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

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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.