Abstract
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.
Highlights
Contractile responses were compared between non-irradiated and irradiated bladder strips with the mucosal layer intact and the mucosa removed. This was to establish: (1) if radiation affected contractile responses in intact or mucosa-free strips; (2) if the mucosal layer modified the contractile responses of the detrusor layer and (3) if this relationship was changed after irradiation
Neurogenic contractions were evoked by Electrical field stimulation (EFS) in non-irradiated (N = 12, n = 18) and irradiated intact strips (N = 12, n = 19) (Fig 1A)
The atropine-sensitive component (22%) and PPADs-effect here was similar to that reported by Kennedy et al [25] in guinea-pig bladder intact strips (28% atropine-sensitive, 50– 60% reduction of atropine-resistant component by PPADs) who concluded that a non-cholinergic, non-P2X1-mediated component of neurogenic contractions was present
Summary
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. We aimed to determine how ex vivo irradiation affected contractile responses
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