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

在NO清除剂羧基-2-苯基-4，4，5，5，四甲基咪唑啉-1-氧基-3-氧化物(Carxy-PTIO)用于临床治疗尿失禁之前，我们对其在动物全身器官中的药理学特性进行了评价。在兔的尿失禁治疗中，自由基NO和NO生物递质都参与了氮能神经介导的松弛。氮能神经和肾上腺素能神经之间存在反馈机制，它们相互调节NO和去甲肾上腺素的释放。氮能神经释放的NO对肾上腺素能神经释放去甲肾上腺素有抑制作用。硝酸能神经释放NO的增加和减少分别通过存在于硝酸神经末梢的α-2和α-1肾上腺素能受体。体外动物实验表明，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。在兔的尿路功能中，羧基PTIO增加了尿路闭合压，但对膀胱容量和排尿压力无明显影响。静脉给药后24小时内尿(80%)和粪便(20%)排泄。大鼠单次或反复给予羧基PTIO后，未见任何组织蓄积和毒性。在大鼠脊髓损伤模型上，静脉注射羧基PTIO可引起大鼠尿路闭合压升高，但对膀胱容量、排尿压力和尿频无明显影响，是治疗尿失禁的一种有前景的药物。然而，还需要进一步的评估来明确其对人类的有效性和安全性。

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.