异氟烷对兔阿霉素心肌损伤QT间期影响的研究
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摘要
目的研究异氟烷对兔阿霉素心肌损伤QT间期的影响,并探讨其机制。方法选择12～14周龄健康日本大耳白雌兔24只,体重2.00～2.30kg。随机分为4组(n=6)：对照组(C组)、异氟烷组(Ⅰ组)、阿霉素组(A组)和阿霉素异氟烷组(AⅠ组)。A组和AⅠ组经兔耳缘静脉注射阿霉素2mg/kg×1次／周×4周,建立阿霉素早期心肌毒性模型。C组和Ⅰ组注射等量生理盐水,方法同前。随之Ⅰ组和AⅠ组进行异氟烷麻醉,并分别于阿霉素心肌毒性模型建立前(T1)、模型建立后异氟烷麻醉前(T2)和异氟烷麻醉后30min (T3)描记心电图,测量QT间期及RR间期,并计算校正后的QT间期(QTc)及校正后的QT离散度(QTcd)；同时,抽取静脉血测血清乳酸脱氢酶(LDH)、丙二醛(MDA)和超氧化物歧化酶(SOD)含量；C组和A组只在T1、T2时间点测量上述指标。4组兔均于T3后快速断头处死,开胸切取左室心肌组织,在透射电镜下行心肌超微结构观察及用FITC标记抗Cx43的免疫荧光组化法染色,在激光共聚焦显微镜下分析心肌Cx43(间隙连接蛋白43)的荧光斑面积。结果(1)QTc及QTcd的变化：与C组T1比较,Ⅰ组T3和A组T2时QTc延长和QTcd增加(P<0.05)；与Ⅰ组T3和A组T2比较,AⅠ组T3时QTc进一步延长,QTcd进一步增加(P<0.05)。(2)LDH的变化：与C组T1比较,Ⅰ组T3时LDH含量无明显变化(P>0.05),A组T2和AⅠ组T3时LDH含量明显增加(P<0.05)；与A组T2比较,AⅠ组T3时LDH含量无明显变化(P＞0.05)。(3) MDA的变化：与LDH的变化一致。(4)SOD的变化：与C组T1比较,Ⅰ组T3时SOD含量无明显变化(P>0.05),A组T2和AⅠ组T3时SOD含量明显减少(P<0.05)；与A组T2比较,AⅠ组T3时SOD含量无明显变化(P＞0.05)。(5) Cx43的变化：与C组比较,Ⅰ组Cx43荧光斑面积无明显变化(P>0.05),A组和AⅠ组Cx43荧光斑面积减小(P<0.05)；与A组比较,AⅠ组Cx43荧光斑面积无明显变化(P>0.05)。(6)透射电镜心肌超微结构：C组和Ⅰ组,肌丝排列整齐,肌节清晰；闰盘结构完整清晰,可见桥粒、粘着斑和侧-侧间隙连接；线粒体呈匀质样,嵴排列整齐。A组和AⅠ组,心肌纤维排列连续,肌节长短不一；闰盘结构部分模糊,侧-侧间隙连接增多,间隙略增宽；线粒体轻度水肿。结论(1)阿霉素和异氟烷分别可延长和增大兔的QTc和QTcd。(2)阿霉素可导致兔左室心肌Cx43表达量的减少和分布的紊乱。提示Cx43参与了阿霉素对QT间期影响的机制。(3)异氟烷麻醉可进一步延长和增大阿霉素心肌损伤兔的QTc和QTcd,其机制可能还是主要与异氟烷影响心肌细胞膜上的离子通道功能有关。两药共同作用可增加室性心律失常发生的几率。
Objective To investigate the effects of isoflurane on QT interval in rabbits with myocardial injury induced by adriamycin and explore its mechanism. Methods Twenty-four 12-14 week-old healthy female Japanese white ear rabbits, weight 2.00-2.30kg, were randomly divided into 4 groups (n=6):control group (group C), isoflurane group (groupⅠ), adriamycin group (group A) and adriamycin isoflurane group (Group AI). To establish the models of primitive adriamycin cardiotoxicity as follows:group A and AI were injected with adriamycin via auricular vein of ears by 2mg/kg×1time/week×4weeks. In the same way, group C and I were injected with equivalent NS. Group I and AI were anesthetized by isoflurane. QT interval and RR interval were recorded and QTc interval (QTc) and QTc dispersion (QTcd) were calculated respectively before the establishment of the models of adriamycin cardiotoxicity (T1), before anesthesia (T2) and 30 min after anesthesia (T3) in group I and AI. At the same time, blood samples were taken in vein to measure the content of lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD). The above indexes were measured in group C and A only at T1, T2. The left ventricular myocardium was cut by thoracotomy under rapid sacrifice in 4 groups after T3. Then the Cx43 (connexin 43) fluorescent plaque area was analyzed by immunofluorescence under Laser scanning confocal microscope and the myocardial ultrastructure was observed under transmission electron microscope. Results (1) QTc and QTcd changes: Compared with group C at T1, QTc was extended and QTcd was increased in group I at T3 and group A at T2 (P＜0.05); compared with group I at T3 and group A at T2, QTc and QTcd were further extended in group AI at T3 (P＜0.05). (2) LDH changes:Compared with group C at T1, no significant change in LDH level was observed in group I at T3 (P＞0.05), while LDH was significantly increased in group A at T2 and group AI at T3 (P＜0.05); compared with group A at T2, there was no obvious change of LDH in group AI at T3 (P＞0.05). (3) MDA changes:The changes of MDA were consistent with those of LDH. (4) SOD changes:Compared with group C at T1, the statistical results showed no significant change of SOD in group I at T3 (P＞0.05), but SOD was significantly reduced in group A at T2 and group AI at T3 (P＜0.05); compared with group A at T2, there was no obvious change of SOD in group AI at T3 (P＞0.05). (5) Cx43 changes:Compared with group C, no significant change of Cx43 fluorescenc plaque area was observed in group I (P＞0.05), however, the size decreased in group A and AI (P＜0.05); compared with group A, the size unchanged in group AI (P＞0.05). (6) Myocardial ultrastructure under the Transmission Electron Microscopy:In group C and I, myofilaments was aligned, sarcomere was clear; intercalated disc was integral and clear, desmosomes, focal adhesions and side-side of the gap junction were visible; mitochondria showed a homogeneous sample, neat crest. In group A and AI, myocardial fiber arranged in a consecutive row; part of intercalated disc structure was fuzzy, side-side of the gap junctions increased and the gap slightly widened; the mitochondria were mild swelling.
Conclusion (1) QTc and QTcd of rabbits can be extended and increased by isoflurane or adriamycin. (2) Adriamycin may lead to the reduction and disorder distribution of Cx43 in the left ventricular myocardium of rabbits. Therefore, Cx43 is involved in the mechanism of QT interval affected by adriamycin. (3) QTc and QTcd of rabbits with myocardial injury induced by adriamycin can be further extended and increased by isoflurane anesthesia. the mechanism of which may have relations with the function of the ion channel on myocardial cell membrane, and isoflurane can increase the probability of arrhythmia of rabbits with myocardial injury induced by adriamycin.
Objective To investigate the effects of isoflurane on QT interval in rabbits with myocardial injury induced by adriamycin and explore its mechanism. Methods Twenty-four 12-14 week-old healthy female Japanese white ear rabbits, weight 2.00-2.30kg, were randomly divided into 4 groups (n=6):control group (group C), isoflurane group (groupⅠ), adriamycin group (group A) and adriamycin isoflurane group (Group AI). To establish the models of primitive adriamycin cardiotoxicity as follows:group A and AI were injected with adriamycin via auricular vein of ears by 2mg/kg×1time/week×4weeks. In the same way, group C and I were injected with equivalent NS. Group I and AI were anesthetized by isoflurane. QT interval and RR interval were recorded and QTc interval (QTc) and QTc dispersion (QTcd) were calculated respectively before the establishment of the models of adriamycin cardiotoxicity (T1), before anesthesia (T2) and 30 min after anesthesia (T3) in group I and AI. At the same time, blood samples were taken in vein to measure the content of lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD). The above indexes were measured in group C and A only at T1, T2. The left ventricular myocardium was cut by thoracotomy under rapid sacrifice in 4 groups after T3. Then the Cx43 (connexin 43) fluorescent plaque area was analyzed by immunofluorescence under Laser scanning confocal microscope and the myocardial ultrastructure was observed under transmission electron microscope. Results (1) QTc and QTcd changes: Compared with group C at T1, QTc was extended and QTcd was increased in group I at T3 and group A at T2 (P＜0.05); compared with group I at T3 and group A at T2, QTc and QTcd were further extended in group AI at T3 (P＜0.05). (2) LDH changes:Compared with group C at T1, no significant change in LDH level was observed in group I at T3 (P＞0.05), while LDH was significantly increased in group A at T2 and group AI at T3 (P＜0.05); compared with group A at T2, there was no obvious change of LDH in group AI at T3 (P＞0.05). (3) MDA changes:The changes of MDA were consistent with those of LDH. (4) SOD changes:Compared with group C at T1, the statistical results showed no significant change of SOD in group I at T3 (P＞0.05), but SOD was significantly reduced in group A at T2 and group AI at T3 (P＜0.05); compared with group A at T2, there was no obvious change of SOD in group AI at T3 (P＞0.05). (5) Cx43 changes:Compared with group C, no significant change of Cx43 fluorescenc plaque area was observed in group I (P＞0.05), however, the size decreased in group A and AI (P＜0.05); compared with group A, the size unchanged in group AI (P＞0.05). (6) Myocardial ultrastructure under the Transmission Electron Microscopy:In group C and I, myofilaments was aligned, sarcomere was clear; intercalated disc was integral and clear, desmosomes, focal adhesions and side-side of the gap junction were visible; mitochondria showed a homogeneous sample, neat crest. In group A and AI, myocardial fiber arranged in a consecutive row; part of intercalated disc structure was fuzzy, side-side of the gap junctions increased and the gap slightly widened; the mitochondria were mild swelling.
Conclusion (1) QTc and QTcd of rabbits can be extended and increased by isoflurane or adriamycin. (2) Adriamycin may lead to the reduction and disorder distribution of Cx43 in the left ventricular myocardium of rabbits. Therefore, Cx43 is involved in the mechanism of QT interval affected by adriamycin. (3) QTc and QTcd of rabbits with myocardial injury induced by adriamycin can be further extended and increased by isoflurane anesthesia. the mechanism of which may have relations with the function of the ion channel on myocardial cell membrane, and isoflurane can increase the probability of arrhythmia of rabbits with myocardial injury induced by adriamycin.
引文
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