There is increasing evidence which suggests that hypertension induces several alterations in urinary function. In humans, vascular risk factors such as hypertension and aging are linked to the progressive development of an overactive bladder and polyuria [1-3].  Consequently, polyuria causes the development of chronic bladder overdistension [1]. Dahl/salt sensitive rats, a hypertensive rat model with high-salt diet show an increased water intake, greater urine volume, and higher bladder capacity and compliance. Polyuria induced by hypertension causes alterations in bladder morphology and function [1]. The spontaneously hypertensive rats (SHRs) are known to have high blood pressure and bladder dysfunction such as increased frequency of micturition [2]. SHRs also showed bladder hypertrophy compared with the Wistar Kyoto (WKY) rats used as normotensive controls [2]. In the present study, we investigated how aging affects the urine output and bladder function of SHRs.

Six-week-old male WKY rats and SHRs were obtained and kept under identical conditions. They had access to food and drinking water ad libitum. WKY rats and SHRs at the ages of 18, 36, 54, or 72 weeks (W) were used (n = 6~7). 
(1) Metabolic cage study was performed to measure the micturition frequency, urine output, water intake and single voided volume for 24 hours. Urine osmolality was measured using an automatic osmometer.
(2) Blood pressure was measured by the tail cuff method. After single cystometry as described below, the rats were euthanized with an overdose of sodium pentobarbital (100 mg/kg, i.p.). The bladders were removed, weighted, and subjected to hematoxylin and eosin (H&E) staining.
(3) Single cystometry (2.4 mL/h) under urethane (1.0 g/kg, i.p.) anaesthesia was performed to measure the single voided volume, post-void residual volume, and bladder capacity.
(4) The rat kidneys were removed, weighed, and subjected to periodic acid-schiff staining.

(1) SHRs at 72 W showed a significant increase in micturition frequency, urine output, water intake and single voided volume per day compared with the SHRs at 18 W, 36 W, or 54 W. Similarly, SHRs at 54 W showed a significant increase in water intake and single voided volume per day compared with the SHRs at 18 W. SHRs at 36 W showed a significant increase in single voided volume per day compared with the SHRs at 18 W. There were no significant differences in voiding parameters among WKY rats at each age. (Figure 1). Micturition frequency and urine output per light (14 h) or dark cycle (10 h) in SHRs at 72W were also significantly larger compared with those in SHRs at 18 W, 36 W, or 54 W (data not shown).    
(2) Body weight was significantly larger in the SHRs at 36 W or 54 W compare to the SHRs at 18 W. While, there was no significant difference in body weight between SHRs at 72 W and 18 W. Body weight was significantly larger in the WKY rats at 36 W, 54 W, or 72 W compared with the WKY rats at 18 W. Body weight was significantly larger in the WKY rats at 72 W compared with the WKY rats at 36 W or 54 W.  Bladder weight and bladder weight to body weight ratio (BBR) were significantly larger in the SHRs at 72 W compared with the SHRs at 18 W, 36 W, or 54 W. However, there were no significant differences in bladder weight and BBR among WKY rats at each age (Figure 1). SHRs at 72 W showed bladder wall thickening in H&E staining, while SHRs at 18 W did not. Moreover, the morphological change in WKY rats at 72 W and 18 W was not observed (data not shown). Mean blood pressure in the SHRs at 36 W, 54 W, or 72 W was significantly larger than that in the SHRs at 18 W. Mean blood pressure in the SHRs at 72 W was also significantly larger than that in the SHRs at 36 W or 54 W. There was no significant difference on mean blood pressures among WKY rats at each age (Figure 1).  
(3) Single voided volume, post residual urine volume and bladder capacity in SHRs at 72 W were significantly larger than in SHRs at 18 W. On the other hand, there were no significant differences in these voiding parameters between WKY rats at 72 W and 18 W (Figure 2).
(4)  SHRs at 72 W showed renal tubular damage and inflammatory change compared with the SHRs at 18 W. On the other hand, these morphological changes in WKY rats at 72 W was not observed compared with WKY rats at 18W. The left renal weight and left renal weight/body weight ratio (RBR) in the SHRs at 72 W were significantly increased compared with the SHRs at 18 W. The left renal weigh but not RBR in WKY rats at 72 W was significantly increased compared with the WKY rats at 18 W (Figure 3).

Aging caused an increase in blood pressure in SHRs. Moreover, aging caused frequent urination, bladder hypertrophy, polydipsia, and associated polyuria with bladder overdistension in SHRs. Aged SHRs also showed a decrease in urine osmolality and increase of renal damage.  Decreased urine osmolality is clinically observed in diabetes insipidus patients [3]. Aged SHRs may be correlated with nephrogenic diabetes insipidus. These data suggest that aging causes bladder and renal dysfunctions in SHRs. And, aging-related increase in blood pressure could cause renal damage and polyuria, subsequently leading to the change in bladder function and morphology.

The development of hypertension as a result of aging causes polyuria and bladder overdistension in SHRs. Aged SHRs may be considered animal models for understanding polyuria induced chronic bladder overdistension.

Velasquez Flores M, Mossa AH, Cammisotto P et al. Bladder overdistension with polyuria in a hypertensive rat model. Neurourol Urodyn 2018;37(6):1904-1912.
Shen S, Xia CM, Qiao LY. The urinary bladder of spontaneously hypertensive rat demonstrates bladder hypertrophy, inflammation, and fibrosis but not hyperplasia. Life Sci. 2015;121:22-27.
Leroy C, Karrouz W, Douillard C et al. Diabetes insipidus. Ann Endocrinol (Paris). 2013;74(5-6):496-507.