逼尿肌活动低下模型中尿道功能障碍及 PDE5 抑制剂（他达拉非）的治疗效果。该模型由骨盆神经挤压损伤诱导。
Urethral dysfunction and therapeutic effects of a PDE 5 inhibitor (tadalafil) in a rat model of detrusor underactivity induced by pelvic nerve crush injury.
机构信息
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Department of Urology, International University of Health and Welfare, Chiba, Japan.
出版信息
Neurourol Urodyn. 2020 Mar;39(3):916-925. doi: 10.1002/nau.24310. Epub 2020 Feb 10.
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.
目的
采用骨盆神经挤压（PNC）损伤制作的周围神经源性逼尿肌活动低下（DU）大鼠模型，研究尿道功能障碍，并测试磷酸二酯酶 5（PDE5）抑制剂他达拉非的作用。
方法
在 PNC 大鼠模型产生后 10 天，进行清醒膀胱测压（CMG）和等容膀胱测压（IC-UPP）测量，并进行尿道灌注压（IC-UPP）测量。此外，在对照大鼠中，静脉注射阿托品前后记录 IC-UPP，以确定膀胱收缩压降低是否影响排尿时尿道松弛。然后，记录 PNC 大鼠静脉注射他达拉非后的 CMG 和 IC-UPP 测量结果。最后，使用实时聚合酶链反应测量 PNC 和对照大鼠尿道标本中神经元型一氧化氮合酶（nNOS）、内皮型一氧化氮合酶和 PDE5 的转录水平。
结果
PNC 大鼠在 CMG 中表现出 DU 的特征。此外，PNC 大鼠的等容膀胱收缩幅度和尿道松弛明显降低。阿托品减弱了等容膀胱收缩幅度；然而，阿托品对对照大鼠的尿道松弛没有影响。他达拉非降低了残余尿量，提高了排空效率，而不改变 PNC 大鼠的膀胱收缩幅度。此外，他达拉非改善了 PNC 大鼠膀胱收缩时尿道松弛的幅度。与对照大鼠相比，PNC 大鼠的尿道 nNOS 转录水平上调。
结论
PNC 大鼠表现出 DU 和尿道松弛受损。PNC 大鼠的 PDE5 抑制增强了排尿时尿道松弛，从而提高了排空效率。因此，尿道功能障碍可能是治疗与神经源性 DU 相关的低效排尿的潜在靶点。
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