Abstract
Most physiological systems show daily variations in functional output, entrained to the day–night cycle. Humans exhibit a daily rhythm in urinary voiding (micturition), and disruption of this rhythm (nocturia) has significant clinical impact. However, the underlying mechanisms are not well-understood. Recently, a circadian rhythm in micturition was demonstrated in rodents, correlated with functional changes in urodynamics, providing the opportunity to address this issue in an animal model. Smooth muscle cells from mouse bladder have been proposed to express a functional and autonomous circadian clock at the molecular level. In this study, we addressed whether a semi-intact preparation of mouse urinary bladder smooth muscle (UBSM) exhibited measurable differences in contractility between day and night. UBSM tissue strips were harvested at four time points over the diurnal cycle, and spontaneous (phasic) and nerve-evoked contractions were assessed using isometric tension recordings. During the active period (ZT12-24) when micturition frequency is higher in rodents, UBSM strips had no significant differences in maximal- (high K+) or nerve-evoked contractions compared to strips harvested from the resting period (ZT0-12). However, a diurnal rhythm in phasic contraction was observed, with higher amplitudes at ZT10. Consistent with the enhanced phasic amplitudes, expression of the BK K+ channel, a key suppressor of UBSM excitability, was lower at ZT8. Higher expression of BK at ZT20 was correlated with an enhanced effect of the BK antagonist paxilline (PAX) on phasic amplitude, but PAX had no significant time-of-day dependent effect on phasic frequency or nerve-evoked contractions. Overall, these results identify a diurnal difference for one contractile parameter of bladder muscle. Taken together, the results suggest that autonomous clocks in UBSM make only a limited contribution to the integrated control of diurnal micturition patterns.
Highlights
Most physiological systems, including the urinary system, exhibit daily (24-hr) variations in functional output that are entrained to the day–night cycle
We hypothesized that strips of urinary bladder smooth muscle (UBSM) tissue harvested during the dark period would demonstrate stronger contractile activity than strips harvested during the day, when micturition frequency is low and the bladder relaxes to store urine (Herrera and Meredith, 2010; Negoro et al, 2012)
To determine whether contractile properties of UBSM varied by time of day, isometric tension recordings were performed at ZT4, 10, 16, and 22 (Figure 1A)
Summary
Most physiological systems, including the urinary system, exhibit daily (24-hr) variations in functional output that are entrained to the day–night cycle. Humans exhibit a daily rhythm in urinary voiding (micturition), and nocturia, excessive urination at night, is a persistent disorder affecting >50% of people in some age groups and significantly decreasing quality of life (Ticher et al, 1994; Hetta, 1999; Neveus et al, 1999; Weiss et al, 2008). The circadian variation in urination depends on daily urine production, the physical properties of the bladder, and neural control. Dysfunction in these pathways may contribute to nocturia, but the identification of causal relationships has been limited. The aspects of the lower urinary tract that influence normal circadian micturition patterns, and that contribute to nocturia, are essentially unknown
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