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研究生:鄒惠霞
論文名稱:KMUP1103在大鼠血管平滑肌及人類血小板的藥理作用
論文名稱(外文):Pharmacology studies of KMUP 1103 in rat smooth muscle and human platelets
指導教授:陳英俊陳英俊引用關係羅怡卿
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
中文關鍵詞:大鼠血管平滑肌人類血小板
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摘 要
本研究目的是合成 KMUP 1103 及探討其藥理活性。KMUP 1103是以 xanthine 為骨架於其第七位氮基導入 piperazine 進行分子結構修飾,並經由Mass, IR及 NMR 證明合成成功。藥理活性之探討包括 KMUP 1103 對於大鼠血壓心跳、離體血管及人類血小板之作用。
靜脈注射 KMUP 1103 (0.1, 1.0, 3.0 mg/kg) 於 pentobarbital (40 mg/kg) 麻醉之正常血壓 Wistar 系大鼠,可引起劑量相關性之血壓下降及心跳減緩。但 KMUP 1103 在高劑量下 (3.0 mg/kg) 會引起心跳增加。在大鼠離體之左右心房,KMUP 1103在0.1, 1 mM 濃度下 對心房之收縮力及頻率並沒有明顯的差異,但在濃度10 mM及100 mM 則輕微抑制左心房之收縮力及右心房之收縮頻率作用。
在離體血管實驗中,不論是去除內皮或是具有內皮之大鼠胸主
動脈,累積投予KMUP 1103 (0.01 mM~100 mM),在以 phenylephrine (PE, 10 mM) 誘發收縮的離體血管均產生劑量相關性的鬆弛。KMUP 1103 的血管鬆弛作用會因去除內皮以及一氧化氮合成酶 (nitric oxide synthase;NOS) 抑制劑L-NAME (1 mM) 的前處理而降低其作用。在內皮細胞完整之血管組織,KMUP 1103 的血管鬆弛作用能被下列藥物抑制 : soluble guanylyl cyclase (sGC) 抑制劑 methylene blue (10 mM), ODQ (1 mM), adenylyl cyclase 抑制劑 SQ 22536 (100 mM), prostaglandin (PG) biosynthesis 抑制劑 indomethacin (1 mM), 鉀離子通道阻斷劑 tetraethylammonium chloride (TEA, 10 mM), glibenclamide (1 mM) 或 4-aminopyridine (4-AP, 100 mM) 。此外,對 80 mM高鉀溶液所引起的收縮,KMUP 1103 之血管鬆弛作用亦會被減弱。另外,磷酸二酯酶 (phosphodiesterase) 抑制劑 IBMX (0.5 mM) 會加成 KMUP 1103 的血管鬆弛作用。
在去內皮之血管組織,SQ 22536 和 ODQ 可抑制 KMUP 1103引起的血管鬆弛作用。而且,在大鼠血管胸主動脈細胞株 A-10 上,KMUP 1103 呈現劑量相關性增加細胞內 cyclic AMP 及 cyclic GMP 的釋放量,並可被前處理 ODQ (1 mM) 所抑制。
在人類血小板,KMUP 1103具有抑制collagen, arachidonic acid, adenosine diphosphate, thrombin及epinephrine所誘發之血小板凝集作用。利用放射性免疫法測定人類血小板得知KMUP 1103對於PDE3, PDE4, PDE5之抑制程度分別為52 ± 5.9%, 32 ± 3.6% 和8 ± 1.1%。KMUP 1103 亦呈現劑量相關性增加血小板 cyclic AMP 和 cyclic GMP 的釋放量。
以上結果顯示 KMUP 1103 所產生之血管鬆弛及抑制血小板凝集之作用是經由(1) 抑制磷酸二酯酶;(2) 活化AC/cyclic AMP途徑,進而增加cyclic AMP產生;(3) 活化NO/sGC/cyclic GMP進而增加 cyclic GMP 產生及(4) 活化 PG/AC/cyclic AMP (5) 開啟鉀離子通道。
目錄
1. 摘要-----------------------------------------------------1
2. 英文摘要-----------------------------------------------4
3. 縮寫表--------------------------------------------------6
4. 緒論-----------------------------------------------------8
5. 研究材料---------------------------------------------11
6. 研究方法---------------------------------------------17
7. 研究結果---------------------------------------------27
8. 討論---------------------------------------------------38
9. 參考文獻---------------------------------------------41
10. 附圖---------------------------------------------------45
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