| Abstract: | 摘要
Sildenuafil citrate 是Viagra的成份學名，而Viagra是在1996年由美國輝瑞藥廠（Pfizar）所研發，原先為治療心血管疾病用藥，後來成為是第一個能克服勃起障礙(Erectile dysfunction, ED)的口服藥物，Sildenuafil經由活化內皮細胞一氧化氮合成酶(endothelial nitric oxide synthase, eNOS)產生一氧化氮(NO)進而抑制磷酸雙酯酶第五型(phosophodiesterase type 5，PDE5)的活性以發揮其藥理功能；然而在超氧陰離子(superoxide anion，O2‧- )存在下，NO將被快速的轉換成活性氮分子（reactive nitrogen species；RNS），而造成氧化壓力，目前探討Sildenuafil及其類緣物對氧化壓力的產生和抗氧化酵素系統的影響的文獻相當少；故本實驗目的以新型sildenafil 類緣物(分子量為484)為材料，探討其對大鼠體內NO合成、脂質代謝、肝功能、抗氧化酵素活性及精子品質之影響。32隻八週大Sprague-Dawley(SD)雄性大鼠並隨機分為四組(n=8)，(1)Control組-C組，(2) 低劑量組(72 mg sildenafil 類緣物/Kg diet)-L組，(3) 中劑量組(180 mg sildenafil 類緣物/Kg diet)-M組及(4) 高劑量組(360 mg sildenafil 類緣物/Kg diet)-H組，並採用AIN-93G飲食配方，飼料及飲水採自由進食。在飼養30天後，以CO2將其犧牲；並進行樣品分析。結果發現大鼠肝臟、腎臟及睪丸NO的濃度皆隨著sildenafil 類緣物劑量的增加而增加，L組及M組大鼠的膽固醇(TG)及三酸甘油脂顯著低於C組大鼠，三組實驗組大鼠肝臟的氧化壓力(TBARS)和肝功能指標(GOT、GPT)顯著高於C組大鼠，實驗組大鼠精子的品質(精子數目及泳動率)亦顯著高於C組大鼠；從本實驗的結果推論，此新型sildenafil 類緣物對實驗大鼠測試器官的NO合成量均有增加的效果，NO濃度上升對肝臟可能會造成氧化性傷害而使GOT、GPT的昇高，在低劑量的sildenafil analogue具有調控血脂的作用，能降低血清中的TC及TG；此外實驗大鼠精子數目及泳動率也可能和NO濃度上升有關。
關鍵字：Sildenafil 類緣物、內皮細胞一氧化氮合成酶、磷酸雙酯酶第五型、抗氧化酵素、TBARS
Abstract
Sildenafil was developed by Pfizer under the name of Viagra, for the treatment of erectile dysfunction (ED). This drug activated NO-cGMP pathway by enhancing the endothelial nitric oxide synthase (eNOS) and inhibiting phosophodiesterase type 5 (PDE5) activities. However, in the presence of superoxide anion (O2-), the NO induced by sildenafil or its analogues will be quickly converted to reactive nitrogen molecules (RNS) causing oxidative stress. NO is a pro-oxidant, however, very little research has done to investigate the effect of sildenafil and/or its analogues on the oxidative stress, anti-oxidative enzyme activity and sperm quality in animal model. Therefore , the aim of this study was to investigate the effects of a new sildenafil analogue on the NO generation, oxidative stress, antioxidant enzyme systems, lipid metabolism, liver function, and sperm quality in the rat. Thirty-two male Sprague-Dawley (SD) rats (10-week-old) were randomly divided into four groups (n = 8), (1) Control group (C group) (2) High dose group (360 mg sildenafil analogue /Kg diet, H group) (3) Middle dose group (180 mg sildenafil analogue /Kg diet, M group) (4) Low dose group (72 mg sildenafil analogue /Kg/diet, L group). The rats were fed an AIN-93G diets with or without sildenafil analogue. After 30 days, the rats were sacrificed and sample were analyzed. The concentrations of NO in the liver, kidney and testis of rats in H, M, and L groups were increased with the increasing of the dose of the sildenafil analogue supplemented. The concentrations of TC and TG in the plasma of the rats in L and M group were decreased significantly when compared with the rat in C group. The TBARS concentrations and activities of GOP, GPT in the Liver, kidney and testis of rats in H, M, and L groups were significant higher than the rats in C group. The rat’s sperm numbers and mobilites were significant increased in H, M, and L groups when compared with the rats in C group. While, no significant difference was observed in the amount of Reactive Oxygen Species (ROS) in the sperm of rats in these four groups. The results from this study indicate that additional supplement of this new sildenafil analogue may increase the NO production in rats. NO then regulated the lipid metabolism, oxidative stress, antioxidative enzyme activities and spermatogenesis in rats.
Keywords: Sildenafil Analogue, Endothelial Nitric Oxide Synthase, Phosophodiesterase type 5, Anti oxidant Enzyme System，TBARS |
