本文選題：川芎嗪 + 川芎嗪硝酮衍生物��； 參考：《武漢科技大學(xué)》2015年碩士論文

【摘要】：目的：探討川芎嗪（Ligustrazine，TMP）及其硝酮衍生物（TBN）對超極化激活環(huán)核苷酸門控陽離子通道（hyperpolarization-activated cyclic nucleotide-gatedcation channel，HCN）基因家族亞型HCN4參與編碼的超極化激活的陽離子通道電流（If）和家兔竇房結(jié)細胞動作電位的影響。 方法：利用標準的雙極電壓鉗和標準玻璃微電極技術(shù)記錄表達在非洲爪蟾卵母細胞上的HCN4通道電流以及家兔竇房結(jié)動作電位。 結(jié)果：正常表達在卵母細胞上的HCN4通道電流，給予1μM、10μM、100μM川芎嗪（TMP）后，以濃度依賴性方式阻斷HCN4參與編碼的If電流，其半數(shù)最大效應(yīng)濃度[IC50]為48.79±3.1μmol/L，希爾系數(shù)為1.01±0.3。另一組實驗中，1μM、10μM、100μM TBN同樣以濃度依賴性方式減小If電流，其[IC50]值為17.20±1.1μmol/L，希爾系數(shù)為1.01±0.4。此外，在家兔竇房結(jié)動作電位實驗中，100μMTMP使家兔竇房結(jié)細胞動作電位（Action potential, AP）4期自動去極化速率（phase-4spontaneous depolarization rate，DDR）由正常的19.53±1.2mV/s減小到13.79±1.0mV/s，而100μM TBN可使DDR從正常的21.16±1.4mV/s減少到7.10±1.9mV/s。為了進一步證實TBN強大的抗氧化作用，我們在竇房結(jié)AP實驗中預(yù)先給予100μM過氧化氫（H2O2）灌流，然后分別加入100μM TMP和100μM TBN以觀察其作用效果。結(jié)果顯示：100μM H2O2明顯加快竇房結(jié)4期DDR，，從正常的20.98±1.28mV/s和21.66±1.1mV/s增加到33.24±2.3mV/s和35.71±2.1mV/s（n=6，P0.01versus Control）。給予100μM TMP后，4期DDR從33.24±2.3mV/s降低到23.57±2.44mV/s（n=6，P0.01versus H2O2）；而100μM TBN明顯減小H2O2誘導(dǎo)增大的4期DDR（35.71±2.1mV/s to12.27±2.23mV/s，n=6，P0.01versus H2O2）。 結(jié)論：①TMP及TBN對表達在卵母細胞上HCN4參與編碼的超極化激活的陽離子通道電流（If）和家兔竇房結(jié)AP DDR均有明顯的抑制作用；②還可降低H2O2誘導(dǎo)增大的竇房結(jié)細胞4期DDR；③TBN的上述阻斷效果明顯強于母核結(jié)構(gòu)TMP；④TBN明顯抑制H2O2所致的竇性心律失常。以上實驗結(jié)果提示TMP和TBN可能對原發(fā)性竇性心動過速或病理條件下誘發(fā)的竇房結(jié)性快速性心律失常有一定的臨床參考價值。
[Abstract]:Aim: to investigate the effects of ligustrazine (TMP) and its nitrate derivatives on hyperpolarization-activated cyclic nucleotide gated cationic channel (hyperpolarization-activated cyclic nucleotide-gatedcation channel HCN) gene family subtype HCN4 encoded by hyperpolarization-activated cationic channel current (if) and sinoatrial node in rabbits. The effect of cellular action potential. Methods: standard bipolar voltage clamp and standard glass microelectrode technique were used to record the HCN4 channel currents expressed on Xenopus laevis oocytes and the action potential of sinoatrial node in rabbits. Results: the normal HCN4 channel current expressed on oocytes was treated with 1 渭 M 10 渭 M 10 渭 M tetramethylpyrazine (TMP), and HCN4 encoded if current was blocked in a concentration-dependent manner. The IC50 of HCN4 was 48.79 鹵3.1 渭 mol / L and the Hill coefficient was 1.01 鹵0.3. In another group of experiments, 1 渭 MN 10 渭 M 10 渭 M TBN also reduced the if current in a concentration-dependent manner. Its [IC50] value was 17.20 鹵1.1 渭 mol / L, and the Hill coefficient was 1.01 鹵0.4. In addition, in the rabbit sinoatrial node action potential experiment, the phase-4spontaneous depolarization rate of (Action potential, AP decreased from 19.53 鹵1.2 MV / s to 13.79 鹵1.0 MV / s, while 100 渭 M TBN decreased DDR from 21.16 鹵1.4 MV / s to 7.10 鹵1.9 MV / s. In order to further confirm the strong antioxidation effect of TBN, 100 渭 M hydrogen peroxide (H _ 2O _ 2) was preperfused in sinoatrial node AP experiment, and then 100 渭 M TMP and 100 渭 M TBN were added to observe its effect. The results showed that 1: 100 渭 M H 2O 2 significantly increased DDR4 from normal 20.98 鹵1.28 MV / s and 21.66 鹵1.1 MV / s to 33.24 鹵2.3 MV / s and 35.71 鹵2.1 MV / s (n ~ (6) P 0.01versus control). After 100 渭 M TMP, the DDR decreased from 33.24 鹵2.3 MV / s to 23.57 鹵2.44 MV / s (n ~ (6) P _ (0.01) vs H _ 2O _ 2), while 100 渭 M TBN significantly decreased the increase of H2O2 induced DDR (35.71 鹵2.1 MV / s to12.27 鹵2.23 MV / s ~ (6) P _ (0.01versus) H _ 2O _ 2). Conclusion both TMP and TBN can inhibit HCN4 encoded hyperpolarization-activated cationic channel current (if) in oocytes and rabbit sinoatrial node AP DDR significantly. 3The blocking effect of TBN was significantly stronger than that of TMP4 TBN in inhibiting sinus arrhythmias induced by H _ 2O _ 2. These results suggest that TMP and TBN may have some clinical reference value in sinoatrial node tachyarrhythmia induced by primary sinus tachycardia or pathological conditions.
【學(xué)位授予單位】：武漢科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R54

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