犀利士可以藉由恢復胰島素經由膀胱黏膜IRS/PI3K/AKT/eNOS路徑所引發的逼尿肌放鬆功能來改善代謝症大鼠的膀胱過動
李偉嘉1，莊燿吉1，華瑜2，田祐霖3
高雄長庚紀念醫院泌尿科1，轉譯中心2，兒科部.3
Tadalafil can ameliorate bladder overactivity through rescuing insulin-activated detrusor relaxation via bladder mucosal IRS/PI3K/AKT/eNOS pathway in a rat model of metabolic syndrome
Wei-Chia Lee,1, Yao-Chi Chuang1, Julie Y. H. Chan 2, You-Lin Tain,3
Division of Urology1, Institute for Translational Research in Biomedicine3, and Department of pediatrics3, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Purpose: To investigate the effect of tadalafil on bladder mucosal insulin signaling disturbance and bladder overactivity of fructose-fed rats (FFRs).
Materials and methods: Female Wistar rats were divided into control, fructose (received 60% fructose diet for 12 weeks), fructose plus tadalafil (tadalafil started from 9th week), fructose plus metformin (metformin started from 9th week). Micturition behavior was observed by metabolic cage model and cystometry. Concentration-response curve to insulin were performed in full-thickness bladder strips. Expression and phosphorylation of bladder mucosal insulin signaling pathway of insulin receptor (IR), insulin receptor substrate 1(IRS1), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), endothelial nitric oxide synthase (eNOS) were evaluated by Western blots. Detrusor cGMP and urinary nitrite plus nitrate (NOx) were obtained.
Results: Compared to the control group, the fructose group showed increased micturition frequency and bladder overactivity in the bladder functional study; however, the both of tadalafil and metformin treatment groups did not. In organ bath study, a significant reduction of relaxation response to insulin was noted in the fructose group, but not in fructose/tadalafil or fructose/metformin group. The fructose group showed overexpression of IRS-1 and pIRS1 (Ser307), and down-regulation of PI3K, pPI3K (Tyr508), AKT, pAKT (Ser473), eNOS, and peNOS (Ser1177) in the bladder mucosa. The fructose group also had a decrease of detrusor cGMP and urinary NOx. The tadalafil treatment restored the level of mucosal peNOS as well as detrusor cGMP and urinary NOx of FFRs. In addition, the metformin-treated group showed no significant difference when compared with controls among these parameters.
Conclusion:
Our study results indicated that tadalafil can ameliorate the bladder overactivity through rescuing insulin-activated detrusor relaxation in FFRs. High fructose diet may impair bladder mucosal insulin signaling and associated cGMP level and NO availability in rats, which can be restored by metformin treatment. Tadalafil treatment can rescue the urinary NO availability of FFRs by increasing mucosal peNOS expression and detrusor cGMP amount.