Investigation of image-guided in vivo irradiation on voiding patterns and bladder contractility in female mice

Abstract

Abstract Radiotherapy for pelvic malignancies impacts the bladder causing urinary symptoms in many patients. Preclinical models using image-guided irradiation enable investigation of the physiology underlying radiation-response in the bladder. We aimed to characterise voiding patterns and bladder contractility following image-guided irradiation of the mouse bladder. Bladders of adult, female mice were irradiated (IRR) with a single fraction (20 Gy) under cone beam computed tomography. Pre- and post-IRR, void spot assays of urination patterns were performed. Contractility of bladder strips was quantified with myography. At 2-weeks, 1-month and 2-months post-IRR, around 50% of mice exhibited increased void locations. At 2-weeks, 50% had increased void spot counts; moreover, the majority exhibited smaller mean and smaller maximum void spot volumes. In bladder strips, neurogenic-contractions were smaller at 2-weeks, independent of their voiding patterns. Some recovery of contraction-amplitude was noted up to 8-months. At 2-weeks, depolarization-contractions and carbachol-contractions were similar in non-IRR and IRR strips; however, ATP-contractions were smaller. Neurogenic-contractions, carbachol-contractions and ATP-contractions had similar sensitivity to the SK channel blocker, apamin. Neurogenic contractions had similar sensitivity to paxilline (BK) and TEA (pan-K + ) in non-IRR and IRR tissue. Targeted bladder irradiation resulted in altered urination patterns in the acute post-IRR phase, coincident with reduced neurogenic-contractions which might limit voiding. The ability of the bladder to contract per se and the contribution of K + -channels to contractility was minimally impacted by irradiation. Whilst the underlying mechanisms of the observations require further investigation, the study demonstrates the application of image-guided irradiation for quantifying radiation-induced changes in mouse bladder.