Urethral dysfunction and therapeutic effects of a PDE 5 inhibitor (tadalafil) in a rat model of detrusor underactivity induced by pelvic nerve crush injury

Abstract

Aims The urethral dysfunction produced by a rat model of peripheral neurogenic detrusor underactivity (DU) using pelvic nerve crush (PNC) injury was characterized and then tested with the administration of tadalafil, a phosphodiesterase type 5 (PDE 5) inhibitor. Methods Ten days after producing PNC rats, awake cystometrograms (CMGs) and isovolumetric cystometrograms with urethral perfusion pressure (IC‐UPP) measurements were performed. Also, in control rats, IC‐UPP was recorded before and after intravenous atropine administration to determine if the reduction of bladder contraction pressure affects urethral relaxation during voiding. Then, CMG and IC‐UPP measurements in PNC rats were recorded after intravenous administration of tadalafil. Lastly, real‐time polymerase chain reaction was used to measure transcript levels of neuronal nitric oxide synthases (nNOS), endothelial nitric oxide synthases, and PDE 5 in urethral specimens from PNC and control rats. Results PNC rats demonstrated the characteristics of DU in CMG. Also, PNC rats exhibited significant decreases in isovolumetric bladder contraction amplitudes and urethral relaxation. Atropine attenuated the amplitude of isovolumetric bladder contractions; however, atropine did not affect urethral relaxation in control rats. Tadalafil decreased postvoid residual and increased voiding efficiency without changing bladder contraction amplitude in PNC rats. Also, tadalafil improved the amplitude of urethral relaxation during bladder contraction in PNC rats. Urethral nNOS transcript levels were upregulated in PNC rats compared to control rats. Conclusions PNC rats revealed both DU and impaired urethral relaxation. PDE 5 inhibition in PNC rats enhanced urethral relaxation during voiding, resulting in improved voiding efficiency. Thus, urethral dysfunction could be a potential target for the treatment of inefficient voiding associated with neurogenic DU.

Underactive Bladder and Detrusor Underactivity: New Advances and Prospectives

“…Recently, Matsukawa et al conducted a study that found that both tadalafil and silodosin had a significant impact on improving LUTS and voiding function in patients with non-neurogenic DU, and that tadalafil was associated with an improvement in BCI (19.7 ± 17.7 vs. 6.0 ± 12.5, p < 0.001) and Q max (3.0 ± 3.0 mL/s vs. 1.7 ± 1.4, p < 0.001) [116]. The mechanism of action of tadalafil may be linked to enhanced urethral relaxation [117], increased blood flow to the lower urinary tract [118], improved oxygenation [119], and decreased chronic inflammation [120] of the bladder and prostate.…”

Muscarinic M3 positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats

“…We hypothesize that a considerable number of patients suffering from lower urinary tract symptoms with various possible pathophysiologies including aging 30 have such a condition but are left underdiagnosed because of a lack of clear urodynamically confirmed DU or BOO. 31 We pharmacologically reproduced this condition by administering a combination of atropine and midodrine at doses lower than those used in previous studies, 19,32,33 and applying the experimental methods we used previously 19,20 (Figure 3). In this model, we used the effects of distigmine at 0.003 mg/kg iv as a benchmark because it significantly enhanced the PNS-induced elevation of IVP (Figure 2C) at the plasma concentration similar to that of the clinically efficacious dose (15 mg/man/d) 34,35 (data not shown).…”

Phosphodiesterase type 5 inhibitors in treatment of lower urinary tract dysfunctions

“…Поскольку расслабление гладких миоцитов подпузырной области опосредуется оксидом азота, применение иФДЭ-5 у таких больных также может иметь терапевтический эффект. В недавно опубликованной работе данная концепция была подтверждена в эксперименте [60]. На модели нейрогенной гипоактивности детрузора в сочетании с детрузорно-сфинктерной диссинергией было показано, что назначение тадалафила приводило к достоверному уменьшению объема остаточной мочи и увеличению эффективности мочеиспускания, при этом сократительная активность детрузора не увеличивалась.…”

“…На модели нейрогенной гипоактивности детрузора в сочетании с детрузорно-сфинктерной диссинергией было показано, что назначение тадалафила приводило к достоверному уменьшению объема остаточной мочи и увеличению эффективности мочеиспускания, при этом сократительная активность детрузора не увеличивалась. Таким образом, эффективность лечения была достигнута за счет усиления релаксации уретры во время опорожнения, что приводило к повышению эффективности опорожнения [60].…”