臺灣博碩士論文加值系統

本研究主要以 theophylline 為核心，進行結構分子修飾，在 theophylline 結構上之第七位氮基修飾，合成出新型 theophylline 衍生物，KMUP-3和 KMUP-4，並進一步利用活體及離體之動物實驗，來探討其藥理特性。
在活體心臟血管實驗，由靜脈注射KMUP-3和 KMUP-4 (1.0, 2.0, 3.0 mg/kg)於 pentobarbital 麻醉之正常血壓Wistar 系大鼠， KMUP-3可引起大約一小時以上的血壓上升及短暫性心跳增加的反應；KMUP-4可引起大約一小時以上的血壓下降及短暫性心跳減緩的反應。
在離體組織實驗，KMUP-3和 KMUP-4 ( 10-9~10-4 M )之累積投予在phenylephrine所誘發收縮的大鼠離體胸主動脈血管，不論是去除內皮或是具有內皮的存在，均會產生劑量相關性的血管鬆弛作用。但是，KMUP-3和 KMUP-4 的血管鬆弛作用卻會因去除內皮以及一氧化氮合成酶 (nitric oxide synthase；NOS) 抑制劑L-NAME (100 mM) 的加入而降低其作用。KMUP-3和 KMUP-4的血管鬆弛作用亦能被 soluble guanylyl cyclase (sGC) 抑制劑ODQ (1 mM), adenylyl cyclase 抑制劑SQ 22536 (100 mM), 鉀離子通道阻斷劑 tetraethylammonium chloride (TEA, 10 mM), glibenclamide (1 mM), 4-aminopyridine (4-AP, 100 mM)以及apamin (1 mM) and charybdotoxin (ChTX, 0.1 mM)等藥物之前處理而抑制。
在大鼠離體胸主動脈，KMUP-3和 KMUP-4 對80 mM 高鉀溶液引起血管收縮之鬆弛作用可明顯遞減。而在KMUP-3和 KMUP-4 (10-6 M) 處理後，對於 sodium nitroprusside(SNP)引起之血管鬆弛，KMUP-3和 KMUP-4有將之加強之作用。
在離體大鼠心房上， KMUP-3和 KMUP-4 (10-6~10-4 M) 之累積給藥後，KMUP-3呈現心房收縮力增強及跳動頻率抑制之現象， KMUP-4則呈現心房收縮力及跳動頻率抑制之現象。KMUP-3和 KMUP-4 也能在 carbachol 以及 histamine所引起天竺鼠氣管收縮呈現劑量相關性的鬆弛作用。
在phenylephrine所誘發收縮之離體白兔陰莖海綿體上，給予 KMUP-3和 KMUP-4 ( 10-9~10-4 M )，可產生劑量相關性的鬆弛作用，而此鬆弛作用亦可被L-NAME, , ODQ, TEA, glibenclamide, 4-AP, apamin and charybdotoxin (ChTX) 等藥物所拮抗。
在活體白兔海綿體內壓 ( intracaverous pressure ) 之測定上，KMUP-3和 KMUP-4 ( 0.2, 0.4, 0.6 mg/kg ) 呈現劑量相關性增加白兔海綿體內壓 ( ICP ) 以及腫脹持續的時間 ( duration of tumescene )。
另外，在大鼠胸主動脈平滑肌細胞 ( RASMC ) 上，以放射性免疫分析方法 (RIA)評估 cGMP 之釋放量，利用 [125I]cGMP 進行分析，可發現KMUP-3和 KMUP-4 (0.1~100 mM) 呈現劑量相關性增加細胞內 cGMP 的釋放量，在L-NAME (100 mM) 以及ODQ (10 mM) 等藥物之處理後，KMUP-3和 KMUP-4 所引起之cGMP釋放作用則減少。另於大鼠胸主動脈平滑肌細胞上，同樣以放射性免疫分析方法來評估細胞內cAMP的釋放量， KMUP-3和 KMUP-4 可增加cAMP的釋放量，而在經SQ 22,536 (100 mM)藥物處理後，結果發現KMUP-3和 KMUP-4 所引起之 cAMP之釋放作用減弱。
由以上活體及離體組織實驗，可以顯示 KMUP-3和 KMUP-4在血管以及海綿體平滑肌的鬆弛作用，可能是經由刺激一氧化氮釋放、活化 sGC 而增加 cGMP 釋放，經由活化 AC而增加 cAMP 釋放，並具有促進鉀離子通道開啟之作用。

1. 摘要----------------------------------------------1
2. 英文摘要------------------------------------------4
3. 縮寫表--------------------------------------------6
4. 緒論----------------------------------------------7
5. 研究材料------------------------------------------10
6. 研究方法------------------------------------------15
7. 研究結果------------------------------------------29
8. 討論----------------------------------------------37
9. 參考文獻------------------------------------------43
10. 附圖與附表----------------------------------------48

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