Bladder outlet obstruction (BOO) caused by benign prostatic hyperplasia (BPH) is a primary factor inducing male lower urinary tract symptoms (LUTS). It is known that chronic BOO induces time-dependent changes in the bladder structures including detrusor smooth muscles, contributing to the development of both overactive and underactive bladder conditions.  In the clinical management of patients with BPH/BOO, uroflowmetry and ultrasonography are commonly conducted as noninvasive methods for evaluating lower urinary tract dysfunction (LUTD). However, in the basic research using animal models of BOO, few studies have assessed BOO-related functional parameters such as voiding time, maximal flow rate, and bladder wall thickness. Therefore, this study aims to clarify time-dependent changes in these parameters to assess LUTD in a male rat model of partial BOO using noninvasive approaches such as uroflowmetry and ultrasonography.

Adult male Sprague-Dawley rats were used to evaluate changes in lower urinary tract function over time before and after BOO. The partial BOO model was created by making a midline incision in the lower abdomen of the rats, separating the prostate to expose the urethra, and then placing an 18G metal rod on the ventral side of the urethra. The urethra and rod were tied together with a 4-0 silk thread before the rod was removed to produce partial urethral obstruction. voiding behavior data were obtained by metabolic cage measurements for 12 hours from 7 pm to 7 am on the following day, preoperatively (n=5), and one week (n=3), two weeks (n=5), and four weeks (n=4) postoperatively. Urine flow curves were plotted from urine volume collected over time based on metabolic cage data (Figure 1), and parameters such as voiding time and maximal urine flow rate were compared at different time points before and after BOO induction. The bladder morphology of the rats during the filling phase was observed by ultrasonography under isoflurane anesthesia. The fully filled phase was determined by observing a small amount of urine flow leaked from the external urethral orifice (i.e., overflow incontinence). Changes in bladder capacity and wall size over time in the fully filled and post-voiding phases were compared. Values of p<0.05 were considered statistically significant.

Body weight was significantly increased at four weeks postoperatively compared to preoperative values (371.5±4.43 g vs. 311.6±65.9 g, p=0.04). The average urinary frequency was significantly increased in rats one week postoperatively compared to that measured preoperatively (16.0±5.3 times vs. 9.6±2.1 times, p=0.04) and gradually decreased by four weeks postoperatively. However, there was no significant difference in the average voided volume. In addition, urinary flow curves plotted from metabolic cage data showed more pronounced sawtooth-like waveforms in rats rather than typical human bell-shaped urinary flow curves. The voiding time was significantly increased from preoperatively 7.2±2.1 sec to two weeks postoperatively 12.0±1.6 sec (p<0.01) (Figure 1A). The maximal urine flow rate was significantly decreased from preoperatively 0.53±0.14 g/sec to one week postoperatively 0.23±0.11 g/sec (p=0.01), and to two weeks postoperatively 0.28±0.91 g/sec (p=0.04) (Figure 1B). Ultrasound examinations of the bladder showed no significant changes in bladder capacity, but there was a significant increase in anterior bladder wall thickness both in the fully filled phase and post-void phases at four weeks postoperatively compared to preoperative values of wall thickness (fully filled phase: preoperatively 0.22±0.25 mm vs. four weeks BOO 0.62±0.07 mm, p=0.01; Post-voiding phase: preoperatively 0.21±0.76 mm vs. four weeks BOO 0.65±0.25, p=0.02, respectively).

The serrated wave pattern in urine flow curves in male rats may be attributed to the bursting activity of the external urethral sphincter during voiding, which induces the pumping action of the urethra that causes intermitted urination. While this urine flow pattern differs from the typical human bell-shaped urine flow curve, it showed a decrease in maximal urine flow rate and prolonged voiding time, which are characteristics of human patients with BPH/BOO. Furthermore, the bladder wall thickness observed in ultrasound examinations four weeks after surgery strongly suggests compensatory changes of the bladder, including bladder muscle hypertrophy evident as thicker bladder walls, in response to BOO. These results imply that this animal model at 1-4 weeks of BOO mimics the pathophysiological changes of the bladder after BOO.

In this study, assessment using metabolic cage measurements and ultrasonography enabled to detect an early, postoperative bladder distention phase (1 week) with frequent urination and low maximal flow rate and a late bladder compensation phase (2-4 weeks) with bladder wall hypertrophy, longer voiding time and increased flow rate after BOO. Thus, it seems feasible to track time-dependent, functional and morphological changes inducing LUTD in the same BOO rats using noninvasive approaches, which could be extrapolated to the pathophysiological process during the bladder compensation phase in male LUTS patients with BOO/BPH.