Tadalafil, a phosphodiesterase type 5 inhibitor, restores urethra and detrusor function in the initial phase of diabetes in rats

Abstract

Objective This study investigated the effects of tadalafil on the urethra and detrusor in the initial phase of diabetes in rats. Methods Thirty‐six female Sprague‐Dawley rats were assigned to a non‐diabetes (ND), diabetes (D), or tadalafil‐treated diabetes (DT) group (n = 12 per group), with the DT group receiving oral tadalafil (2 mg/kg/d) for 7 days before the experiments. Seven weeks after diabetes induction (by a single intraperitoneal injection of streptozotocin), urethral and intravesical pressure were simultaneously recorded in vivo, whereas responses of detrusor strips to potassium chloride (30 mM), electrical field stimulation (EFS) and carbachol were measured in vitro. Results The intravesical pressure at which the urethra started to relax was significantly lower in the DT than D group (mean [± s.d.] 18.9 ± 2.9 vs 29.1 ± 6.6 cm H2O; P < .05). In addition, the reduction in urethral pressure was significantly larger in the DT than D group (−10.9 ± 4.0 vs −4.0 ± 2.9 cm H2O; P < .05). Detrusor stimulation revealed that the mean contractile responses to EFS and carbachol were significantly lower in the ND and DT groups than in the D group (120.7 ± 26.5% and 130.8 ± 15.8% vs 200.1 ± 47.9% of the 30 mM KCl‐induced contraction, respectively, in response to 50 Hz EFS [P < .05]; 211.1 ± 35.4% and 208.4 ± 25.3% vs 425.7 ± 125.0% of the 30 mM KCl‐induced contraction, respectively, in response to 10−3 M carbachol [P < .05]). Conclusions Tadalafil restored urethral relaxation function and detrusor responses to EFS and carbachol during the initial phase of diabetes.

Pathophysiological changes of the lower urinary tract behind voiding dysfunction in streptozotocin-induced long-term diabetic rats

“…However, it was in fact opposite. We presumed that the higher maximal voiding pressure and opening pressure demonstrated in the DM rats may be due to urethral relaxant dysfunction during voiding, as this type of urethral dysfunction was reported at an early phase (5-7 weeks) of STZ-induced DM rats 7,8 . To determine whether urethral relaxant dysfunction occurs also in the present (16 weeks STZ-induced) DM rats, we performed simultaneous recordings of bladder pressure under isovolumetric conditions and UPP.…”

“…Torimoto et al reported that diabetic urethral dysfunction associated with NO deficiency occurred at an early phase (at 5 weeks) 7 . Gotoh et al reported that tadalafil restored bladder blood flow and lower urinary tract function, including urethral function, at an early phase of DM (at 7 weeks) 8,17 . Our results suggest that long-term diabetes caused NO/cGMP deficiency, resulting in urethral relaxant dysfunction.…”

“…A previous study showed urethral relaxant dysfunction in an early phase (5 weeks) of STZ-induced DM rats 7 . In addition, a recent study demonstrated that tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, improved urethral dysfunction in an early phase (7 weeks) of DM rats 8 . These findings led us a hypothesis that the major cause of voiding dysfunction observed even in a later phase of STZ-induced DM rats should be urethral relaxation failure but not simply detrusor underactivity (decreased bladder contractility).…”

Effects of tadalafil versus silodosin on voiding function in male patients with non‐neurogenic detrusor underactivity: A comparative study using propensity score matching

“…In contrast, tadalafil might intensify the action of NO and relieve urethral resistance regardless of the presence or absence of BOO. In fact, tadalafil has been reported to restore urethral relaxation function in the initial phase of a diabetes‐induced DU rat model 23 . It was considered that the difference in these actions between the two drugs might influence the difference in the improvement of voiding functions, such as Qmax.…”

Established and emerging treatments for diabetes-associated lower urinary tract dysfunction

“…Seven weeks after STZ injection in rats, a 7-day treatment with tadalafil restored prolonged inter-contraction intervals and diminished bladder blood flow to values comparable to those in control animals (Gotoh et al 2018 ). In a follow-up study, tadalafil restored urethral relaxation and detrusor contraction (Gotoh et al 2019 ). Restoration of detrusor function by tadalafil in UAB observed at late time points after administration of STZ was also reported by others (Masuda et al 2020 ).…”