Afferent Nerve Activity Ex Vivo and Voiding Frequency In Vivo are Driven by Bladder Filling Rate in a Mouse Model of Polydipsia‐Polyuria

Abstract

The mechanisms regulating urinary voiding function are not entirely understood. Many disorders of the lower urinary tract such as overactive bladder, urinary incontinence, and underactive bladder are associated with dysfunctional voiding behavior. Developing treatments to improve voiding function in afflicted individuals has proved to be problematic, in part due to a lack of basic understanding of the mechanisms responsible for controlling voiding function.We have shown previously in an ex vivo bladder model that afferent nerve activity increases as the bladder is filled. Furthermore, transient pressure events occurring during bladder filling trigger substantial rises in afferent nerve activity, more so than would occur during a similar rise in bladder pressure associated with bladder filling. This observation suggests that localized wall deformations associated with transient pressure events could transduce important sensory information to the central nervous system as to the filling state of the bladder. In the present study, we hypothesized that bladder filling rate is an important parameter that controls voiding function in vivo. We used an acute sucrose induced polydipsia/polyuria model that allows us to determine the impact of bladder filling rate on voiding behavior noninvasively in conscious freely moving mice.Male C57Bl6 mice (6 weeks old) were placed into a UroVoid apparatus for 48 hour voiding studies. One group of mice had access to tap water while a second group of mice had access to 5% sucrose in water. All mice had access to standard rodent chow. The UroVoid apparatus allows us to quantify the time and volume for each micturition.Mice drinking 5% sucrose consumed substantially more fluid than mice consuming tap water (26.98 ± 13.12 ml vs. 7.23 ± 1.35 ml). This polydipsia was reflected in a profound polyuria in mice consuming sucrose, as these mice voided a total of 18.98 ± 13.52 ml of urine over 79 ± 42 voids compared to 3.91 ± 0.54 ml of urine over 22 ± 16 voids in mice consuming tap water. Using the voided urine volume and the intermicturition interval for each void, we calculated that the urine production rate (UPR) is ~2 μl/min in mice consuming tap water, whereas the UPR is greatly elevated to ~25 μl/min in mice consuming 5% sucrose. Voiding frequency is greatly increased in mice consuming 5% sucrose, which we believe reflects underlying sensory function.To address the impact of bladder filling rate on sensory function, we measured afferent pelvic nerve activity in ex vivo bladder preparations at filling rates of 3.3, 10, and 30 μl/min. As expected, sensory nerve activity was increased at higher filling rates. For example, at an intravesical pressure of 15–20 mmHg, afferent nerve frequency increased from 91.5 ± 43.0 Hz at 3.3 μl/min to 174.9 ± 64.1 Hz at 30 μl/min.In conclusion, sucrose‐induced polydipsia/polyuria in mice is an effective way to examine the impact of bladder filling rate on voiding behavior. Increases in bladder filling rate are associated with increases in afferent nerve outflow in the bladder, and this increase in sensory outflow may contribute to elevated voiding frequency at higher bladder filling rates.Support or Funding InformationSupported by NIH R37 DK053832