Nocturnal polyuria is the most common cause of nocturia, which decreases the quality of life [1]. We have reported that decreased nitric oxide (NO) production leads to intrarenal renin-angiotensin system (RAS) activity and salt-induced nocturnal polyuria [2]. We hypothesized that an exercise-induced increase in NO production would improve salt-induced nocturnal polyuria. The aims of this study were to elucidate the impact of an exercise-induced increase in NO production on intrarenal RAS activity and salt-induced nocturnal polyuria.

First, we evaluated the effects of exercise on NO production, intrarenal RAS activity, sodium excretion, and nocturnal polyuria. We used 80-week-old C57/BL6 male mice. Mice were given 1% high salt diet (1%HSD) for two weeks and were randomized into sedentary (Sed), low-intensity exercise (Low-Ex), and moderate-intensity exercise (Mod-Ex) groups. Mice in the Low-Ex and Mod-Ex groups underwent forced treadmill exercises for four weeks, while mice in the Sed group were exposed to the sound of the treadmill running. We evaluated 24h urinary NOx, renal angiotensinogen (AGT), sodium chloride co-transporter (NCC) activity, sodium excretion kinetics and diurnal polyuria index (DPi). DPi was calculated by dividing the volume of urine produced during inactive periods (8 a.m. to 8 p.m.) by the volume of urine produced per day. Next, we evaluated the effects of NO suppression on exercise-induced changes in NO production, intrarenal RAS activity, and nocturnal polyuria using Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Mice were randomized into Mod-Ex, Mod-Ex with L-NAME, and Sed with L-NAME. Mice in the Mod-Ex with L-NAME and Sed with L-NAME groups were administered L-NAME for four weeks. After four weeks, we evaluated 24h urinary NOx and renal AGT, and DPi.

The 24-hour urinary NOx amount of the Mod-Ex group was significantly higher than those of the Sed and Low-Ex group (Sed vs. Low-Ex vs. Mod-Ex: P = 0.017 and 0.006, respectively, Fig. 1A). The renal AGT level and NCC activity of the Mod-Ex group were significantly lower than those of the Sed group (P=0.002 and 0.003, respectively, Fig. 1B). The sodium excretion during the active period of the Mod-Ex group was significantly higher than that of the Sed group (P=0.022, Fig. 1C). The DPi of the Mod-Ex group decreased significantly compared to that of the Sed group (P=0.018, Fig. 1D). The 24h urinary NOx of the Mod-Ex with L-NAME and Sed with L-NAME groups were significantly lower than that of the Mod-Ex group (P = 0.020 and 0.005, respectively, Fig. 2A). The renal AGT level and NCC activity in the Mod-Ex with L-NAME and Sed with L-NAME groups significantly exceeded those in the Mod-Ex group (P= 0.001 and 0.001, respectively, Fig. 2B). The exercise-induced decrease in the DPi in the Mod-Ex group was abolished in the Mod-Ex with L-NAME group (P=0.015, Fig. 2C).

In this study, we provide experimental evidence that an increase in NO production by four weeks of moderate-intensity exercise can suppress intrarenal RAS and NCC activity, increase sodium excretion during active periods, decrease sodium excretion during inactive periods, and improve salt-induced polyuria during inactive periods in aged mice. These findings suggest that increased NO production is a potential new treatment for salt-induced nocturnal polyuria in elderly individuals.

An increase in NO production by moderate-intensity exercise suppressed intrarenal RAS, and decreased salt-induced nocturnal polyuria in aged mice, suggesting that an increase in NO production is a new treatment strategy for nocturnal polyuria in the elderly.

Andersson, F. et al. Assessing the impact of nocturia on health-related quality-of-life and utility: results of an observational survey in adults. J. Med. Econ. 19, 1200–1206, 2016.
Sekii, Y. et al. Dietary salt with nitric oxide deficiency induces nocturnal polyuria in mice via hyperactivation of intrarenal angiotensin II-SPAK-NCC pathway. Commun. Biol. 5, 175, 2022.

Continence 19S (2026) 102660
DOI: 10.1016/j.cont.2026.102660