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446 Alpha1A-adrenoceptor antagonist improves bladder function by increasing bladder blood flow in rat model of lower urinary tract dysfunction with or without bladder outlet obstruction
446
Alpha1A-adrenoceptor antagonist improves bladder function by increasing bladder blood flow in rat model of lower urinary tract dysfunction with or without bladder outlet obstruction Eur Urol Suppl 2013;12;e446
Goi Y.1, Nomiya M.2, Sagawa K.2, Aikawa K.2, Tomiyama Y.1, Tatemichi S.1, Maruyama K.1, Kobayashi M.1, Kusama H.1, Yamaguchi O.3 1
Kissei Pharmaceutical Co. Ltd., Development Research, Azumino, Japan, 2Fukushima Medical University School of
Medicine, Dept. of Urology, Fukushima, Japan, 3Nihon University School of Engineering, Division of Bioengineering and LUTD Research, Koriyama, Japan INTRODUCTION & OBJECTIVES: It is thought α1-AR antagonists improve lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH) patients by relieving bladder outlet obstruction (BOO). However, several studies show that in more than a third of cases, BPH/LUTS are not associated with BOO. Although α1-AR antagonists also improve BPH/LUTS in cases without BOO, the detailed mechanism remains unclear. Since α1-AR antagonists reportedly improve bladder blood flow (BBF) in LUTS patients, it seemed possible that a given α1-AR antagonist might ameliorate LUTS by improving BBF, whether or not BOO was present. Thus, we examined whether the BBF improvement induced by the α1A-AR antagonist silodosin might partially suppress the detrusor overactivity (DO) present in a model of BOO and also in a model of atherosclerosis-induced chronic bladder ischemia (CBI), which is a model without BOO. MATERIAL & METHODS: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. In the CBI study, all groups received a 2% cholesterol diet throughout the experiment. The BOO model was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. Concurrently, silodosin (0.3 mg/kg/day) was administered subcutaneously via an osmotic pump (CBI model: 8 weeks; BOO model: 2 weeks). Then, a metabolic-cage study was performed without anesthesia. Bladder blood flow was measured using a Laser Speckle Blood Flow Imager. The 8-hydroxy-2’-deoxyguanosine level in the urine was measured as a marker of oxidative stress. The expression of each α1-AR subtype mRNA in bladder microvessels was examined by in situ hybridization. RESULTS: At eight weeks after preparation of the CBI model, voiding frequency had increased significantly, while mean voided volume had decreased significantly, in the CBI group. The eight-week silodosin administration significantly ameliorated both of those effects of CBI. Similarly, silodosin ameliorated DO in the BOO model. In both CBI rats and BOO rats, silodosin abrogated the decreases in BBF in the empty bladder, and improved the decreases in BBF seen during bladder distensions. The levels of the above oxidative-stress marker present in these models were significantly decreased by silodosin administration. All α1-AR subtype mRNA were expressed in rat microvessels, with α1a-AR mRNA being more strongly expressed than either α1b- or α1d-AR mRNA. CONCLUSIONS: In rat models with or without BOO, silodosin can improve DO and BBF. The α1a-AR mRNA is the
most strongly expressed in bladder microvessels. These results suggest that the BBF increase secondary to the relaxation of bladder microvessels induced by this α1A-AR antagonist might contribute to an improvement of storage symptoms in patients who have BPH/LUTS with or without BOO.
Alpha1A-adrenoceptor antagonist improves bladder function by increasing bladder blood flow in rat model of lower urinary tract dysfunction with or without bladder outlet obstruction Eur Urol Suppl 2013;12;e446
Goi Y.1, Nomiya M.2, Sagawa K.2, Aikawa K.2, Tomiyama Y.1, Tatemichi S.1, Maruyama K.1, Kobayashi M.1, Kusama H.1, Yamaguchi O.3 1
Kissei Pharmaceutical Co. Ltd., Development Research, Azumino, Japan, 2Fukushima Medical University School of
Medicine, Dept. of Urology, Fukushima, Japan, 3Nihon University School of Engineering, Division of Bioengineering and LUTD Research, Koriyama, Japan INTRODUCTION & OBJECTIVES: It is thought α1-AR antagonists improve lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH) patients by relieving bladder outlet obstruction (BOO). However, several studies show that in more than a third of cases, BPH/LUTS are not associated with BOO. Although α1-AR antagonists also improve BPH/LUTS in cases without BOO, the detailed mechanism remains unclear. Since α1-AR antagonists reportedly improve bladder blood flow (BBF) in LUTS patients, it seemed possible that a given α1-AR antagonist might ameliorate LUTS by improving BBF, whether or not BOO was present. Thus, we examined whether the BBF improvement induced by the α1A-AR antagonist silodosin might partially suppress the detrusor overactivity (DO) present in a model of BOO and also in a model of atherosclerosis-induced chronic bladder ischemia (CBI), which is a model without BOO. MATERIAL & METHODS: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. In the CBI study, all groups received a 2% cholesterol diet throughout the experiment. The BOO model was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. Concurrently, silodosin (0.3 mg/kg/day) was administered subcutaneously via an osmotic pump (CBI model: 8 weeks; BOO model: 2 weeks). Then, a metabolic-cage study was performed without anesthesia. Bladder blood flow was measured using a Laser Speckle Blood Flow Imager. The 8-hydroxy-2’-deoxyguanosine level in the urine was measured as a marker of oxidative stress. The expression of each α1-AR subtype mRNA in bladder microvessels was examined by in situ hybridization. RESULTS: At eight weeks after preparation of the CBI model, voiding frequency had increased significantly, while mean voided volume had decreased significantly, in the CBI group. The eight-week silodosin administration significantly ameliorated both of those effects of CBI. Similarly, silodosin ameliorated DO in the BOO model. In both CBI rats and BOO rats, silodosin abrogated the decreases in BBF in the empty bladder, and improved the decreases in BBF seen during bladder distensions. The levels of the above oxidative-stress marker present in these models were significantly decreased by silodosin administration. All α1-AR subtype mRNA were expressed in rat microvessels, with α1a-AR mRNA being more strongly expressed than either α1b- or α1d-AR mRNA. CONCLUSIONS: In rat models with or without BOO, silodosin can improve DO and BBF. The α1a-AR mRNA is the
most strongly expressed in bladder microvessels. These results suggest that the BBF increase secondary to the relaxation of bladder microvessels induced by this α1A-AR antagonist might contribute to an improvement of storage symptoms in patients who have BPH/LUTS with or without BOO.