There is an increasing prevalence of age-related diseases such as lower urinary tract dysfunction (LUTD). Detrusor underactivity (DU) is a common LUTD among elderly people. Although aging is an obvious risk factor for DU, the etiology of DU is not well understood. There is limited effective pharmacotherapy for DU. Hypertension is one of the most common chronic diseases among the elderly that induces several alterations in bladder function [1,2]. Spontaneously hypertensive rats (SHRs) have high blood pressure and bladder dysfunction [1]. A previous report showed that aging caused bladder dysfunction in SHRs, which resembles the DU phenotype [increased single voided volume (SVV) and post-void residual volume (RV)] [1]. Clinically, many elderly patients with LUTD take several medications, including antihypertensive drugs, for a long period. A clinical study showed that an antihypertensive drug, angiotensin II type 1 receptor blocker (ARB), has therapeutic effects on storage and voiding symptoms in male patients with hypertension, whereas other antihypertensive drugs had no significant effect on lower urinary tract symptoms [3]. In the current study, we investigated the protective effects of an ARB losartan on bladder dysfunction like DU in aged SHRs.

Thirty-six-week-old male SHRs were orally treated with losartan (3 or 10 mg/kg) or vehicle (0.5% methylcellulose) once daily for 18 weeks. Age-matched normotensive Wistar Kyoto (WKY) rats were used as vehicle-treated controls (n = 7).
(1) A metabolic cage study was performed to measure micturition frequency, urine output, water intake, and SVV for 24 hours. Urine osmolality was measured using an automatic osmometer.
(2) Blood pressure was measured using the tail-cuff method. 
(3) Under urethane (1.0 g/kg, i.p.) anesthesia, single cystometry (2.4 mL/h) was performed to measure SVV, RV, bladder capacity (BC), and voiding efficiency (VE). Continuous cystometry (2.4 mL/h) was also performed to measure maximum voiding pressure (MVP) and intercontraction interval (ICI). 
(4) After blood was drawn from the vena cava, rats were euthanized by administering high doses of pentobarbital sodium (100 mg/kg, i.p.). The bladder and renal tissues were harvested and weighed. Serum creatinine levels were also measured.
(5) Detrusor thickness of the bladder was measured using hematoxylin and eosin-stained sections.

Vehicle-treated SHRs and low-dose losartan-treated SHRs showed significantly higher bladder weight/body weight ratio (BBR) and mean blood pressure than vehicle-treated WKYs. High-dose losartan-treated SHRs had significantly lower BBR and mean blood pressure than vehicle-treated SHRs. There was no significant difference in mean blood pressure between vehicle-treated and low-dose treated SHRs. In the metabolic cage study, vehicle-treated SHRs showed significantly higher micturition frequency, urine output, water intake, and SVV for 24 h than vehicle-treated WKYs. Significantly lower micturition frequency, urine output, and water intake were observed in both dose of losartan-treated SHRs than vehicle-treated SHRs. There was no significant difference in SVV among vehicle-treated WKYs and losartan-treated SHRs at either dose. In single cystometry, vehicle-treated SHRs had significantly higher SVV, RV, and BC and lower VE than vehicle-treated WKYs. Losartan-treated SHRs with both doses had significantly higher SVV, RV, and BC than vehicle-treated SHRs. In continuous cystometry, vehicle-treated SHRs demonstrated significantly increased ICI compared to vehicle-treated WKYs. Losartan-treated SHRs showed lower ICI than vehicle-treated SHRs in a dose dependent manner. There was no significant difference in MVP among vehicle-treated WKYs and vehicle-treated SHRs. In bladder histology, vehicle-treated SHRs had significantly greater detrusor thickness than vehicle-treated WKYs. Both doses of losartan-treated SHRs had significantly lower detrusor thickness than vehicle-treated SHRs. Regarding renal parameters, vehicle-treated SHRs had significantly higher left or right renal weight/body weight and serum creatinine and lower urine osmolality than vehicle-treated WKYs. High-dose losartan-treated SHRs had significantly lower serum creatinine and higher urine osmolarity than vehicle-treated SHRs.

The current data showed that vehicle-treated 54-weeks-old SHRs had significantly higher SVV, RV, BC, and ICI and lower VE than vehicle-treated age-matched WKYs, which resemble bladder dysfunction like DU in humans. These data suggest that aged SHRs may be a useful DU model. A previous study showed that aging exacerbates high blood pressure, renal damage, and polyuria in SHRs [1]. Dahl salt-sensitive rats fed a high-salt diet also demonstrated increased blood pressure, water intake, urine output, BC, and ICI compared to rats fed a normal chow [2]. Moreover, vehicle-treated SHRs had significantly higher BBR, renal weight, urine output, water intake, and serum creatinine and lower urine osmolality than vehicle-treated WKYs. These data suggest that severe blood pressure and polyuria can cause DU. A previous report showed that aged (72-weeks old) SHRs showed significantly higher SVV, RV, and BC than young (18-weeks old) SHRs [1]. According to a previous study, the current study investigated the protective effects of losartan on bladder dysfunction, such as DU, in SHRs at 36 to 54 weeks of age for a period of 18 weeks. Treatment with losartan ameliorated bladder dysfunction (increased SVV, RV, BC, and ICI), such as DU, polyuria, and renal damage, in aged SHRs without affecting blood pressure. A high dose of losartan significantly decreased blood pressure, renal damage, and bladder dysfunctions, such as DU, in aged SHRs.

Chronic treatment with losartan ameliorated bladder dysfunction like DU in aged SHRs, independent of decreased blood pressure. ARB losartan might be a possible protective drug against severe hypertension-induced DU.

Shimizu S, Nagao Y, Shimizu T et al. Aging causes polyuria and bladder overdistension in spontaneously hypertensive rats. International Continence Society 2020, abstract 124.
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.
Ito H, Taga M, Tsuchiyama K et al. IPSS is lower in hypertensive patients treated with angiotensin-II receptor blocker: posthoc analyses of a lower urinary tract symptoms population. Neurourol Urodyn 2013;32(1):70-74.