Age-related symptoms, such as urinary retention and a poor urinary stream have been attributed to detrusor underactivity. Our recent studies showed that by simultaneously recording intravesical pressure and urethral perfusion pressure (UPP), urethral relaxation during bladder contractions was diminished in aged rats. Nevertheless, L-arginine (a substrate of nitric oxide (NO) synthase) could not restore a diminished urethral relaxation. Thus, we hypothesized that age-associated oxidative stress would impair NO/soluble guanylyl cyclase (sGC) system which induces urethral relaxation. This hypothesis was tested by measuring an oxidative stress marker in the bladder and also by simultaneously recording intravesical pressure and UPP using BAY 41-2272 as a novel NO-independent stimulator of sGC.

Female Sprague Dawley rats (young rats aged 3 months and old rats aged 12–15 months) were used. 1) Oxidative stress marker staining for 8-hydroxy-2’-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in the bladder was performed in both groups. 2) Urethral activity was evaluated by simultaneously recording the intravesical pressure under isovolumetric conditions and UPP under urethane anesthesia. 3) BAY 41-2272 (1 mg/kg) was administered intravenously in both groups under isovolumetric conditions. N-nitro-L-arginine methyl ester hydrochloride (L-NAME) (100mg/kg) was injected intraveneously to inhibit NO synthase activity in both groups. P values < 0.05 were considered statistically significant.

1) Oxidative marker staining revealed that 8-OHdG and MDA levels were higher in aging rats than those in young rats. 2) UPP nadir during urethral relaxation was significantly higher (38%) in aging rats than in young rats (p < 0.05). The mean amplitude of high frequency oscillation (HFO) of the urethral striated muscle was also significantly lower (49%) in aging rats than in normal rats (p < 0.05). 3) BAY 41-2272 increased urethral relaxation in young rats while restoring impaired urethral relaxation in aged rats.  When L-NAME was intravenously administered after BAY 41-2272 treatment,  the UPP nadir during reflex bladder contractions was significantly increased in young and aged rats.

These results indicate that aging induces a dysfunction in urethral relaxation during voiding, as evidenced by a decrease in HFO activity of the urethral striated muscle as well as NO mediated urethral relaxation of the urethral smooth muscle. Because NO-independent stimulator could restore impaired urethral relaxation in the aged bladder, age-associated oxidative stress in the NO/sGC system might be correlated with an age associated impairment in bladder and urethral coordination.

This novel study coupled with physiological and morphological changes in the aged bladder would contribute to elucidating the process of aging in bladders.