茶鹼衍生物改變睪固酮誘導之攝護腺蛋白表現 及抑制去甲羥麻黃鹼引起之收縮

Xanthine derivative regulates testosterone-induced prostate protein expression and inhibited phenylephrine-enhanced smooth muscle contraction

范雅琴(Ya-Chin Fan)

指導教授 ： 陳英俊

高雄醫學大學/醫學院/藥理學科研究所/碩士(2009年)

摘要

良性攝護腺肥大 (benign prostatic hyperplasia, BPH)，是由於尿道周圍的攝護腺腺體 (glandular) 及肌基質 (stromal) 過度增生 (hyperplasia)，增大的攝護腺壓迫尿道、攝護腺組織內平滑肌張力增強，造成膀胱排尿功能的障礙，症狀包括尿流柱弱、排尿遲滯、排尿間歇、排尿不完全等，臨床稱為下泌尿道症狀 (lower urinary tract symptoms, LUTS) 。我們之前的研究發現茶鹼衍生物 KMUP-1 能鬆弛 phenylephrine所引起的攝護腺平滑肌收縮反應；並且有拮抗 α1 接受器的效力、增加sGC/PKG 的蛋白表現促使攝護腺舒張。在本研究當中，本研究目標為 KMUP-1 是否能改善由睪固酮 (testosterone) 誘導的攝護腺收縮，及探討其作用機轉。實驗所設計的誘導模式是採皮下注射 testosterone (3 mg/kg/day) 於大鼠。結果顯示，四個星期後，睪固酮誘導的病態組的 prostate ratio (PW/BW) 明顯高於正常組。實驗上將動物分成六組，分別是控制組 (control)、病態組 (BPH)、預防組包括餵食 KMUP-1 (2.5 mg/kg/day) 組、餵食 KMUP-1 (5 mg/kg/day) 組、餵食 sildenafil (5 mg/kg/day) 組及餵食 doxazosin (5 mg/kg/day) 組直到第 28 天，以西方墨點法分析大鼠攝護腺組織內的蛋白質表現，發現預防性給予 KMUP-1 可抑制經由睪固酮活化的 ERK、MEK、ROCK-II，並且可活化使平滑肌舒張的蛋白質如 sGCα1、sGCβ1、PKG及抑制 PDE5A 之表現。除此之外我們用病態組的攝護腺組織做離體張力的實驗，發現病態組攝護腺對 phenylephrine 有較高的收縮張力，KMUP-1 也能舒張 phenylephrine 引起的攝護腺收縮。根據以上的實驗結果，本研究推論 KMUP-1 可以有效改善病態攝護腺過度的收縮張力，希望在未來可以進行更多相關的研究，以探討 KMUP-1 是否增加治療良性攝護腺增生所引起的下泌尿道症狀 (LUTS) 之可行性的證據。

關鍵字

攝護腺肥大

並列摘要

Benign prostatic hyperplasia (BPH) is the uncontrolled growth of glandular and stromal of the prostate, characterized by obstruction of the bladder and urethra found in lower urinary tract symptoms (LUTS). Our previous studies have demonstrated that KMUP-1, a unique xanthine and piperazine derivative, is an α1A/α1D-adrenoceptor blocker, activated sGC/PKG protein expression and inhibited phenylephrine-induced contraction of normal prostate which could lead to prostate smooth muscle relaxation. In this study, we examined whether KMUP-1 could improve the LUTS caused by testosterone-induced BPH rat prostate, and elucidate its action mechanisms. The BPH model was induced by subcutaneous injection (s.c.) of testosterone (3 mg/kg/day). After 4 weeks, prostate ratio (PW/BW) was increased significantly in BPH group. Animals were divided into 6 groups: (1) control, (2) BPH, for prevention of disease worsening (3) KMUP-1 (2.5 mg/kg/day), (4) KMUP-1 (5 mg/kg/day), (5) sildenafil (5 mg/kg/day) and (6) doxazosin (5 mg/kg/day) orally by gastric gavage for 4 weeks. In this study, western blot analysis demonstrated that KMUP-1 inhibited testosterone-induced overexpression of extracellular signal-regulated protein kinase (ERK), mitogen-activated protein kinase (MEK), ROCK-II and phosphodiesterases type 5 (PDE5A). Soluble guanylate cyclase α1 (sGCα1), soluble guanylate cyclase β1 (sGC β1) and protein kinase G (PKG) were markedly increased in KMUP-1 groups. In addition, in testosterone-treated prostate (BPH groups), the phenylephrine-induced contraction force is greater than in control group, and KMUP-1 significantly relaxed phenylephrine-induced contraction in BPH prostate. Based on the above findings, In conclusion, KMUP-1 can improve testosterone-induced prostate contractility and has beneficial merits in treatment of BPH/LUTS.

並列關鍵字

prostate

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