and frequency were similar (P>0.05, Fig 5B–5D ). This observation was absent in irradiated strips, suggesting that irradiation eliminated a mucosal-modulatory effect on detrusor spontaneous contractions.…”

Section: Resultssupporting

confidence: 92%

“…Similarly, irradiation did not affect ATP-evoked contractions (5mM [ 21 , 22 ]) in intact (both N = 13, n = 19 non-irradiated, n = 17, irradiated) or mucosa-free strips (both N = 6, n = 12; P>0.05, Fig 4B ). Absence of the mucosal layer had little effect on ATP-evoked contractions in non-irradiated strips but was associated with larger contractions in irradiated tissues (P<0.001).…”

Section: Resultsmentioning

confidence: 76%

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

et al. 2018

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Radiation-induced bladder toxicity is associated with radiation therapy for pelvic malignancies, arising from unavoidable irradiation of neighbouring normal bladder tissue. This study aimed to investigate the acute impact of ionizing radiation on the contractility of bladder strips and identify the radiation-sensitivity of the mucosa vs the detrusor. Guinea-pig bladder strips (intact or mucosa-free) received ex vivo sham or 20Gy irradiation and were studied with in vitro myography, electrical field stimulation and Ca2+-fluorescence imaging. Frequency-dependent, neurogenic contractions in intact strips were reduced by irradiation across the force-frequency graph. The radiation-difference persisted in atropine (1μM); subsequent addition of PPADs (100μM) blocked the radiation effect at higher stimulation frequencies and decreased the force-frequency plot. Conversely, neurogenic contractions in mucosa-free strips were radiation-insensitive. Radiation did not affect agonist-evoked contractions (1μM carbachol, 5mM ATP) in intact or mucosa-free strips. Interestingly, agonist-evoked contractions were larger in irradiated mucosa-free strips vs irradiated intact strips suggesting that radiation may have unmasked an inhibitory mucosal element. Spontaneous activity was larger in control intact vs mucosa-free preparations; this difference was absent in irradiated strips. Spontaneous Ca2+-transients in smooth muscle cells within tissue preparations were reduced by radiation. Radiation affected neurogenic and agonist-evoked bladder contractions and also reduced Ca2+-signalling events in smooth muscle cells when the mucosal layer was present. Radiation eliminated a positive modulatory effect on spontaneous activity by the mucosa layer. Overall, the findings suggest that radiation impairs contractility via mucosal regulatory mechanisms independent of the development of radiation cystitis.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 76%

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

et al. 2018

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“…The complexity of detrusor‐mucosal interactions induced by stimulation is underscored by conflicting findings among studies. In contrast to mucosa‐dependent inhibition, removal of the mucosa has also been shown to decrease the contractile response to muscarinic receptor stimulation, electrical field stimulation, and ATP, or to have no effect on the response to electrical field stimulation, carbachol, and KCl in the rat bladder. Similarly, in the guinea pig, the presence of the mucosa did not affect (or slightly increased) the response to histamine, bethanechol, KCl, and electrical stimulation .…”

Section: Introductionmentioning

confidence: 95%

The role of the mucosa in modulation of evoked responses in the spinal cord injured rat bladder

Doyle

Cristofaro

Sack

et al. 2018

Neurourology and Urodynamics

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AimsMounting evidence indicates that a variety of factors released from the urothelium or suburothelium can modulate smooth muscle activity. Although the relationship between the mucosa and smooth muscle has been investigated, little is known about the pathophysiologic changes in detrusor‐mucosa interactions in neurogenic bladders. The goal of the study was to determine the impact of the mucosa on evoked responses in spinal cord injured (SCI) bladders.MethodsUrinary bladders were obtained from 6wk SCI rats or age‐matched uninjured controls. Ex vivo isometric tension studies were performed and muscarinic receptor expression was measured in bladder tissue with and without mucosa.ResultsThe magnitude and area of nerve evoked responses in SCI tissue with mucosa was higher than without mucosa. The duration and decay time of nerve‐evoked responses were longer in SCI than control tissue irrespective of the mucosa. The level of the muscarinic M2 receptor was decreased in the mucosa of SCI bladders.ConclusionsDetrusor‐mucosa interactions are substantially altered in the neurogenic bladder. After spinal cord injury, an excitatory modulation of smooth muscle contraction by the mucosa emerges, and could be targeted via intravesical treatment in the context of neurogenic bladder dysfunction.

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“…The myogenic hypothesis is a current rationale for the pathophysiology of overactive bladder disease 16 . Recently, Botulinum toxin A (BoNT-A) was described as attenuating myogenic contractions of the rat bladder 17 , and is currently used as a treatment for overactive bladder and detrusor overactivity 18 . We now demonstrate that human prostate contractility also possesses a myogenic component.…”

Section: Discussionmentioning

confidence: 99%

Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate

Lee

Chakrabarty²,

Wittmer

et al. 2017

Sci Rep

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Lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) are highly prevalent in older men, having a profound impact on patient quality of life. Current therapeutics for BPH/LUTS target neurogenic smooth muscle tone, but response is unpredictable and many patients fail to respond. Spontaneous myogenic tone is another component of smooth muscle contractility that is uncharacterized in human prostate. To better understand and improve the predictability of patient response, we defined myogenic contractility using human prostate specimens and examined the effect of existing therapeutics. We show that myogenic activity is present in the human prostate with the frequency of contractions in transition zone (TZ) specimens from BPH diagnosed patients approximately 160% greater than matched controls. α1-adrenoreceptor antagonists (Tamsulosin) and PDE5 inhibitors (Sildenafil) both significantly reduced myogenic contractile parameters, including frequency, with notable interpatient variability. Tamsulosin was more effective in older patients (R2 = 0.36, p < 0.01) and men with larger prostate volumes (R2 = 0.41, p < 0.05), while Sildenafil was more effective in younger men (R2 = 0.45, p < 0.05). As myogenic tone is significantly increased in BPH, therapeutics targeting this mechanism used with reference to patient characteristics could improve clinical outcomes and better predict patient response.

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Mucosal modulation of contractility in bladder strips from normal and overactive rat models and the effect of botulinum toxin A on overactive bladder strips

Cited by 5 publications

References 26 publications

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

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

The role of the mucosa in modulation of evoked responses in the spinal cord injured rat bladder

Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate

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