辛伐他汀及山莨菪碱对兔心肌缺血再灌注后心律失常的防治作用及心肌细胞电重构的逆转效应研究
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摘要
经皮冠状动脉介入治疗(PCI)技术,是急性心肌梗死治疗史上里程碑式的进步,然而随之带来的再灌注损伤直接影响到患者的预后。心肌缺血后发生再灌注可产生再灌注心律失常,特别是室速、室颤是导致心源性猝死的主要危险因素,约占心血管死亡事件的50%左右。但关于再灌注心律失常发生的细胞学离子机制以及如何预防发生,研究尚少。急性心肌梗死后梗死及其边缘区缺血心肌细胞可发生一系列电生理变化,形成电重构,为心律失常发生的细胞学基质[2]。所以阻断或逆转这种电重构的形成,应当成为临床治疗心律失常的一个新的重要靶点。
他汀类药物,3-羟基-3甲基戊二酰辅酶A(HMG-Co A)抑制剂,不仅能降低血脂水平,而且有独立于降脂作用之外的其它有益作用,称之为他汀的多效性。动物实验及临床研究,证实,他汀类药物预处理可明显降低缺血再灌注心律失常的发生率。所以,研究他汀类药物的抗心律失常效应具有重要的临床意义,但其抗心律失常作用的机理仍不明确。目前从离子通道水平研究他汀类药物的抗心律失常的细胞学离子机制作用国内外尚未见报道。
山莨菪碱(Anisodamine)为我国从茄科植物唐古特莨菪中分离出的一种生物碱,具有改善微循环、减轻缺血/再灌注损伤的作用,临床上也发现山莨菪碱可减少各种心律失常的发生,但是山莨菪碱药物预处理是否可降低缺血再灌注心律失常的发生率,尚无研究报道,其抗心律失常作用的机理仍不明确。
本文建立兔心肌缺血再灌注动物模型,研究辛伐他汀和山莨菪碱预处理对缺血再灌注期间心律失常的防治作用。采用全细胞膜片钳技术,记录缺血再灌注后兔心室肌细胞跨膜钠离子通道电流(sodium current ,INa)、L-钙通道电流(L-type calcium current, ICa-L)及瞬间外向钾通道电流(outward potassium current ,Ito)的变化,研究辛伐他汀和山莨菪碱预处理对兔心肌缺血再灌注动物模型心室肌细胞电重构的逆转效应,探讨他汀类药物和山莨菪碱抗心律失常的细胞学离子机制。
本研究的内容分为以下四个部分:
第一部分:辛伐他汀对血脂正常兔心肌缺血再灌注后心律失常的防治作用及电重构的逆转保护效应
目的:已往研究发现他汀类药物可明显降低心律失常的发生率,但机理不明。本文建立兔心肌缺血再灌注动物模型,研究辛伐他汀预处理对缺血再灌注期间心律失常的防治作用,并采用全细胞膜片钳技术,记录缺血再灌注后兔心室肌细胞INa、ICa-L及Ito的变化,研究辛伐他汀预处理对兔心肌缺血再灌注动物模型的电重构的逆转效应,探讨他汀类药物抗心律失常的细胞学离子机制。
方法:45只新西兰大耳白兔随机分为3组:缺血再灌注动物模型组(I-R组,结扎冠脉左前降支30min后再开放120min);辛伐他汀治疗组(他汀组,手术前给予辛伐他汀3天5 mg·kg-1·d-1);假手术对照组(只开胸不结扎血管)。观察缺血再灌注期间室性心律失常(室早、室速和室颤)的发生率及持续时间。采用酶解的方法分离缺血部位心室肌外膜单个心室肌细胞,采用全细胞膜片钳技术,记录跨膜钠离子通道电流(INa)、L-钙通道电流(ICa-L)及瞬间外向钾通道电流(Ito),同时检测各组血脂水平。
结果:①血脂:各组动物血脂水平无显著差异。②心律失常的发生率:与I-R组比较,他汀组兔室速、室颤发生率及持续时间明显下降,其心律失常的评分明显低于I-R组(2.3±0.6 VS 3.6±0.8,P<0.05)。③INa:对照组、I-R组、他汀组INa电流密度峰值(-30mV)分别为–42.78±5.48 (n=16),–22.46±5.32 (n=12),–40.66±5.89 pA/pF (n=15),I-R组较对照组明显下降(P<0.01),他汀组较I-R组明显升高(P<0.01)。④ICa-L:对照组、I-R组、他汀组ICa-L电流密度峰值(0mV)分别为–3.13±1.22 pA/pF(n= 13),–4.34±0.92(n=15),–3.46±0.85 pA/pF(n= 16),I-R组较对照组明显升高(P<0.05),他汀组较I-R组明显下降(P<0.05)。⑤Ito:对照组、I-R组、他汀组Ito电流密度峰值(+60mV)分别为17.41±3.13 (n=15), 9.49±1.91 (n=11), 15.24±2.41 pA/pF (n=11) ,I-R组较对照组明显下降(P<0.01);他汀组较I-R组明显升高(P<0.01),但他汀组仍明显小于对照组(P<0.05)。
结论:①辛伐他汀可增加心肌细胞膜稳定性,显著减少缺血再灌注期间室性心律失常的发生率。②缺血再灌注可导致缺血心肌细胞INa和Ito明显下降,ICa-L.明显增加,形成电重构,可引起心肌细胞动作电位延长,并且不同区域之间存在电生理异质性,为再灌注心律失常发生的机制。③辛伐他汀预处理可减轻这些离子通道的异常变化,逆转电重构,而不依赖于其降血脂效应,可能为他汀类药物降低心律失常发生率的细胞学离子机制。所以,阻断或逆转异常电重构的形成,应当成为临床治疗心律失常的一个新的重要靶点。并且本研究扩展了他汀类药物的多效性。
第二部分辛伐他汀对血脂正常兔急性心肌梗死再灌注后梗死面积的影响
目的:探讨辛伐他汀预处理对急性心肌梗死后再灌注后心肌梗死范围的影响及其作用机制。
方法:采用结扎冠状动脉左前降支3 h后再开放60 min的方法建立兔急性心肌梗死再灌注模型, 20只兔随机分为4组:A组:急性心肌梗死再灌注组;B组:辛伐他汀+急性心肌梗死再灌注组;C组:格列苯脲+急性心肌梗死再灌注组;D组:格列苯脲+辛伐他汀+急性心肌梗死再灌注组。再灌注结束后测定各组血清CK-MB活性,并于再灌注结束后,再次原位结扎LAD阻断冠状动脉血流,注射20%伊文氏蓝20 ml进入左心室进行心肌染色,蓝染区为正常心肌,非蓝染区为缺血心肌。心室肌沿心脏纵轴切成约2 mm的薄片,置于1% TTC磷酸缓冲液内孵育20 min进行染色,并用10%甲醛溶液固定24 h,以确定梗死组织,白色为梗死心肌,计算心肌梗死面积。。
结果:B组CK-MB活性较A组和C组显著减少(P<0.01), C组与A组相似(P>0.05),D组较A组显著减小(P<0.05),但仍明显高于B组(P<0.05)。各组间心肌缺血范围(AAR/LV)无明显统计学差异(P>0.05),即四组心肌缺血危险程度相似。B组心肌梗死范围为(23.6±2.8%),较A组(43.6±4.6%)显著减少(P<0.01), C组心肌梗死范围(45.1±4.5%)与A组相似(P>0.05),D组心肌梗死范围(36.8±3.4%)较A组显著减小(P<0.05),但仍明显高于B组(P<0.05)。
结论:辛伐他汀可明显减小心肌梗死面积,对急性心肌梗死再灌注损伤具有保护作用,机制可能与辛伐他汀激活ATP敏感性钾通道有关。
第三部分:山莨菪碱对正常及缺血再灌注后心室肌细胞离子通道电流的影响
目的:山莨菪碱(Anisodamine)具有改善微循环、减轻缺血/再灌注损伤的作用,临床上也发现山莨菪碱可减少各种心律失常的发生,但是山莨菪碱药物预处理是否可降低缺血再灌注心律失常的发生率,尚无研究报道,其抗心律失常作用的机理仍不明确。本文建立兔心肌缺血再灌注动物模型,研究山莨菪碱对兔正常离体心室肌细胞及在体缺血再灌注后心室肌细胞INa、ICa-L及Ito的影响,探讨山莨菪碱抗再灌注心律失常的细胞学离子机制。
方法:45只新西兰大耳白兔随机分为3组:缺血再灌注动物模型组(I-R组,结扎冠脉左前降支30min后再开放120min);山莨菪碱治疗组(Ani组,手术前1min给予动物耳缘静脉注射山莨菪碱5mg/Kg,);假手术对照组(只开胸不结扎血管)。观察缺血再灌注期间室性心律失常(室早、室速和室颤)的发生率及持续时间。采用酶解的方法分离缺血部位心室肌外膜单个心室肌细胞,采用全细胞膜片钳技术,研究不同浓度山莨菪碱对兔正常心室肌细胞INa、ICa-L及Ito的影响,并且记录在体缺血再灌注后各组动物心室肌细胞跨膜INa、ICa-L及Ito的变化。
结果:①心律失常发生率:与I-R组比较,Ani组兔室速、室颤发生率及持续时间明显下降,其心律失常的评分明显低于I-R组(2.6±0.7VS 3.6±0.8,P<0.05)。②不同浓度山莨菪碱对正常心肌细胞ICa-L、INa及Ito的影响:山莨菪碱浓度为10nmol·L - 1时,对ICa-L无明显影响(p>0.05)。山莨菪碱浓度为100和1000 nmol/ L,分别使ICa-L电流密度由(–3.13±1.22 pA/pF, n= 16)减少到(–2.15±1.02 pA/pF,n = 12 , P <0.01)和(–1.82±0.86 pA/pF,n = 10 , P < 0.01),抑制率分别为31.3%和41.8%)。山莨菪碱浓度为10 nmol/L时,对INa无明显影响(n= 16,P >0.05)。山莨菪碱浓度为100和1000 nmol/ L,分别使INa电流密度(pA/ pF)由(–42.78±5.48, n=16)减少到(–33.25±4.46 pA/pF,n = 14, P <0.01)和(–29.32±3.55 pA/pF,n = 11 , P < 0.01),抑制率分别为22.3%和31.5%。山莨菪碱浓度为10、100和1000 nmol/ L时,分别使Ito电流密度(pA/ pF)由(17.41±3.13 pA/pF,n=15)减少到(16.13±2.93 pA/pF,n=14)、(15.11±2.88 pA/pF,n=11)和(14.96±2.82 pA/pF,n=11),抑制率分别为7.3%、13.2%和14.1%,但均无统计学差异(p>0.05)。③山莨菪碱对兔在体缺血再灌注后心肌细胞离子通道电流的影响: ICa-L:对照组ICa-L电流密度峰值(0mV)为–3.13±1.22 pA/pF(n= 16),I-R组(–4.34±0.92 pA/pF,n=15)较对照组显著升高(P<0.05),Ani组(–3.25±0.79 pA/pF,n= 12)较I-R组明显下降(P<0.05)。Ani组与对照组无明显差异(P>0.05)。INa:对照组、I-R组、Ani组INa电流密度峰值(-30mV)分别为–42.78±5.48 (n=16),–22.46±5.32 (n=12),–38.89±5.24 pA/pF (n=13),I-R组较对照组明显下降(P<0.01),Ani组较I-R组明显升高(P<0.01)。Ito:对照组、I-R组、Ani组Ito电流密度(+60mV时)分别为(17.41±3.13)pA/pF(n=15)、(9.49±1.91)pA/pF (n=11)、(16.55±2.86) pA/pF (n=10),I-R组与对照组相比显著下降(P<0.01)。Ani组与I-R组相比显著升高(P<0.01),Ani组与对照组相比,无明显差异。
结论:①山莨菪碱可降低心肌缺血再灌注期间心律失常的发生率。②山莨菪碱对离体正常单个心肌细胞INa和ICa-L.具有剂量依赖性抑制作用。③心肌缺血再灌注后,其电生理特性发生改变,INa和Ito明显下降,ICa-L.明显增加,山莨菪碱预处理可减轻这些离子通道的异常变化,使下降的INa和Ito上调,增加的ICa-L.下调,恢复跨膜离子通道活性,逆转电重构。④山莨菪碱可能通过多个靶点起到综合调整作用,从而发挥抗心律失常效应,并且没有促心律失常的副作用。
第四部分:山莨菪碱对兔心肌缺血再灌注后QT间期离散度及室颤阈值的影响
目的:建立兔心肌缺血再灌注动物模型,研究山莨菪碱对兔心肌缺血再灌注后QT间期离散度(QTcd)及有效不应期(ERP)和室颤阈(VFT)的影响,探讨山莨菪碱抗心律失常的电生理机制。
方法:45只新西兰大耳白兔随机分为3组:缺血再灌注动物模型组(I-R组,结扎冠脉左前降支30min后再开放120min);山莨菪碱治疗组(Ani组,手术前1min给予动物耳缘静脉注射山莨菪碱5mg/Kg,);假手术对照组(只开胸不结扎血管)。12导联同步心电图观察各组QTcd。S1-S2程控电刺激方法测定兔ERP和VFT。
结果:①3组术前QTcd比较均无明显差异(36.3±3.5 VS 35.8±3.6 VS 36.5±3.4 ms,P>0.05)。I-R组在术后较术前QTcd明显增大(64.6±7.2 VS 35.8±3.6 ms,P<0.01)。术后I-R组较对照组QTcd也明显增大(64.6±7.2 VS 37.5±3.8 ms,P<0.01)。术后Ani组QTcd明显小于I-R组(40.3±5.3 VS 64.6±7.2 ms ,P<0.01)。②在缺血再灌注术后,I-R组ERP较对照组明显缩短(126.2±11.8 VS 154.6±13.2 ms,P<0.05)。Ani组ERP较I-R组明显延长(148.5±12.3 VS 126.2±11.8 ms,P<0.05),与对照组比较无明显差异(148.5±12.3 VS 154.6±13.2 ms,P>0.05)。③在缺血再灌注术后,I-R组VFT较对照组明显降低(0.26±0.11 VS 3.51±0.56 mJ,P<0.01)。Ani组VFT较I-R组明显增高(2.06±0.48 VS 0.26±0.11 mJ,P<0.01),但仍低于对照组(2.06±0.48 VS 3.51±0.56 mJ,P<0.05)。
结论:①缺血再灌注后QTcd明显增大,ERP明显缩短,VFT明显降低,很容易诱发室速、室颤等致命性心律失常。②山莨菪碱治疗可明显缩短QTcd,延长ERP,增加室颤阈,从而可增加心电的稳定性,减少室速、室颤等致命性心律失常的发生。
Percutaneous coronary intervention (PCI) is frequently associated with the potential ischemic-reperfusion injury. Especially, ventricular tachyarrhythmias, including ventricular tachycardia (VT) and ventricular fibrillation (VF), induced by coronary artery occlusion / reperfusion, are the major direct causes of sudden cardiac death in patients with coronary artery disease, and sudden cardiac death is a leading cause in increasing cardiovascular mortality. However, there is little information regarding the ionic mechanism and prevention of reperfusion arrhythmia. After coronary artery occlusion / reperfusion, surviving myocardium in and around the infarct zone plays an important role in arrhythmogenesis , which is thought to be strongly associated with the alterations of electrophysiological characteristics ,called as“electrical remodeling”. So preventing or reversing electrical remodeling induced by ischemia and reperfusion should also be a clinical therapeutic target.
Hydroxymethylglutary coenzyme A reductase inhibitors (statins) have been shown to have effects independent of their cholesterol- lowering effects, referred to as pleiotropic effects. It has been shown that pretreatment with statin is effective in preventing reperfusion arrhythmia after ischemia- reperfusion in the experimental model and clinical study. Therefore, it is important to investigate possible anti-arrhythmic effects of statins, but its electrophysiological mechanism is unclear.
Anisodamine is a alkaloid isolated from nightshade henbane in China. Being a M-choline receptor blocker, anisodamine have been shown by previous studies that it can improve microcirculation and protect against myocardial damage by ischemia-reperfusion. Clinical studies have also suggested that anisodamine is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear.
Based on these observations, the present study was designed to examine the effect of pretreatment with simvastatin as well as anisodamine on the changes in membrane ionic currents, including sodium channel current (INa), L-type calcium channel current (ICa-L) and transient outward potassium channel current (Ito) in left ventricular myocytes of normocholesterolemic rabbits undergoing ischemia and reperfusion, by the whole cell patch-clamp recording technique, so as to explore the ionic mechanism responsible for the anti-arrhythmic effect of statin . The study is comprised of four parts described as follows:
Part I:Cardioprotective effects of simvastatin on reversing electrical remodeling induced by myocardial ischemia-reperfusion in normocholesterolemic rabbits
Objective: Recent studies have revealed that pretreatment with statin is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear. This study was conducted to investigate the cardioprotective effects of simvastatin on reversing electrical remodeling in left ventricular myocytes of rabbit heart undergoing ischemia- reperfusion ,so as to explore the ionic mechanisms responsible for the anti-arrhythmic effect of statin .
Methods: Forty-five rabbits were randomly divided into three groups : ischemic-reperfusion group (I-R), simvastatin intervention group (Statin) and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-min ischemia by ligating left anterior descending coronary artery and 60-min reperfusion after administration of oral simvastatin (5 mg·kg-1·d-1 ) (Statin group) or placebo (I-R group) for 3 days.The incidence of ventricular arrhythmia of premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF) were observed. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infarcted region derived from the hearts in I-R , statin group and the same anatomy region in CON. Whole cell patch clamp technique was used to record membrane ionic currents, including sodium current (INa), L-type calcium current (ICa-L) and transient outward potassium current (Ito). Simultaneously, the level of serum cholesterol was examined.
Results:①The concentration of serum cholesterol: there was not significant difference in serum cholesterol concentration among three groups.②The incidence of ventricular arrhythmia: compared with I-R group, Statin decreased the incidence and duration of ventricular arrhythmia by reperfusion, resulting in significant decrease of the scores of arrhythmia(2.3±0.6 VS 3.6±0.8,P<0.05).③Effect of simvastatin on INa in rabbit ischemic myocytes: the peak INa current density (at–30 mV) was significantly decreased in I-R(–22.46±5.32 pA/pF, n=12) compared with CON (–42.78±5.48 pA/pF ,n=16 ,P<0.01) and Statin (–40.66±5.89 pA/pF,n=15 ,P<0.01), while the peak INa current density in Statin group was no different from CON( P>0.05).④Effect of simvastatin on ICa-L in rabbit ischemic myocytes: the peak ICa-L current density (at 0 mV) was significantly increased in I-R (–4.34±0.92 pA/pF, n=15) compared with CON (–3.13±1.22 pA/pF, n= 16, P<0.05) and Statin (–3.46±0.85 pA/pF, n= 16,P<0.05), while the Peak ICa-L current density in Statin was no different from CON (P>0.05).⑤Effect of simvastatin on Ito in rabbit ischemic myocytes: the Ito current density (at +60 mV) was significantly decreased in I-R (9.49±1.91 pA/pF, n=11) compared with CON (17.41±3.13 pA/pF ,n=15 ,P<0.01) and Statin (15.24±2.41 pA/pF, n=11, P<0.01), although there was slight reduction in Statin group compared with CON( P<0.05).
Conclusions: Our study showed that simvastatin has the ability to increase electrical stability of the cardiomyocytes and thereby reduce the occurrence of ventricular arrhythmia. Our study also showed that ischemia-reperfusion induced significant down-regulation of INa and Ito, and up-regulation of ICa-L, which may underlie the altered electrical activity and long abnormal transmembrane APD of the surviving ventricular myocytes, thus contributing to ventricular arrhythmias in the infarcted heart. Pretreatment with simvastatin could attenuate these changes, suggesting that simvastatin could reverse this electrical remodeling and attenuate inhomogeneity without lowering the serum cholesterol level, thus contributing to the ionic mechanism responsible for the anti-arrhythmic effect of statin. It might imply that the ionic mechanism of statin for anti-arrhythmia is a pharmacological effect independent on decreasing cholesterol. Accordingly, simvastatin, may contribute to reducing cardiovascular mortality, through its anti-arrhythmic effects. So preventing or reversing electrical remodeling induced by ischemia and reperfusion should also be a clinical therapeutic target. Our findings expand the pleiotropic spectrum of the statins’favorable effects on cardiovascular diseases.
Part II: Effects of pretreatment with simvastatin on the area of myocardial infarction in reperfusion injury rabbits after acute myocardial infarction
Objective: To investigate the effects and mechanism of the pretreatment with simvastatin on the area of myocardial infarction in reperfusion injury rabbits after acute myocardial infarction(AMI) .
Method: Twenty New Zealand white rabbits were randomly divided into four groups : group A, AMI/ reperfusion; group B, pretreated with simvastatin( 5 mg/kg) for 3 days before AMI ;group C, treated with glibenclamide (KATP channel blocker) (5mg/Kg ) before AMI, group D, treated with glibenclamide and simvastatin before AMI . Models of AMI/ reperfusion were established by 180- minute of coronary occlusion and 60- minute of reperfusion. At the end of reperfusion,the coronary artery was reoccluded ,and the risk zone was delineated with Evan’blue. Hearts were sectioned (2mm) and incubated in 1% TTC in phosphate buffer for 20 min to define white necrotic tissue when fixed in 10% formalin for 24 h, and the level of plasma creatine kinase-MB (CK-MB) was assessed and evaluated.
Result:①The content of CK-MB was significantly decreased in group B than that in group A and group C (P < 0. 01) , however, it was markedly decreased in group D than that of group A (P<0.05), and significantly increased than that of group B (P<0.05).②The risk zone sizes were similar among all the groups. The infarct size was (43.6±4.6)% in group A. Simvastatin treatment resulted in a significant limitation of infarct size in group B (23.6±2.8% VS group A, P<0.01), and the infarct size was similar in group C (45.1±4.5%) compared with that in group A (P>0.05). However, it was markedly decreased in group D (36.8±3.4%) than that of group A(P<0.05), and significantly increased than that of group B (P<0.05).
Conclusion: Simvastatin significantly reduce myocardial infarct size and the level of of plasma myocardial enzyme during AMI and reperfusion in rabbits, which has protective action against ischemia-reperfusion injury , and the activation of ATP-sensitive K channels might be involved in this protective mechanism.
Part III: Effects of anisodamine on multiple ion channels in isolated ventricular myocytes from normal and ischemia-reperfusion myocardium
Objective :Previous studies have shown that anisodamine can protect myocardium against damage by ischemia-reperfusion. Clinical studies have also suggested that anisodamine is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear. This study was conducted to investigate the cardioprotective effects of anisodamine on reversing electrical remodeling in left ventricular myocytes of rabbit heart undergoing ischemia-reperfusion , and to explore the ionic mechanism responsible for the anti-arrhythmic effect of anisodamine .
Methods: Forty-five rabbits were randomly divided into three groups : ischemic-reperfusion group (I-R), anisodamine intervention group (Ani) and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-min ischemia by ligation of the left anterior descending coronary artery and 60-min reperfusion . Ani group was injected with anisodamine at a dose of 5mg/kg via femoral vein 1 min before operation.The incidence of ventricular arrhythmia of premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF) was observed. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region derived from the hearts in I-R , Ani group and the same anatomy region in CON .Whole cell patch clamp technique was used to record membrane ionic currents, including sodium current (INa), L-type calcium current (ICa-L) and transient outward potassium current (Ito).
Results:①The incidence of ventricular arrhythmia: compared with I-R group , Ani decreased the incidence and duration of ventricular arrhythmia by reperfusion, resulting in significant decrease the scores of arrhythmia (2.6±0.7 VS 3.6±0.8,P<0.05).②Effects of anisodamine on membrane ionic currents of normal rabbit ventricular myocytes: Ani of 10 nmol/L did not affect the ICa-L, Ani of 100, 1000 nmol/ L inhibited ICa-L by 31.3% and 41.8% respectively( borh P < 0.01). Ani of 10 nmol/L did not affect the INa, Ani of 100, 1000 nmol/ L inhibited INa by 22.3% and 31.5% respectively( borh P < 0.01). Ani of 10 , 100, 1000 nmol/ L inhibited Ito by 7.3%、13.2% and 14.1% respectively(P all >0.05).③Effect of Ani on membrane ionic currents (ICa-L ,INa and Ito)of rabbit ischemic/reperfusion myocytes : ICa-L—the peak ICa-L current density(at 0 mV) was significantly increased in I-R (–4.34±0.92 pA/pF, n=15) compared with CON (–3.13±1.22 pA/pF, n= 16, P<0.05),while it was significantly decreased in Ani group (–3.25±0.79 pA/pF,n= 12) compared with I-R group(P<0.05); INa—the peak INa current density (at–30 mV) was significantly decreased in I-R(–22.46±5.32 pA/pF, n=12) compared with CON (–42.78±5.48 pA/pF ,n=16 ,P<0.01), while it was significantly increased in Ani group(–38.89±5.24 pA/pF, n=13 ) compared with I-R group(P<0.01); Ito—the Ito current density (at +60 mV) was significantly decreased in I-R(9.49±1.91 pA/pF, n=11) compared with CON (17.41±3.13 pA/pF, n=15, P<0.01), while it was significantly increased in Ani group(16.55±2.86 pA/pF,n=10) compared with I-R group (P<0.01).
Conclusions:①Anisodamine have the ability to reduce the occurrence of ventricular arrhythmia.②Anisodamine can inhibit ICa-L and INa from isolated normal cardiac myocytes in a concentration dependent manner and has calcium antagonistic effect, so as to decrease the development of reperfusion arrhythmias .③Our study also showed that ischemia- reperfusion induced significant down-regulation of INa and Ito, and up-regulation of ICa-L, while pretreatment with anisodamine could attenuate this change, suggesting that anisodamine could reverse this electrical remodeling, which may be partly responsible for its antiarrhythmia effects.
④Anisodamine , may be expected to have a wide spectrum of antiarrhythmic effects through multiple target with fewer proarrhythmic side effects.
Part IV:Influence of anisodamine on QT dispersion and ventricular fibrillation threshold in rabbits during ischemia-reperfusion
Objective: This study was conducted to investigate the influence of anisodamine on QT dispersion(QTcd),effective refractory period (ERP) and ventricular fibrillation thr eshold (VFT) in rabbits during ischemia- reperfusion , and to explore the physiological mechanism responsible for the anti-arrhythmic effect of anisodamine .
Methods: Forty-five rabbits were randomly divided into three groups : ischemic-reperfusion (I-R) group, anisodamine intervention (Ani) group and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-min ischemia by ligation of the left anterior descending coronary artery and 60-min reperfusion . Ani group was injected with anisodamine at a dose of 5mg/Kg via femoral vein 1 minute before operation.Surface 12-lead ECG was recorded before and after operation to measure the QTd. ERP and VFT were measured simultaneously using S1-S2 programmed electrical stimulation method.
Results:①There was not significant difference in QTcd among three groups before operation. After reperfusion ,QTcd was increased significantly in I-R group compared with CON (64.6±7.2 VS 37.5±3.8 ms,P<0.01), however , QTcd was decreased significantly in Ani group compared with I-R group (40.3±5.3 VS 64.6±7.2 ms ,P<0.01).②The ERP of I-R group was shortened compared with CON ( 126.2±11.8 VS 154.6±13.2 ms ,P<0.05),and it was prolonged in Ani group compared with I-R group(148.5±12.3 VS 126.2±11.8 ms,P<0.05).③VFT of I-R group was decreased compared with CON(0.26±0.11 VS 3.51±0.56 mJ , P<0.01),which increased significantly in Ani group compared with I-R group(2.06±0.48 VS 0.26±0.11 mJ,P<0.01)
Conclusions: Anisodamine could reduce rabbit’s QTcd , prolong ERP and increase VFT, suggesting that anisodamine have the ability to increase electrical stability of the cardiac muscle and reduce the occurrence of ventricular arrhythmia.
他汀类药物,3-羟基-3甲基戊二酰辅酶A(HMG-Co A)抑制剂,不仅能降低血脂水平,而且有独立于降脂作用之外的其它有益作用,称之为他汀的多效性。动物实验及临床研究,证实,他汀类药物预处理可明显降低缺血再灌注心律失常的发生率。所以,研究他汀类药物的抗心律失常效应具有重要的临床意义,但其抗心律失常作用的机理仍不明确。目前从离子通道水平研究他汀类药物的抗心律失常的细胞学离子机制作用国内外尚未见报道。
山莨菪碱(Anisodamine)为我国从茄科植物唐古特莨菪中分离出的一种生物碱,具有改善微循环、减轻缺血/再灌注损伤的作用,临床上也发现山莨菪碱可减少各种心律失常的发生,但是山莨菪碱药物预处理是否可降低缺血再灌注心律失常的发生率,尚无研究报道,其抗心律失常作用的机理仍不明确。
本文建立兔心肌缺血再灌注动物模型,研究辛伐他汀和山莨菪碱预处理对缺血再灌注期间心律失常的防治作用。采用全细胞膜片钳技术,记录缺血再灌注后兔心室肌细胞跨膜钠离子通道电流(sodium current ,INa)、L-钙通道电流(L-type calcium current, ICa-L)及瞬间外向钾通道电流(outward potassium current ,Ito)的变化,研究辛伐他汀和山莨菪碱预处理对兔心肌缺血再灌注动物模型心室肌细胞电重构的逆转效应,探讨他汀类药物和山莨菪碱抗心律失常的细胞学离子机制。
本研究的内容分为以下四个部分:
第一部分:辛伐他汀对血脂正常兔心肌缺血再灌注后心律失常的防治作用及电重构的逆转保护效应
目的:已往研究发现他汀类药物可明显降低心律失常的发生率,但机理不明。本文建立兔心肌缺血再灌注动物模型,研究辛伐他汀预处理对缺血再灌注期间心律失常的防治作用,并采用全细胞膜片钳技术,记录缺血再灌注后兔心室肌细胞INa、ICa-L及Ito的变化,研究辛伐他汀预处理对兔心肌缺血再灌注动物模型的电重构的逆转效应,探讨他汀类药物抗心律失常的细胞学离子机制。
方法:45只新西兰大耳白兔随机分为3组:缺血再灌注动物模型组(I-R组,结扎冠脉左前降支30min后再开放120min);辛伐他汀治疗组(他汀组,手术前给予辛伐他汀3天5 mg·kg-1·d-1);假手术对照组(只开胸不结扎血管)。观察缺血再灌注期间室性心律失常(室早、室速和室颤)的发生率及持续时间。采用酶解的方法分离缺血部位心室肌外膜单个心室肌细胞,采用全细胞膜片钳技术,记录跨膜钠离子通道电流(INa)、L-钙通道电流(ICa-L)及瞬间外向钾通道电流(Ito),同时检测各组血脂水平。
结果:①血脂:各组动物血脂水平无显著差异。②心律失常的发生率:与I-R组比较,他汀组兔室速、室颤发生率及持续时间明显下降,其心律失常的评分明显低于I-R组(2.3±0.6 VS 3.6±0.8,P<0.05)。③INa:对照组、I-R组、他汀组INa电流密度峰值(-30mV)分别为–42.78±5.48 (n=16),–22.46±5.32 (n=12),–40.66±5.89 pA/pF (n=15),I-R组较对照组明显下降(P<0.01),他汀组较I-R组明显升高(P<0.01)。④ICa-L:对照组、I-R组、他汀组ICa-L电流密度峰值(0mV)分别为–3.13±1.22 pA/pF(n= 13),–4.34±0.92(n=15),–3.46±0.85 pA/pF(n= 16),I-R组较对照组明显升高(P<0.05),他汀组较I-R组明显下降(P<0.05)。⑤Ito:对照组、I-R组、他汀组Ito电流密度峰值(+60mV)分别为17.41±3.13 (n=15), 9.49±1.91 (n=11), 15.24±2.41 pA/pF (n=11) ,I-R组较对照组明显下降(P<0.01);他汀组较I-R组明显升高(P<0.01),但他汀组仍明显小于对照组(P<0.05)。
结论:①辛伐他汀可增加心肌细胞膜稳定性,显著减少缺血再灌注期间室性心律失常的发生率。②缺血再灌注可导致缺血心肌细胞INa和Ito明显下降,ICa-L.明显增加,形成电重构,可引起心肌细胞动作电位延长,并且不同区域之间存在电生理异质性,为再灌注心律失常发生的机制。③辛伐他汀预处理可减轻这些离子通道的异常变化,逆转电重构,而不依赖于其降血脂效应,可能为他汀类药物降低心律失常发生率的细胞学离子机制。所以,阻断或逆转异常电重构的形成,应当成为临床治疗心律失常的一个新的重要靶点。并且本研究扩展了他汀类药物的多效性。
第二部分辛伐他汀对血脂正常兔急性心肌梗死再灌注后梗死面积的影响
目的:探讨辛伐他汀预处理对急性心肌梗死后再灌注后心肌梗死范围的影响及其作用机制。
方法:采用结扎冠状动脉左前降支3 h后再开放60 min的方法建立兔急性心肌梗死再灌注模型, 20只兔随机分为4组:A组:急性心肌梗死再灌注组;B组:辛伐他汀+急性心肌梗死再灌注组;C组:格列苯脲+急性心肌梗死再灌注组;D组:格列苯脲+辛伐他汀+急性心肌梗死再灌注组。再灌注结束后测定各组血清CK-MB活性,并于再灌注结束后,再次原位结扎LAD阻断冠状动脉血流,注射20%伊文氏蓝20 ml进入左心室进行心肌染色,蓝染区为正常心肌,非蓝染区为缺血心肌。心室肌沿心脏纵轴切成约2 mm的薄片,置于1% TTC磷酸缓冲液内孵育20 min进行染色,并用10%甲醛溶液固定24 h,以确定梗死组织,白色为梗死心肌,计算心肌梗死面积。。
结果:B组CK-MB活性较A组和C组显著减少(P<0.01), C组与A组相似(P>0.05),D组较A组显著减小(P<0.05),但仍明显高于B组(P<0.05)。各组间心肌缺血范围(AAR/LV)无明显统计学差异(P>0.05),即四组心肌缺血危险程度相似。B组心肌梗死范围为(23.6±2.8%),较A组(43.6±4.6%)显著减少(P<0.01), C组心肌梗死范围(45.1±4.5%)与A组相似(P>0.05),D组心肌梗死范围(36.8±3.4%)较A组显著减小(P<0.05),但仍明显高于B组(P<0.05)。
结论:辛伐他汀可明显减小心肌梗死面积,对急性心肌梗死再灌注损伤具有保护作用,机制可能与辛伐他汀激活ATP敏感性钾通道有关。
第三部分:山莨菪碱对正常及缺血再灌注后心室肌细胞离子通道电流的影响
目的:山莨菪碱(Anisodamine)具有改善微循环、减轻缺血/再灌注损伤的作用,临床上也发现山莨菪碱可减少各种心律失常的发生,但是山莨菪碱药物预处理是否可降低缺血再灌注心律失常的发生率,尚无研究报道,其抗心律失常作用的机理仍不明确。本文建立兔心肌缺血再灌注动物模型,研究山莨菪碱对兔正常离体心室肌细胞及在体缺血再灌注后心室肌细胞INa、ICa-L及Ito的影响,探讨山莨菪碱抗再灌注心律失常的细胞学离子机制。
方法:45只新西兰大耳白兔随机分为3组:缺血再灌注动物模型组(I-R组,结扎冠脉左前降支30min后再开放120min);山莨菪碱治疗组(Ani组,手术前1min给予动物耳缘静脉注射山莨菪碱5mg/Kg,);假手术对照组(只开胸不结扎血管)。观察缺血再灌注期间室性心律失常(室早、室速和室颤)的发生率及持续时间。采用酶解的方法分离缺血部位心室肌外膜单个心室肌细胞,采用全细胞膜片钳技术,研究不同浓度山莨菪碱对兔正常心室肌细胞INa、ICa-L及Ito的影响,并且记录在体缺血再灌注后各组动物心室肌细胞跨膜INa、ICa-L及Ito的变化。
结果:①心律失常发生率:与I-R组比较,Ani组兔室速、室颤发生率及持续时间明显下降,其心律失常的评分明显低于I-R组(2.6±0.7VS 3.6±0.8,P<0.05)。②不同浓度山莨菪碱对正常心肌细胞ICa-L、INa及Ito的影响:山莨菪碱浓度为10nmol·L - 1时,对ICa-L无明显影响(p>0.05)。山莨菪碱浓度为100和1000 nmol/ L,分别使ICa-L电流密度由(–3.13±1.22 pA/pF, n= 16)减少到(–2.15±1.02 pA/pF,n = 12 , P <0.01)和(–1.82±0.86 pA/pF,n = 10 , P < 0.01),抑制率分别为31.3%和41.8%)。山莨菪碱浓度为10 nmol/L时,对INa无明显影响(n= 16,P >0.05)。山莨菪碱浓度为100和1000 nmol/ L,分别使INa电流密度(pA/ pF)由(–42.78±5.48, n=16)减少到(–33.25±4.46 pA/pF,n = 14, P <0.01)和(–29.32±3.55 pA/pF,n = 11 , P < 0.01),抑制率分别为22.3%和31.5%。山莨菪碱浓度为10、100和1000 nmol/ L时,分别使Ito电流密度(pA/ pF)由(17.41±3.13 pA/pF,n=15)减少到(16.13±2.93 pA/pF,n=14)、(15.11±2.88 pA/pF,n=11)和(14.96±2.82 pA/pF,n=11),抑制率分别为7.3%、13.2%和14.1%,但均无统计学差异(p>0.05)。③山莨菪碱对兔在体缺血再灌注后心肌细胞离子通道电流的影响: ICa-L:对照组ICa-L电流密度峰值(0mV)为–3.13±1.22 pA/pF(n= 16),I-R组(–4.34±0.92 pA/pF,n=15)较对照组显著升高(P<0.05),Ani组(–3.25±0.79 pA/pF,n= 12)较I-R组明显下降(P<0.05)。Ani组与对照组无明显差异(P>0.05)。INa:对照组、I-R组、Ani组INa电流密度峰值(-30mV)分别为–42.78±5.48 (n=16),–22.46±5.32 (n=12),–38.89±5.24 pA/pF (n=13),I-R组较对照组明显下降(P<0.01),Ani组较I-R组明显升高(P<0.01)。Ito:对照组、I-R组、Ani组Ito电流密度(+60mV时)分别为(17.41±3.13)pA/pF(n=15)、(9.49±1.91)pA/pF (n=11)、(16.55±2.86) pA/pF (n=10),I-R组与对照组相比显著下降(P<0.01)。Ani组与I-R组相比显著升高(P<0.01),Ani组与对照组相比,无明显差异。
结论:①山莨菪碱可降低心肌缺血再灌注期间心律失常的发生率。②山莨菪碱对离体正常单个心肌细胞INa和ICa-L.具有剂量依赖性抑制作用。③心肌缺血再灌注后,其电生理特性发生改变,INa和Ito明显下降,ICa-L.明显增加,山莨菪碱预处理可减轻这些离子通道的异常变化,使下降的INa和Ito上调,增加的ICa-L.下调,恢复跨膜离子通道活性,逆转电重构。④山莨菪碱可能通过多个靶点起到综合调整作用,从而发挥抗心律失常效应,并且没有促心律失常的副作用。
第四部分:山莨菪碱对兔心肌缺血再灌注后QT间期离散度及室颤阈值的影响
目的:建立兔心肌缺血再灌注动物模型,研究山莨菪碱对兔心肌缺血再灌注后QT间期离散度(QTcd)及有效不应期(ERP)和室颤阈(VFT)的影响,探讨山莨菪碱抗心律失常的电生理机制。
方法:45只新西兰大耳白兔随机分为3组:缺血再灌注动物模型组(I-R组,结扎冠脉左前降支30min后再开放120min);山莨菪碱治疗组(Ani组,手术前1min给予动物耳缘静脉注射山莨菪碱5mg/Kg,);假手术对照组(只开胸不结扎血管)。12导联同步心电图观察各组QTcd。S1-S2程控电刺激方法测定兔ERP和VFT。
结果:①3组术前QTcd比较均无明显差异(36.3±3.5 VS 35.8±3.6 VS 36.5±3.4 ms,P>0.05)。I-R组在术后较术前QTcd明显增大(64.6±7.2 VS 35.8±3.6 ms,P<0.01)。术后I-R组较对照组QTcd也明显增大(64.6±7.2 VS 37.5±3.8 ms,P<0.01)。术后Ani组QTcd明显小于I-R组(40.3±5.3 VS 64.6±7.2 ms ,P<0.01)。②在缺血再灌注术后,I-R组ERP较对照组明显缩短(126.2±11.8 VS 154.6±13.2 ms,P<0.05)。Ani组ERP较I-R组明显延长(148.5±12.3 VS 126.2±11.8 ms,P<0.05),与对照组比较无明显差异(148.5±12.3 VS 154.6±13.2 ms,P>0.05)。③在缺血再灌注术后,I-R组VFT较对照组明显降低(0.26±0.11 VS 3.51±0.56 mJ,P<0.01)。Ani组VFT较I-R组明显增高(2.06±0.48 VS 0.26±0.11 mJ,P<0.01),但仍低于对照组(2.06±0.48 VS 3.51±0.56 mJ,P<0.05)。
结论:①缺血再灌注后QTcd明显增大,ERP明显缩短,VFT明显降低,很容易诱发室速、室颤等致命性心律失常。②山莨菪碱治疗可明显缩短QTcd,延长ERP,增加室颤阈,从而可增加心电的稳定性,减少室速、室颤等致命性心律失常的发生。
Percutaneous coronary intervention (PCI) is frequently associated with the potential ischemic-reperfusion injury. Especially, ventricular tachyarrhythmias, including ventricular tachycardia (VT) and ventricular fibrillation (VF), induced by coronary artery occlusion / reperfusion, are the major direct causes of sudden cardiac death in patients with coronary artery disease, and sudden cardiac death is a leading cause in increasing cardiovascular mortality. However, there is little information regarding the ionic mechanism and prevention of reperfusion arrhythmia. After coronary artery occlusion / reperfusion, surviving myocardium in and around the infarct zone plays an important role in arrhythmogenesis , which is thought to be strongly associated with the alterations of electrophysiological characteristics ,called as“electrical remodeling”. So preventing or reversing electrical remodeling induced by ischemia and reperfusion should also be a clinical therapeutic target.
Hydroxymethylglutary coenzyme A reductase inhibitors (statins) have been shown to have effects independent of their cholesterol- lowering effects, referred to as pleiotropic effects. It has been shown that pretreatment with statin is effective in preventing reperfusion arrhythmia after ischemia- reperfusion in the experimental model and clinical study. Therefore, it is important to investigate possible anti-arrhythmic effects of statins, but its electrophysiological mechanism is unclear.
Anisodamine is a alkaloid isolated from nightshade henbane in China. Being a M-choline receptor blocker, anisodamine have been shown by previous studies that it can improve microcirculation and protect against myocardial damage by ischemia-reperfusion. Clinical studies have also suggested that anisodamine is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear.
Based on these observations, the present study was designed to examine the effect of pretreatment with simvastatin as well as anisodamine on the changes in membrane ionic currents, including sodium channel current (INa), L-type calcium channel current (ICa-L) and transient outward potassium channel current (Ito) in left ventricular myocytes of normocholesterolemic rabbits undergoing ischemia and reperfusion, by the whole cell patch-clamp recording technique, so as to explore the ionic mechanism responsible for the anti-arrhythmic effect of statin . The study is comprised of four parts described as follows:
Part I:Cardioprotective effects of simvastatin on reversing electrical remodeling induced by myocardial ischemia-reperfusion in normocholesterolemic rabbits
Objective: Recent studies have revealed that pretreatment with statin is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear. This study was conducted to investigate the cardioprotective effects of simvastatin on reversing electrical remodeling in left ventricular myocytes of rabbit heart undergoing ischemia- reperfusion ,so as to explore the ionic mechanisms responsible for the anti-arrhythmic effect of statin .
Methods: Forty-five rabbits were randomly divided into three groups : ischemic-reperfusion group (I-R), simvastatin intervention group (Statin) and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-min ischemia by ligating left anterior descending coronary artery and 60-min reperfusion after administration of oral simvastatin (5 mg·kg-1·d-1 ) (Statin group) or placebo (I-R group) for 3 days.The incidence of ventricular arrhythmia of premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF) were observed. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infarcted region derived from the hearts in I-R , statin group and the same anatomy region in CON. Whole cell patch clamp technique was used to record membrane ionic currents, including sodium current (INa), L-type calcium current (ICa-L) and transient outward potassium current (Ito). Simultaneously, the level of serum cholesterol was examined.
Results:①The concentration of serum cholesterol: there was not significant difference in serum cholesterol concentration among three groups.②The incidence of ventricular arrhythmia: compared with I-R group, Statin decreased the incidence and duration of ventricular arrhythmia by reperfusion, resulting in significant decrease of the scores of arrhythmia(2.3±0.6 VS 3.6±0.8,P<0.05).③Effect of simvastatin on INa in rabbit ischemic myocytes: the peak INa current density (at–30 mV) was significantly decreased in I-R(–22.46±5.32 pA/pF, n=12) compared with CON (–42.78±5.48 pA/pF ,n=16 ,P<0.01) and Statin (–40.66±5.89 pA/pF,n=15 ,P<0.01), while the peak INa current density in Statin group was no different from CON( P>0.05).④Effect of simvastatin on ICa-L in rabbit ischemic myocytes: the peak ICa-L current density (at 0 mV) was significantly increased in I-R (–4.34±0.92 pA/pF, n=15) compared with CON (–3.13±1.22 pA/pF, n= 16, P<0.05) and Statin (–3.46±0.85 pA/pF, n= 16,P<0.05), while the Peak ICa-L current density in Statin was no different from CON (P>0.05).⑤Effect of simvastatin on Ito in rabbit ischemic myocytes: the Ito current density (at +60 mV) was significantly decreased in I-R (9.49±1.91 pA/pF, n=11) compared with CON (17.41±3.13 pA/pF ,n=15 ,P<0.01) and Statin (15.24±2.41 pA/pF, n=11, P<0.01), although there was slight reduction in Statin group compared with CON( P<0.05).
Conclusions: Our study showed that simvastatin has the ability to increase electrical stability of the cardiomyocytes and thereby reduce the occurrence of ventricular arrhythmia. Our study also showed that ischemia-reperfusion induced significant down-regulation of INa and Ito, and up-regulation of ICa-L, which may underlie the altered electrical activity and long abnormal transmembrane APD of the surviving ventricular myocytes, thus contributing to ventricular arrhythmias in the infarcted heart. Pretreatment with simvastatin could attenuate these changes, suggesting that simvastatin could reverse this electrical remodeling and attenuate inhomogeneity without lowering the serum cholesterol level, thus contributing to the ionic mechanism responsible for the anti-arrhythmic effect of statin. It might imply that the ionic mechanism of statin for anti-arrhythmia is a pharmacological effect independent on decreasing cholesterol. Accordingly, simvastatin, may contribute to reducing cardiovascular mortality, through its anti-arrhythmic effects. So preventing or reversing electrical remodeling induced by ischemia and reperfusion should also be a clinical therapeutic target. Our findings expand the pleiotropic spectrum of the statins’favorable effects on cardiovascular diseases.
Part II: Effects of pretreatment with simvastatin on the area of myocardial infarction in reperfusion injury rabbits after acute myocardial infarction
Objective: To investigate the effects and mechanism of the pretreatment with simvastatin on the area of myocardial infarction in reperfusion injury rabbits after acute myocardial infarction(AMI) .
Method: Twenty New Zealand white rabbits were randomly divided into four groups : group A, AMI/ reperfusion; group B, pretreated with simvastatin( 5 mg/kg) for 3 days before AMI ;group C, treated with glibenclamide (KATP channel blocker) (5mg/Kg ) before AMI, group D, treated with glibenclamide and simvastatin before AMI . Models of AMI/ reperfusion were established by 180- minute of coronary occlusion and 60- minute of reperfusion. At the end of reperfusion,the coronary artery was reoccluded ,and the risk zone was delineated with Evan’blue. Hearts were sectioned (2mm) and incubated in 1% TTC in phosphate buffer for 20 min to define white necrotic tissue when fixed in 10% formalin for 24 h, and the level of plasma creatine kinase-MB (CK-MB) was assessed and evaluated.
Result:①The content of CK-MB was significantly decreased in group B than that in group A and group C (P < 0. 01) , however, it was markedly decreased in group D than that of group A (P<0.05), and significantly increased than that of group B (P<0.05).②The risk zone sizes were similar among all the groups. The infarct size was (43.6±4.6)% in group A. Simvastatin treatment resulted in a significant limitation of infarct size in group B (23.6±2.8% VS group A, P<0.01), and the infarct size was similar in group C (45.1±4.5%) compared with that in group A (P>0.05). However, it was markedly decreased in group D (36.8±3.4%) than that of group A(P<0.05), and significantly increased than that of group B (P<0.05).
Conclusion: Simvastatin significantly reduce myocardial infarct size and the level of of plasma myocardial enzyme during AMI and reperfusion in rabbits, which has protective action against ischemia-reperfusion injury , and the activation of ATP-sensitive K channels might be involved in this protective mechanism.
Part III: Effects of anisodamine on multiple ion channels in isolated ventricular myocytes from normal and ischemia-reperfusion myocardium
Objective :Previous studies have shown that anisodamine can protect myocardium against damage by ischemia-reperfusion. Clinical studies have also suggested that anisodamine is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear. This study was conducted to investigate the cardioprotective effects of anisodamine on reversing electrical remodeling in left ventricular myocytes of rabbit heart undergoing ischemia-reperfusion , and to explore the ionic mechanism responsible for the anti-arrhythmic effect of anisodamine .
Methods: Forty-five rabbits were randomly divided into three groups : ischemic-reperfusion group (I-R), anisodamine intervention group (Ani) and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-min ischemia by ligation of the left anterior descending coronary artery and 60-min reperfusion . Ani group was injected with anisodamine at a dose of 5mg/kg via femoral vein 1 min before operation.The incidence of ventricular arrhythmia of premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF) was observed. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region derived from the hearts in I-R , Ani group and the same anatomy region in CON .Whole cell patch clamp technique was used to record membrane ionic currents, including sodium current (INa), L-type calcium current (ICa-L) and transient outward potassium current (Ito).
Results:①The incidence of ventricular arrhythmia: compared with I-R group , Ani decreased the incidence and duration of ventricular arrhythmia by reperfusion, resulting in significant decrease the scores of arrhythmia (2.6±0.7 VS 3.6±0.8,P<0.05).②Effects of anisodamine on membrane ionic currents of normal rabbit ventricular myocytes: Ani of 10 nmol/L did not affect the ICa-L, Ani of 100, 1000 nmol/ L inhibited ICa-L by 31.3% and 41.8% respectively( borh P < 0.01). Ani of 10 nmol/L did not affect the INa, Ani of 100, 1000 nmol/ L inhibited INa by 22.3% and 31.5% respectively( borh P < 0.01). Ani of 10 , 100, 1000 nmol/ L inhibited Ito by 7.3%、13.2% and 14.1% respectively(P all >0.05).③Effect of Ani on membrane ionic currents (ICa-L ,INa and Ito)of rabbit ischemic/reperfusion myocytes : ICa-L—the peak ICa-L current density(at 0 mV) was significantly increased in I-R (–4.34±0.92 pA/pF, n=15) compared with CON (–3.13±1.22 pA/pF, n= 16, P<0.05),while it was significantly decreased in Ani group (–3.25±0.79 pA/pF,n= 12) compared with I-R group(P<0.05); INa—the peak INa current density (at–30 mV) was significantly decreased in I-R(–22.46±5.32 pA/pF, n=12) compared with CON (–42.78±5.48 pA/pF ,n=16 ,P<0.01), while it was significantly increased in Ani group(–38.89±5.24 pA/pF, n=13 ) compared with I-R group(P<0.01); Ito—the Ito current density (at +60 mV) was significantly decreased in I-R(9.49±1.91 pA/pF, n=11) compared with CON (17.41±3.13 pA/pF, n=15, P<0.01), while it was significantly increased in Ani group(16.55±2.86 pA/pF,n=10) compared with I-R group (P<0.01).
Conclusions:①Anisodamine have the ability to reduce the occurrence of ventricular arrhythmia.②Anisodamine can inhibit ICa-L and INa from isolated normal cardiac myocytes in a concentration dependent manner and has calcium antagonistic effect, so as to decrease the development of reperfusion arrhythmias .③Our study also showed that ischemia- reperfusion induced significant down-regulation of INa and Ito, and up-regulation of ICa-L, while pretreatment with anisodamine could attenuate this change, suggesting that anisodamine could reverse this electrical remodeling, which may be partly responsible for its antiarrhythmia effects.
④Anisodamine , may be expected to have a wide spectrum of antiarrhythmic effects through multiple target with fewer proarrhythmic side effects.
Part IV:Influence of anisodamine on QT dispersion and ventricular fibrillation threshold in rabbits during ischemia-reperfusion
Objective: This study was conducted to investigate the influence of anisodamine on QT dispersion(QTcd),effective refractory period (ERP) and ventricular fibrillation thr eshold (VFT) in rabbits during ischemia- reperfusion , and to explore the physiological mechanism responsible for the anti-arrhythmic effect of anisodamine .
Methods: Forty-five rabbits were randomly divided into three groups : ischemic-reperfusion (I-R) group, anisodamine intervention (Ani) group and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-min ischemia by ligation of the left anterior descending coronary artery and 60-min reperfusion . Ani group was injected with anisodamine at a dose of 5mg/Kg via femoral vein 1 minute before operation.Surface 12-lead ECG was recorded before and after operation to measure the QTd. ERP and VFT were measured simultaneously using S1-S2 programmed electrical stimulation method.
Results:①There was not significant difference in QTcd among three groups before operation. After reperfusion ,QTcd was increased significantly in I-R group compared with CON (64.6±7.2 VS 37.5±3.8 ms,P<0.01), however , QTcd was decreased significantly in Ani group compared with I-R group (40.3±5.3 VS 64.6±7.2 ms ,P<0.01).②The ERP of I-R group was shortened compared with CON ( 126.2±11.8 VS 154.6±13.2 ms ,P<0.05),and it was prolonged in Ani group compared with I-R group(148.5±12.3 VS 126.2±11.8 ms,P<0.05).③VFT of I-R group was decreased compared with CON(0.26±0.11 VS 3.51±0.56 mJ , P<0.01),which increased significantly in Ani group compared with I-R group(2.06±0.48 VS 0.26±0.11 mJ,P<0.01)
Conclusions: Anisodamine could reduce rabbit’s QTcd , prolong ERP and increase VFT, suggesting that anisodamine have the ability to increase electrical stability of the cardiac muscle and reduce the occurrence of ventricular arrhythmia.
引文
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