臺灣博碩士論文加值系統

(一)實驗目的：
肌質網鈣離子幫浦抑制劑 cyclopiazonic acid ( CPA ) 對正常倉鼠 (Biobreeders F1B hamster)、擴張心肌病變倉鼠 ( Bio 14.6 dilated cardiomyopathic hamster, DCM ) 與人類心肌病變心室肌比較收縮力和動作電位的影響，以瞭解病變心肌肌質網 ( sarcoplasmic reticulum, SR ) 調節細胞內鈣離子的異常情形。
(二)實驗方法：
1.從美國 Biobreeders 公司進口 8隻健康倉鼠及12隻心肌病變倉鼠 ( 16週齡) 置於動物中心飼養到 39 ~ 43週齡，才開始實驗。除此之外還自國科會國家實驗動物中心採購健康倉鼠 8 隻進行實驗。
2.將倉鼠左心室乳突肌 (直徑 1.5 mm ) 連接於張力轉換器，記錄心室乳突肌收縮的功能，並利用傳統的玻璃微電極記錄心室肌的動作電位，並使用CPA ( 10 μM ) 以評估細胞內肌漿質網上鈣離子幫浦的活性及鈣離子釋放量。另外利用酵素法分離出倉鼠單一心室細胞，以全細胞膜電位箝定技術 ( whole-cell patch clamp technique ) 記錄細胞離子流。
3.取 8 位 ( 7 位男性， 1 位女性，年齡 37 ± 7 歲) 患有心肌病變病人接受換心手術切除心臟右心室肌，研究動作電位及收縮力的變化。
(三) 實驗結果：
1.健康及心肌病變倉鼠心室乳突肌在基礎 ( 2 Hz ) 頻率下，靜息後的第一跳明顯大於前一跳，收縮加強可以維持好幾跳後才慢慢恢復成穩定收縮，而病人心室肌在基礎 ( 1 Hz ) 頻率下，靜息後的收縮力增強現象 ( PRPC )，只發生在第一跳，第二跳就小於穩定收縮，之後才慢慢恢復成穩定收縮力。給予CPA ( 10 mM ) 處理後，兩者的 PRPC 都會被抑制，顯示與 SR 回收鈣離子有關，且 CPA 的作用就是抑制 SR 回收鈣離子。
2.病人心室肌的收縮力隨著頻率的升高 ( 0.5 Hz ~ 3 Hz ) 而增加，顯示會增加細胞內的鈣離子，也會增加 SR 回收鈣離子，在3 Hz 電刺激頻率下，舒張期張力沒有完全舒張。給予 CPA ( 10 μM ) 後，全面使收縮力被抑制，高頻率刺激下，會發現心舒期張力 ( diastolic tension ) 明顯增加產生攣縮現象，而倉鼠在 4 Hz 電刺激頻率沒有發生。
3.病人心室肌在 3 Hz電刺激頻率下的 PRPC 明顯大於 1 Hz，相較於1 Hz 下，快速刺激時收縮張力較小，但舒張期張力升高。在 3 Hz 刺激頻率下，給予 CPA ( 10 μM ) 後，PRPC 明顯被抑制，顯示 SR 在此情況下鈣離子釋出量減少。
4.在年老心肌病變倉鼠 ( 39 ~ 43 週) 乳突肌的PRPC 明顯小於健康倉鼠，CPA ( 10 μM ) 明顯抑制兩者曲線的上升段，與年輕 ( 17 ~ 27 週) 健康及心肌病變倉鼠乳突肌的 PRPC ( 2 ~ 60 s ) 與靜息期間關係曲線相比，顯示年老心肌病變倉鼠心室乳突肌受到較明顯抑制。心肌病變病人心室肌的 PRPC 在 40 ~ 60 s會達到頂點，給予 CPA之後，會全面抑制 PRPC 曲線，顯示心肌病變病人心室肌的 SR 回收鈣離子明顯抑制，已達到較嚴重的地步。
5.在健康倉鼠心室肌靜息後第一跳的動作電位APD0mV 顯著的縮短，給予CPA ( 10 μM ) 之後更是明顯，顯示瞬間外向鉀離子電流 ( transient outward current, Ito ) 經長時間靜息後會完全恢復，但在心肌病變倉鼠 APD0mV 變化很小，顯示病變倉鼠細胞 Ito 較小。
6.在健康及心肌病變倉鼠靜息 ( 20 s ) 後的動作電位 APD90 有明顯的延長，造成的原因可能經由產電性鈉鈣離子交換 (排鈣進鈉) 所致。
7.在健康倉鼠細胞經長時間去極化( 從 -40 mV 到 +40 mV, > 3 s) 後，發現有短暫內流電流 ( Iti ) 的發生。給予 CPA ( 3 μM ) 後，在7個細胞中會有4個細胞使 Iti 的現象加強，且作用可逆；另2個細胞使 Iti 完全被抑制，且作用不可逆。前者可能與 CPA 促進 SR釋放鈣離子有關，後者顯示 CPA 造成 SR 內鈣離子排空。
(四) 結論：
本實驗結果有三項重要的結論：
(一) 人類衰竭心室肌與倉鼠病變心室肌有相同及相異之處。因此動物模式雖然可供研究人類心肌功能的重要參考，由於種屬不同正常功能即有差異，並且須顧慮疾病各種不同病因及損傷程度，但由動物實驗結果推論到人類仍需要直接在人類心室肌求證。
(二) 在健康倉鼠心室細胞有很強的鉀離子外流 ( Ito )，也可從健康倉鼠組織 APD0mV 比較窄看出。給予 CPA 之後會增加 Ito，但對內向電流 ( Iti ) 會有加強或是抑制的現象，此種 CPA 對 Iti 不同的作用，可能與心律不整的產生或對抗有關係。未來須更進一步實驗探討健康與心肌病變倉鼠以及心肌病變病人與心肌病變倉鼠心室細胞之間電生理性質的差異性。
(三) 功能之異常反映疾病的嚴重程度，本論文在年老 ( 39 ~ 43 週齡)
倉鼠與心衰竭病人心室肌的研究結果，反映出取自換心人心室肌有較嚴重的缺損，CPA 的抑制作用也比較明顯且持久。

1. Aims:
(1) To investigate the role of the sarcoplasmic reticulum ( SR ) in the abnormal force development of the Syrian hamster model in late stage of cardiomyopathy (39~43 week-old). (2) We studied the role of SR by evaluating the change in twitch force after a rest interval as the change in force is believed to be a function of Ca reuptake into the terminal cisternae of the SR. Furthermore, we used a SR Ca2+ reuptake inhibitor ( cyclopiazonic acid, CPA ) to unmask an abnormal Ca2+ uptake by the SR. (3) To evaluate whether and to what extent the results obtained in our animal model applies to human tissue, we also studied ventricular tissue from human myopathic heart ( idiopathic dilated myopathy ) under the same conditions as ventricular myocardium of hamster to compare and contrast the abnormality of function.
2. Methods:
(1) Three groups of Syrian hamsters were used in the present study: 12 male myopathic hamsters ( strain Bio 14.6 ) at age of 16 weeks were obtained from the Biobreeders Company ( USA ) and raised in the animal house of our medical center until age of 39~43 weeks. Eight age-matched healthy hamsters ( strain F1B ) were obtained and raised in the same manner and served as control. In addition, 8 healthy Syrian hamsters were obtained locally from the National Science Coucil Animal Center for comparative study.
(2) Papillary muscle ( diameter around 1.5 mm ) obtained from left ventricle and perfused in vitro at 37 oC. Action potentials ( APs ) were recorded with the conventional microelectrode techniques. Twitch and diastolic force were recorded by means of a force-displacement transducer. In an additional series of experiments, hamster hearts were perfused in a Langendorff apparatus with perfusate containing digesting enzymes. Single cardiomyoctes were isolated and ionic currents were determined with the whole-cell patch-clamp techniques at room temperature.
(3) Human ventricular muscles obtained from the right ventricles of 8 patients with ideopathic dilated cardiomyopathy (7 male 1 female, age 37 ± 7 years) underwent heart transplantation were studied in a similar manner.
3. Results and discussion:
(1) Steady-state twitch force and PRPC after a rest interval
The relation between PRPC and the ability of SR to take up cytoplasmic Ca2+ was tested in hamster driven at a basic rate of 2 Hz. When the stimulation was interrupted for 2 ~ 60 s, the first post-rest twitch force was markedly increased with respect to that prior to the pause. Also, the second twitch curve was still larger than control and it took several beats for force to go back to control value. Also in the human tissue driven at a basic rate of 1 Hz, after the 2 ~ 60 s pause the twich force was larger than prior to the pause. However, not only the increase in force was less than in myopathic hamster, but the potentiation had already subsided by the second twitch after the pause.
(2) Force development at increasing driving rates
When the active and passive force development was recorded while the driving rate was increased from 0.5 Hz to 1, 2 and 3 Hz, the twitch force became larger as driving rate was increased, consistent with an increased intracellular Ca2+ and therefore an increased Ca2+ uptake into the SR. However, at 3 Hz the diastolic tension did not relax completely. After the pause, there was a PRPC only for the first beat. When the same procedure was repeated in the presence of CPA, the contraction was smaller. But as Ca2+ load was increased at 3 Hz, there was a marked increase in diastolic force, as the further limitation of the uptake of Ca into the SR by CPA resulted in a larger increase cytoplasmic diastolic Ca2+. During the pause, contracture subsided quickly. Consistent with a reduced uptake of Ca2+ by the SR, first post-rest twitch force was markedly reduced.
(3) Post-rest potentiation of contraction (PRPC) and CPA at two different rates
PRPC was studied in human ventricular tissue at 1 and 3 Hz to compare and contrast the effect of a different Ca2+ load. The faster rate resulted in a smaller systolic tension and an increase in diastolic tension compared to the slower rate. However, during the pause the diastolic tension quickly decreased to the baseline, which suggests that Ca2+ was moved from the cytoplasm into the SR. This appears to be confirmed by the fact that at 3 Hz PRPC was larger and also by the fact that in the presence of CPA (10 µM) the resting tension decreased far more slowly and PRPC was almost eliminated. Also the recovery from CPA effects was rather slow and incomplete.
(4) Influences of rest interval on PRPC
PRPC was studied as a function of duration of the rest interval (2, 5, 10, 20, 40 and 60 s) in ventricular myocardium of 39~43 week-old healthy and myopathic hamsters. The general shape of the PRPC-rest interval relationship was similar to that of the younger hamsters (17~27 week-old) in our previous study, but the curve of the older myopahtic ventricular myocardium was obviously shifted downward. CPA decreased predominantly the ascending part of the curve in both the healthy and the myopathic myocardium.
When the PRPC-rest interval relations were tested in human ventricular myocarium. The curve of PRPC-rest interval peaked at longer interval (40~60 s) compared to that of the hamsters. Another difference is that CPA markedly depresses the relation throughout the curve. Therefore the behavior of human tissue again resemble that of the older myopathic hamster, as it might be expected from the fact that the disease is likely to have reached a more advanced stage in human tissues. The fact that in the human ventricular myocardium the relation falls but little at the longer intervals might be due to the fact that Ca extrusion is more compromised (and the cytoplasmic [Ca2+] higher). Also, the marked decrease of the PRPC at all the rest intervals indicates that Ca2+ uptake into the SR may be more markedly affected than in the older myopathic hamster model.
(5) APD near zero potential (APD0mV) was markedly shortened during the first post-rest beat, especially after CPA (10 µM) exposure in healthy hamster, indicating complete recovery of transient outward K currents (Ito) after a rest interval of 20 s and longer. Post-rest shortening in APD0mV was smaller in myopathic hamster. Measurements of ionic currents under voltage-clamp show that the healthy hamster ventricular myocytes have a very strong Ito on depolarization. CPA consistently enhanced the Ito in all 7 myocytes tested.
(6) APD90 was significantly prolonged after a rest interval along with the greatly increased post-rest contraction, especially in hamster ventricular myocardium. It is assumed that an increased extrusion of Ca2+ through the Na+/Ca2+ exchanger could be the underlying ionic mechanism.
(7) After prolonged depolarizing step (from —40 to +40 mV, > 3 s), transient inward currents (Iti) were induced on repolarization in 6 of 7 hamster cardiomyocytes tested. CPA (3 μM) suppressed irreversibly the Iti in 2 myocytes but enhanced reversibly the Iti in other 4 myocytes. A depletion of SR Ca2+ stores and an enhanced release of Ca2+ from the SR, respectively, are assumed to be the underlying causes for these 2 seemingly opposite actions.
4. Conclusions:
(1) The present results show that in ventricular myocardium of patients affected by dilated cardiomyopathy, mechanical behavior shows similarity and differences with the myopathic Syrian hamster model.
(2) The similarities include PRPC with a distinctive dependence on driving rate and the depression of PRPC after inhibition of Ca2+ uptake into the SR by CPA. The differences include the development of diastolic tension at faster rates (especially in the presence of CPA) and the more marked depression of this relation by CPA. Therefore, the present results show there are pecularities that human myopathic ventricular tissue does not share with the hamster model and that might indicate a more serious deterioration of function in ventricular myocardium presumably because patient underwent cardiac transplantation when the disease had reached the stage of cardiac failure.
(3) The hamster ventricular myocytes have a very strong transient outward K currents (Ito) on depolarization, in agreement with a rather narrow APD near zero potential. CPA consistently enhanced the Ito but could depress or enhance the oscillatory transient inward currents (Iti) on repolarization. Changes in Iti may explain the suppression or genesis of arrhythmis during or after CPA exposure. Further experiments are required to clarify the differences between the electrophysiological properties of myopathic vs. healthy hamsters and between human and hamster cardiomyocytes.
(4) A more general conclusion is that, while animal study provide interesting insight for the understanding of human disease, only studies in human tissues provide direct evidence for the abnormalities of function caused by disease.

目錄------------------------------------------------------- I
表目錄----------------------------------------------------- III
圖目錄----------------------------------------------------- IV
中文摘要--------------------------------------------------- VI
英文摘要---------------------------------------------------- X
緒言------------------------------------------------------- 1
材料與方法------------------------------------------------- 6
一、 實驗動物及換心病人-------------------------------- 6
二、 離體心室肌實驗------------------------------------ 6
三、 單一心室細胞實驗---------------------------------- 8
四、 實驗藥品------------------------------------------ 12
五、 實驗數據及統計------------------------------------ 12
實驗結果--------------------------------------------------- 13
一、 Cyclopiazonic acid 對健康倉鼠心室乳突肌的作用----- 13
二、 Cyclopiazonic acid 對心肌病變倉鼠心室乳突肌的作用 14
三、 健康倉鼠與心肌病變倉鼠心室乳突肌的異同------------15
四、 Cyclopiazonic acid 對心肌病變病人心室肌的作用 ----16
五、 心肌病變病人心室肌與心肌病變倉鼠心室乳突肌的異同--17
六、 Cyclopiazonic acid 對倉鼠心室肌細胞間外向鉀離子電流 ( Ito )及 transient inward current ( Iti ) 的影響 ---------- 18
討論------------------------------------------------------ 40
結論------------------------------------------------------ 45
參考文獻-------------------------------------------------- 46
表目錄
表 1、Cyclopiazonic acid 對健康倉鼠及心肌病變倉鼠心室乳突肌
動作電位特徵的影響 ----------------------------------------21
表 2、Cyclopiazonic acid 對健康倉鼠及心肌病變倉鼠心室乳突肌
動作電位的影響------------------------------------------- 22
表 3、Cyclopiazonic acid 對心肌病變倉鼠及心肌病變病人心室肌
動作電位及收縮力的影響----------------------------------- 29
表 4、倉鼠及心肌病變病人心室肌經cyclopiazonic acid 處理後自
動節律的發生率------------------------------------------- 31
表 5、Cyclopiazonic acid 對病人心肌病變心室肌引起舒張期張力
增加的作用----------------------------------------------- 35
圖目錄
圖 1、Cyclopiazonic acid 對健康倉鼠心室乳突肌電機械性質的影響 20
圖 2、灌流cyclopiazonic acid 及洗去藥物後對倉鼠心室乳突肌動作
電位期間及穩定狀態收縮的作用-------------------------------- 23
圖 3、Cyclopiazonic acid 對倉鼠心室乳突肌靜息後收縮力增強的現象- 24
圖 4、Cyclopiazonic acid 對倉鼠心室乳突肌在2 Hz 及4 Hz 靜息後
收縮力增強的影響------------------------------------------- 25
圖 5、灌流cyclopiazonic acid及洗去藥物後對倉鼠心室乳突肌在 2
Hz 及4 Hz刺激頻率下靜息後收縮增強的影響-------------------- 26
圖 6、心肌病變倉鼠與心肌病變病人心室肌的電機械性質--------- 27
圖 7、Cyclopiazonic acid 對心肌病變倉鼠與心肌病變病人心室肌
的電機械性質 ---------------------------------------------- 28
圖 8、Cyclopiazonic acid 對倉鼠心室乳突肌所引發自動節律的影響30
圖 9、Cyclopiazonic acid 對心肌病變病人心室肌的靜息後收縮力增
強作用 ---------------------------------------------------- 32
圖 10、灌流cyclopiazonic acid 後及洗去藥物後對心肌病變病人心
室肌在1 Hz 及3 Hz 靜息後收縮力增強的影響------------------- 33
圖11、給予 cyclopiazonic acid 前後對心肌病變病人心室肌靜息後
收縮增強的變化 -------------------------------------------- 34
圖12、高濃度 cyclopiazonic acid 對健康倉鼠細胞膜的影響----- 36
圖13、Cyclopiazonic acid 對健康倉鼠細胞瞬間外向鉀離子電流 ( Ito ) 的加強作用 ------------------------------------------- 37
圖14、Cyclopiazonic acid 對健康倉鼠細胞瞬間外向鉀離子電流 ( Ito )的加強作用及 transient inward current ( Iti ) 抑制作用--38
圖15、Cyclopiazonic acid 對健康倉鼠細胞瞬間外向鉀離子電流 ( Ito )的加強作用及 transient inward current ( Iti ) 加強作用- 39

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