Study in clinical application of nitric oxide (NO) scavenger for treatment of urinary incontinence

一氧化氮(NO)清除剂治疗尿失禁的临床应用研究

• 批准号: 10557142
• 负责人: YOSHIDA Masaki
• 金额: $ 8.58万
• 依托单位: KUMAMOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10557142/
• 关键词: Nitric oxide; NOS; NO scavenger; Urinary incontinence; Urethral smooth muscle; Nitrergic nerve; Adrenergic nerve; Spinal cord injury; NO消去剤; carboxy-PTIO; 尿失禁; 尿道平滑筋; 平滑筋細胞; 電気刺激; 血圧; 気管平滑筋; 腎機能

We have evaluated pharmacological characteristics of NO scavenger ; carboxy 2-phenyl-4, 4, 5, 5, -tetramethylimidazoline-1-oxyl 3-oxide, (carboxy-PTIO) in systemic organs in animals, in advance of clinical application of this drug for treatment of urinary incontinence.In rabbit urethral smooth muscles, both radical NO and NO bioaducts contributed to the nitrergic nerve-mediated relaxation. There are feedback mechanisms between nitrergic and adrenergic nerves, which regulate releases of NO and noradrenaline each other. NO released from nitrergic nerves had inhibitory regulation for release of noradrenaline from adrenergic nerves. Release of NO from nitrergic nerves was increased and decreased through the alpha-2 and alpha-1 adrenergic receptors existing in nitregic nerve endings, respectively. Experiment using cultured rabbit urethral smooth muscle cells showed that smooth muscle cells itself released NO, which may contribute to the urethral smooth muscle function.In vivo and vitro animal experiments, carboxy-PTIO did not show the adverse effects to cardiovasclular and respiratory systems, digestive system, and renal function. In rabbit urethral function, carboxy-PTIO increased urethral closing pressure without significant effects of bladder capacity and voiding pressure. Carboxy-PTIO administrated intravenously was excreted in urine (80%) and feces (20%) within 24 hours. There was not any tissue accumulation and toxicity after single or recurrent carboxy-PTIO administration in rats. Furthermore, anaphylaxis induced by this drug was not observed in rats.In rats with spinal cord injury, intravenous administration of carboxy-PTIO caused increase in urethral closing pressure, but did not have significant effects on bladder capacity, voiding pressure and urinary frequency.In conclusion, carboxy-PTIO is a promising drug for treatment of urinary incontinence. However, further evaluation is needed to specify the effectiveness and safety for human.

我们评估了NO清除剂的药理学特性；羧基2-苯基- 4,4,5,5，-四甲基咪唑啉-1-氧基3-氧化物，（羧基- ptio）在动物的全身器官中，提前将该药物用于治疗尿失禁的临床应用。在兔尿道平滑肌中，一氧化氮自由基和一氧化氮生物成体都参与了氮神经介导的松弛。氮能神经和肾上腺素能神经之间存在着相互调节NO和去甲肾上腺素释放的反馈机制。氮能神经释放NO对肾上腺素能神经释放去甲肾上腺素具有抑制调节作用。一氧化氮通过存在于氮神经末梢的α -2和α -1肾上腺素能受体释放的一氧化氮分别增加和减少。兔尿道平滑肌细胞培养实验表明，平滑肌细胞自身释放一氧化氮，一氧化氮可能对尿道平滑肌功能有促进作用。在体内和体外动物实验中，羧基ptio对心血管、呼吸系统、消化系统和肾功能均无不良影响。在兔尿道功能中，羧基ptio增加了尿道闭合压力，对膀胱容量和排尿压力无明显影响。羧基ptio静脉给药24小时内随尿液排出（80%），随粪便排出（20%）。大鼠单次或多次给药后，无组织积累和毒性。此外，在大鼠中未观察到该药引起的过敏反应。脊髓损伤大鼠静脉给予羧基ptio可引起尿道闭合压力升高，但对膀胱容量、排尿压力和尿频无显著影响。综上所述，羧基ptio是一种很有前途的治疗尿失禁的药物。但是，还需要进一步的评价来明确其对人体的有效性和安全性。

项目成果

Yoshida Masaki: "Effects of prstaglandin E_2 receptors antagonist in overacitive bladder in the chronic spinal rats"Neurourology and Urodynamics. 19(4). 407-408 (2000)

吉田正树：“前列腺素 E_2 受体拮抗剂对慢性脊髓大鼠膀胱过度活动症的影响”神经泌尿学和尿动力学。

Yono, M., Yoshida, M., Takahashi, W., Inadome, A., Ueda, S.: "Comprison of the effects of novel antimuscarinic drugs on human detrusor smooth muscle."Br.J.Urol.. 86(6). 719-725 (2000)

Yono，M.，Yoshida，M.，Takahashi，W.，Inadome，A.，Ueda，S.：“新型抗毒蕈碱药物对人类逼尿肌平滑肌的影响的比较。”Br.J.Urol.. 86（

Masaki Yoshida: "Age-related changes in acetylcholine and adenosine triphosphate releases from human bladder smooth muscles"Neurourology and Urodynamics. 18. 346-347 (1999)

Masaki Yoshida：“人类膀胱平滑肌释放的乙酰胆碱和三磷酸腺苷的年龄相关变化”神经泌尿学和尿动力学。

Masaki Yoshida: "Efect of the NO scavenger carboxy-PTIO on endothelium-dependent vasorelaxation of various blood vesselsfromrabbits" Life Sciences. 62・3. 203-211 (1998)

Masaki Yoshida：“NO 清除剂羧基-PTIO 对兔子各种血管内皮依赖性血管舒张的影响”生命科学 62・3（1998）。

Masaki Yoshida: "The possible effect of nitric oxide on relaxation and noradrenaline releasein the isolated rabbit urethra" European J. Phamacology. 357・2. 213-219 (1998)

Masaki Yoshida：“一氧化氮对离体兔尿道松弛和去甲肾上腺素释放的可能影响”欧洲药理学杂志 357・2（1998）。