- 學位論文
探討鉀離子通道開啟藥劑對於小鼠骨骼肌肌強直現象的影響
The effect of potassium channel openers on the myotonia of mouse skeletal muscle
摘要
本研究是探討Kv7（potassium channel, voltage-gated, KQT-like subfamily）鉀離子通道開啟藥劑對於處理氯離子通道阻斷劑：anthracene-9-carboxylic acid（9-AC）所引發骨骼肌肌強直現象的影響。肌強直是一種運動神經-骨骼肌的疾病，特色是骨骼肌細胞膜會過度興奮且重覆性產生動作電位並在收縮後肌肉會有延緩鬆弛的現象，原因為骨骼肌細胞膜上的離子通道功能異常所造成，主要為氯離子及鈉離子通道異常。目前在骨骼肌組織上沒有明確的報導具有功能性的氯離子通道開啟藥劑，因此在臨床治療多使用鈉離子通道阻斷藥劑，然而此類藥劑有其一定的副作用。根據報導，KCNQ家族的鉀離子通道於骨骼肌上具有表現，可能與細胞膜電位維持有關，因此想探討處理鉀離子管道開啟藥劑，對於肌強直（myotonia)現象的影響。 在肌肉張力實驗中，發現不論是低頻率或高頻率的電刺激下，retigabine、flupirtine或lidocaine的處理，都能拮抗9-AC處理後所引發的骨骼肌鬆弛期延長與肌強直現象；而lamotrigine無法拮抗9-AC的藥物作用。處理9-AC後骨骼肌縮放期的實驗中，也有相類似的結果，其中retigabine及flupirtine的藥物作用，經由處理鉀離子通道阻斷劑而受到拮抗。紀錄動作電位實驗中，處理retigabine、flupirtine及lidocaine會減少9-AC引起的動作電位產生次數；進一步分析動作電位的產生斜率，處理retigabine及flupirtine對於動作電位的斜率不具有顯著的影響，代表此兩種藥物的作用可能不是經由阻斷鈉離子通道。因此認為retigabine以及flupirtine可以顯著的拮抗處理9-AC所引發的肌強直的現象，其機制可能是經由鉀離子通道開啟的作用。綜合以上實驗結果，證明Kv7鉀離子通道的開啟藥劑在治療肌強直疾病上，可能是一個具有潛力的發展方向。
並列摘要
The purpose of this study was to investigate the effect of KCNQ (potassium channel, voltage-gated, KQT-like subfamily) openers in preventing myotonia caused by anthracene-9-carboxylic acid (9-AC, a chloride channel blocker). Myotonia is a neuromuscular disorder and characterized by the membrane hyperexcitability and slow relaxation of muscles after a contraction. An animal model of myotonia can be elicited in murine skeletal muscle by 9-AC treatment. Retigabine, flupirtine and lidocaine can inhibit the increased twitch amplitude (0.1 Hz stimulation) and reduce the tetanic fade (20 Hz stimulations) observed in the presence of 9-AC. Furthermore, the prolonged twitch duration of skeletal muscle was also inhibited by retigabine, flupirtine or lidocaine. Lamotrigine (an anticonvulsant drug) has a lesser effect on the muscle twitch amplitude, tetanic fade and prolonged twitch duration as compared with other three medicines. In experiments using intracellular recordings, retigabine and flupirtine clearly reduced the firing frequencies of repetitive action potentials induced by 9-AC. Furthermore, we found that the rising slope of action potentials could not be reduced by the addition of retigabine and flupirtine. These data suggested that KCNQ openers prevent the myotonia induced by 9-AC, at least partly through enhancing potassium conductance in skeletal muscle. Taken together, these results indicate that KCNQ openers are potential alternative therapeutic agents for the treatment of myotonia.