Heptanol和16-DSA对心脏缺血/再灌注室性心律失常及血流动力学影响的研究
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摘要
背景:室性心律失常尤其是室性心动过速(室速)、心室颤动(室颤)作为一种常见的危险性心律失常类型,它的防治手段极为重要。而以缝隙连接为靶点的抗心律失常药物可能是一个新的发展方向。缝隙连接是细胞间信息交换的直接通道,此处的电传导速度比细胞膜上其他部位都快。缝隙连接的正常分布和数量水平是维持心肌正常电传导的一个决定因素。在长期研究中发现,许多病态的心脏组织中都有缝隙连接数目及分布上的改变,称为缝隙连接的重构,这种重构使电传导的速度失去均一性,促进了折返性心律失常的发生。目前多数研究发现缝隙连接阻滞剂可以减慢细胞间传导速度,心肌局部灌流缝隙连接阻滞剂可使正常心肌发生折返性心律失常,而通过减少有害物质传递又可以减轻心肌损害,减小心肌梗塞面积,对心肌起到保护作用。但对它是否对局部心室肌缺血/再灌注诱发的快速室性心律失常有作用还未见报道。缝隙连接阻滞剂是否能对此种心律失常起作用,如果有作用,其作用机制是单纯与其阻滞缝隙连接,减慢传导有关,还是有分子生物学作用基础是我们想要进行的研究。
目的:本文主要研究缝隙连接阻滞剂Heptanol及16-DSA对于离体SD大鼠心脏的血流动力学,电生理学指标和局部缺血/再灌注导致的室性心律失常发生率的影响,以及对于CX43,DP(desmoplakin,桥粒斑蛋白),N-cadherin(N-钙粘素)三种细胞连接蛋白在分子水平上的影响,以期探索缝隙连接阻滞剂的作用,以及这种作用的可能分子基础及机制。为缺血所导致的室性心律失常的发生机制及防治办法提供实验上的依据。
方法:把Sprague-Dawley大鼠(SD大鼠)按每组12只随机分为空白组,缺血对照组,0.1mMHeptanol组,0.3mMHeptanol组,0.5mMHeptanol组,1uM16-DSA组,5uM16-DSA组和10uM16-DSA组。建立离体SD大鼠心脏Langendorff灌流模型,稳定15分钟后进行试验记录。对各组分别灌流空白Kreb-Henseleit(K-H)
Background:Ventricular arrhythmia, especially ventricular tachycardia and ventricular fibrillation, is a kind of dangerous arrhythmia. The treatment for it is important. The drugs targeting gap junctions (gj) may be a new promising approach for the prevention and treatment of ventricular arrhythmia. Gap junctions are the direct pathways to exchange signals among cardiac myocytes. The electrical conduction velocity there is faster than other place on cell membrane. The normal distribution and amount of gap junctions are the crucial factors for remaining normal conduction. In the long term research, the changes of gap junctions called gap junction remodeling have been observed in most morbid heart tissue, which seemed related with the occurrence of arrhythmias. Previous studies have demonstrated gap junction inhibitors could decrease conduction velocity, and induced reentrant arrhythmias through regional perfusing gap junction inhibitor, and decreased myocardiac infarction area by way of reducing deleterious substance among cells. But there is little report of whether it is effective to the reentrant arrhythmias induced by regional myocardiac ischemia. Whether gap junction inhibitor have effect on this kind of arrhythmia and the mechanism of it is the purpose of our research.Purpose: To study the effects of gap junction inhibitors , heptanol and 16-DSA, on the hemodynamics, electrophysiology and ventricular arrhythmias induced by regional ischemia of isolated SD rat hearts, and the effect on CX43, DP (desmoplakin) and N-cadherin, in order to explore the effect of gap junction inhibitor on ventricular arrhythmia and its mechanism.Method: All SD rats were randomized into 8 groups, including the empty control, the ischemic control, 0.1mM heptanol, 0.3mM heptanol, 0.5mM heptanol, luM16-DSA, 5uM 16-DSA and 10uM 16-DSA.There are 12 rats in each group. Heart was isolated and perfused in Langendorff mode and acute ischemia model was established by ligation of the left
anterior descending (LAD) coronary artery. Afer 15minutes' perfusion with empty KHB or the drugs above, the rat hearts were subjected to regional ischemia by ligating LAD for 30 minutes, then were reperfused again. Surface ECG, MAPD and the pressure of left ventricular were recorded. LVSP, LVEDP, dp/dtmax, MAPD90, HR, PR interval and QT interval were measured. The changes of parameters above were observed at 0min,15min,ischemic lOmin(IslOmin), Is20min and Is 30min. The number of hearts occurring ventricular arrhythmia was recorded and was evaluated. The Protein expression of CX43, DP and N-cadherin in the sections of ischemic myocardium were evaluated by immunofluorescent labeling. And the mRNA levels of three protein above were evaluated by RT-PCR. Statistical analysis: The measurement data are presented as mean plus or minus SEM. Statistical significance for differences between groups was set at P values less than 0.05 as determined by the analysis of repeated measures. Statistical comparisons of enumeration data were performed using Fisher's exact test. Differences were considered significant when P < 0.05.Results: Analyse the data of the percentage of ventricular arrhythmia induced by myocardial ischemia, we found heptanol could decrease the percentage of ventricular arrhythmia, (Ischemia control group, 45%; O.lmM group, 10%; 0.3mM group, 0%; 0.5mM group, 0%; P<0.05). 16-DSA had the same effect. (Ischemia control group, 45%; luM group,0%; 5uM group, 0%; lOuM group, 11%; P<0.05)And heptanol could decrease the percentage of ventricular arrhythmia induced by reperfusion. (Ischemia control group,100%; O.lmM group, 56%; 0.3mM group, 50%; 0.5mM group, 44%; P<0.05). 16-DSA had the same effect (Ischemia control group,100%; luMgroup,50%; 5uM group, 40%; lOuM group, 44%; P<0.05)LVSP and dpmax/dt were significant lower and LVEDP was significant higher in ischemia group than in empty control group; Both QT interval and MAPD90 were shortened and PR interval was prolonged in ischemia group significantly. There was no significant change on heart rate.Compared with the control, 16-DSA and heptanol in high and moderate concentrate decreased dp/dtmax and LVSP, but had no effect on LVEDP. They also decreased
heart rates, prolonged PR interval and QT interval .But there was no significant different among interferential groups.Both heptanol and 16-DSA could decrease heart rate in regional ischemic hearts. The PR interval in each drug treated groups was longer than in ischemic control group. There was significant difference in 0.5mM heptanol group and in 5uM 16-DSA group especially(P<0.05). The effect of the former was more strong than other drug treated groups and control group.(P<0.05)In the regional ischemic hearts, QT interval was shortened first and then was prolonged by heptanol and 16-DSA. Compared with ischemic control group, they prolonged QT interval at any repeated measure points, especially in 0.5mM heptanol group(P=0.053) and in 5uM and lOuM 16-DSA group.(P<0.05) And there was no significant change among drug treated groups.Both heptanol and 16-DSA couldn not affect LVSP ,LVEDP and dp/dtmax of ischemic hearts.Transmission electron microscopy revealed that in ischemic myocardium, the myocytes were swelling, the orientation of myofibrils was irregular,and there were some local necrosis and dissolution. Mitochondria were sweeling. Heptanol and 16-DSA could lessen the damage of myocardium induced by ischemia.The area of CX43 protein evaluated by immunofluorescence microscopy in ischemic myocardium was lower than in normal myocardium immunofluorescent labeling. Heptanol and 16-DSA could reverse this change induced by ischemia, (empty group, 1706 ±397; ischemic group, 561 + 147;0.1mM group, 1027 ± 215; 0.3mM group, 1112 + 301;0.5mM group, 1179±425;luM group, 1037±251;5uM group, 1201 +205;10uM group, 1131 ±236; P<0.05) There was no significant difference among drug treated groups. The expression of DP and N-cadherin was not significant affected by ischemia and drugs.The result of RT-PCR revealed that the mRNA level of CX43 was lower in ischemia control group than in empty group, but heptanol and 16-DSA reversed it significantly. (CX43/ P -actin: empty group/ 0.738 + 0.093; ischemia control group
目的:本文主要研究缝隙连接阻滞剂Heptanol及16-DSA对于离体SD大鼠心脏的血流动力学,电生理学指标和局部缺血/再灌注导致的室性心律失常发生率的影响,以及对于CX43,DP(desmoplakin,桥粒斑蛋白),N-cadherin(N-钙粘素)三种细胞连接蛋白在分子水平上的影响,以期探索缝隙连接阻滞剂的作用,以及这种作用的可能分子基础及机制。为缺血所导致的室性心律失常的发生机制及防治办法提供实验上的依据。
方法:把Sprague-Dawley大鼠(SD大鼠)按每组12只随机分为空白组,缺血对照组,0.1mMHeptanol组,0.3mMHeptanol组,0.5mMHeptanol组,1uM16-DSA组,5uM16-DSA组和10uM16-DSA组。建立离体SD大鼠心脏Langendorff灌流模型,稳定15分钟后进行试验记录。对各组分别灌流空白Kreb-Henseleit(K-H)
Background:Ventricular arrhythmia, especially ventricular tachycardia and ventricular fibrillation, is a kind of dangerous arrhythmia. The treatment for it is important. The drugs targeting gap junctions (gj) may be a new promising approach for the prevention and treatment of ventricular arrhythmia. Gap junctions are the direct pathways to exchange signals among cardiac myocytes. The electrical conduction velocity there is faster than other place on cell membrane. The normal distribution and amount of gap junctions are the crucial factors for remaining normal conduction. In the long term research, the changes of gap junctions called gap junction remodeling have been observed in most morbid heart tissue, which seemed related with the occurrence of arrhythmias. Previous studies have demonstrated gap junction inhibitors could decrease conduction velocity, and induced reentrant arrhythmias through regional perfusing gap junction inhibitor, and decreased myocardiac infarction area by way of reducing deleterious substance among cells. But there is little report of whether it is effective to the reentrant arrhythmias induced by regional myocardiac ischemia. Whether gap junction inhibitor have effect on this kind of arrhythmia and the mechanism of it is the purpose of our research.Purpose: To study the effects of gap junction inhibitors , heptanol and 16-DSA, on the hemodynamics, electrophysiology and ventricular arrhythmias induced by regional ischemia of isolated SD rat hearts, and the effect on CX43, DP (desmoplakin) and N-cadherin, in order to explore the effect of gap junction inhibitor on ventricular arrhythmia and its mechanism.Method: All SD rats were randomized into 8 groups, including the empty control, the ischemic control, 0.1mM heptanol, 0.3mM heptanol, 0.5mM heptanol, luM16-DSA, 5uM 16-DSA and 10uM 16-DSA.There are 12 rats in each group. Heart was isolated and perfused in Langendorff mode and acute ischemia model was established by ligation of the left
anterior descending (LAD) coronary artery. Afer 15minutes' perfusion with empty KHB or the drugs above, the rat hearts were subjected to regional ischemia by ligating LAD for 30 minutes, then were reperfused again. Surface ECG, MAPD and the pressure of left ventricular were recorded. LVSP, LVEDP, dp/dtmax, MAPD90, HR, PR interval and QT interval were measured. The changes of parameters above were observed at 0min,15min,ischemic lOmin(IslOmin), Is20min and Is 30min. The number of hearts occurring ventricular arrhythmia was recorded and was evaluated. The Protein expression of CX43, DP and N-cadherin in the sections of ischemic myocardium were evaluated by immunofluorescent labeling. And the mRNA levels of three protein above were evaluated by RT-PCR. Statistical analysis: The measurement data are presented as mean plus or minus SEM. Statistical significance for differences between groups was set at P values less than 0.05 as determined by the analysis of repeated measures. Statistical comparisons of enumeration data were performed using Fisher's exact test. Differences were considered significant when P < 0.05.Results: Analyse the data of the percentage of ventricular arrhythmia induced by myocardial ischemia, we found heptanol could decrease the percentage of ventricular arrhythmia, (Ischemia control group, 45%; O.lmM group, 10%; 0.3mM group, 0%; 0.5mM group, 0%; P<0.05). 16-DSA had the same effect. (Ischemia control group, 45%; luM group,0%; 5uM group, 0%; lOuM group, 11%; P<0.05)And heptanol could decrease the percentage of ventricular arrhythmia induced by reperfusion. (Ischemia control group,100%; O.lmM group, 56%; 0.3mM group, 50%; 0.5mM group, 44%; P<0.05). 16-DSA had the same effect (Ischemia control group,100%; luMgroup,50%; 5uM group, 40%; lOuM group, 44%; P<0.05)LVSP and dpmax/dt were significant lower and LVEDP was significant higher in ischemia group than in empty control group; Both QT interval and MAPD90 were shortened and PR interval was prolonged in ischemia group significantly. There was no significant change on heart rate.Compared with the control, 16-DSA and heptanol in high and moderate concentrate decreased dp/dtmax and LVSP, but had no effect on LVEDP. They also decreased
heart rates, prolonged PR interval and QT interval .But there was no significant different among interferential groups.Both heptanol and 16-DSA could decrease heart rate in regional ischemic hearts. The PR interval in each drug treated groups was longer than in ischemic control group. There was significant difference in 0.5mM heptanol group and in 5uM 16-DSA group especially(P<0.05). The effect of the former was more strong than other drug treated groups and control group.(P<0.05)In the regional ischemic hearts, QT interval was shortened first and then was prolonged by heptanol and 16-DSA. Compared with ischemic control group, they prolonged QT interval at any repeated measure points, especially in 0.5mM heptanol group(P=0.053) and in 5uM and lOuM 16-DSA group.(P<0.05) And there was no significant change among drug treated groups.Both heptanol and 16-DSA couldn not affect LVSP ,LVEDP and dp/dtmax of ischemic hearts.Transmission electron microscopy revealed that in ischemic myocardium, the myocytes were swelling, the orientation of myofibrils was irregular,and there were some local necrosis and dissolution. Mitochondria were sweeling. Heptanol and 16-DSA could lessen the damage of myocardium induced by ischemia.The area of CX43 protein evaluated by immunofluorescence microscopy in ischemic myocardium was lower than in normal myocardium immunofluorescent labeling. Heptanol and 16-DSA could reverse this change induced by ischemia, (empty group, 1706 ±397; ischemic group, 561 + 147;0.1mM group, 1027 ± 215; 0.3mM group, 1112 + 301;0.5mM group, 1179±425;luM group, 1037±251;5uM group, 1201 +205;10uM group, 1131 ±236; P<0.05) There was no significant difference among drug treated groups. The expression of DP and N-cadherin was not significant affected by ischemia and drugs.The result of RT-PCR revealed that the mRNA level of CX43 was lower in ischemia control group than in empty group, but heptanol and 16-DSA reversed it significantly. (CX43/ P -actin: empty group/ 0.738 + 0.093; ischemia control group
引文
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