扎考必利对大鼠离体心脏心功能及心律的影响

目的 观察扎考比利对大鼠离体心脏心功能和心律的影响.方法应用Langendorff离体心脏灌流装置,以不同浓度(1 μmol/L、3 μmol/L、10 μmol/L、30 μmol/L)灌流大鼠心脏,观察药物对离体心脏心功能指标及Ⅱ导心电图的变化.结果 扎考比利对大鼠离体心脏心功能及心律无明显影响.结论与西沙必利相比,扎考比利对心脏收缩功能及舒张功能均无明显作用,是一种相对安全的药物.     

心肌内向整流钾通道（IK1）激动剂缺血预处理对再灌注性心律失常的影响

目的 在麻醉大鼠或离体灌流大鼠心脏建立缺血/再灌注（再灌注）性心律失常模型,应用心肌内向整流钾通道（IK1） 激动剂zacopride（扎考比利）中文 缺血预处理观察zacopride对再灌注性心律失常的效应并分析可能的机制。方法 在体实验：结扎SD大鼠心脏冠状动脉左前降支,局部缺血15 min,松扎后再灌15 min,建立再灌注性心律失常模型。在缺血前3 min（缺血预处理,pretreatment）分别给予1.5、15 或50 µg/kg zacopride。应用利多卡因（Lidocaine）做阳性对照药,IK1非特异性阻断剂氯喹拮抗zacopride的效应。全程连续记录心电图。离体实验：麻醉SD大鼠,开胸取出心脏,建立Tyrode液-Langendorff离体灌流系统,结扎SD大鼠心脏冠状动脉左前降支,局部缺血15 min,松扎后再灌15 min,建立离体再灌注性心律失常模型。缺血前3 min分别给予0.1、1或10 µmol/L zacopride观察预处理对离体再灌注性心律失常的影响,IK1非特异性阻断剂BaCl2 1 µmol/L拮抗zacopride的效应。结果 在体实验：应用1.5~50 zacopride缺血预处理可显著抑制再灌注诱发的心律失常,最适剂量为15 µg/kg（P<0.05）,与利多卡因效应相仿（P>0.05）;离体实验：Langendorff离体灌流心脏应用0.1~10 μmol/L zacopride缺血预处理可有效抑制再灌注心律失常的发生,1 μmol/L为zacopride作用最适浓度,其效应被1 μmol/L BaCl2明显逆转。结论 大鼠在体和离体实验证明,zacopride预处理可有效抑制再灌注性心律失常;应用低剂量的BaCl2可消除zacopride的抗心律失常作用,表明zacopride抗缺血-再灌注性心律失常作用是通过其激动IK1通道介导的。     

利多卡因和普罗帕酮对离体大鼠心脏功能的影响

目的 观察在非缺血及缺血状态下,不同浓度利多卡因和普罗帕酮对离体大鼠心脏功能的影响.方法 采用Langendorff离体心脏灌流的方法,观察不同浓度利多卡因和普罗帕酮对非缺血及缺血大鼠心脏左室功能的影响.结果 非缺血组含不同浓度利多卡因、普罗帕酮的灌流液灌注大鼠心脏5 min,与基础值相比,利多卡因0.0 μg/mL、2.5 μg/mL、5.0 μg/mL、10.0 μg/mL、20.0 μg/mL使左室功能分别降低(0.5±0.1)%、(34.1±5.7)%、(38.0±7.4)%、(44.2±5.1)%和(64.7±6.0)%,普罗帕酮0.000 μmol/L、0.001 μmol/L、0.010 μmol/L、0.100 μmol/L、1.000 μmol/L使左室功能分别降低(0.5±0.1)%、(13.1±2.1)%、(23.1±2.6)%、(36.3±5.5)%和(46.4±2.5)%.缺血组含不同浓度利多卡因、普罗帕酮的缺血灌流液灌注大鼠心脏5min,与基础值相比,利多卡因0.0 μg/mL、2.5 μg/mL、5.0 μg/mL、10.0 μg/mL、20.0 μg/mL使左室功能分别降低(86.3±4.4)%、(76.6±6.7)%、(85.6±4.4)%、(92.1±1.8)%和(94.2±3.0)%,普罗帕酮0.000 μmol/L、0.001 μmol/L、0.010 μmol/L、0.100 μmol/L、1.000 μmol/L)使左室功能分别降低(86.3±4.4)%、(73.2±2.4)%、(84.0±3.1)%、(88.4±4.8)%和(90.3±0.3)%.结论 利多卡因和普罗帕酮剂量依赖性抑制非缺血大鼠心脏功能.低浓度利多卡因和普罗帕酮保护缺血大鼠心脏功能.     

KB-R7943对心力衰竭家兔哇巴因诱发心律失常的抑制作用

目的 探讨钠-钙交换体抑制剂KB-R7943对哇巴因诱发心衰家兔心律失常的影响.方法 40只成年家兔随机分为5组：假手术组、心衰对照组、哇巴因组、哇巴因合并KB-R7943（1μmol/L）组和哇巴因合并KB-R7943（5μmol/L）组.心衰组、哇巴因组、哇巴因合并KB-R7943（1 μmol/L）组和哇巴因合并K.B-R7943（5 μmol/L）组使用主动脉瓣关闭不全联合腹主动脉缩窄的方法建立心衰模型.建模8周后超声检测心功能,并利用Langendorff离体心脏灌流方法检测家兔各项离体心功能指标.灌流哇巴因（5μmol/L,4ml）诱发家兔心衰心脏产生心律失常,观察KB-R7943对离体心衰家兔心律失常的影响.结果 ①超声结果显示,与假手术组相比,心衰对照组家兔左室射血分数（LVEF）、短轴缩短率（％FS）均明显降低（P＜0.05）.②离体条件下,心衰对照组家兔离体心脏左室发展压（LVDP）、心率（HR）、室内压最大上升速率（＋dp/dtmax）、室内压最大下降速率（-dp/dtmax）较假手术组均明显下降（P＜0.05）.③哇巴因组1h内总心律失常（TT）、室速（VT）、室颤（VF）持续时间较心衰对照组明显增加（P＜0.05）.④与哇巴因组比较,哇巴因联合应用KB-R7943组1h内TT、VT、VF持续时间明显减短（P＜0.05）;与1 μmol/L KB-R7943相比,5μmol/L KB-R7943可使哇巴因诱发TT和VT时间进一步缩短（P＜0.05）.结论 钠-钙交换体抑制剂KB-R7943可抑制哇巴因诱发心衰家兔心律失常的持续时间,且较高浓度（5 μmol/L）KB-R7943对哇巴因诱发心衰家兔心律失常的抑制作用更强.     

蛋白激酶A抑制剂H-89的致心律失常效应及机制

目的观察蛋白激酶A（PKA）抑制剂H-89对大鼠心律和心肌细胞膜内向整流钾电流（Ik1）、钠钙交换体电流（INa/Ca）的影响,从而评估其药理学应用价值。方法成年sD大鼠麻醉后开胸取出心脏行Langendofff主动脉逆行灌流,记录心电图,观察-89给药20min内对离体心脏节律的影响。应用全细胞膜片钳技术观察H-89对胶原酶分解的大鼠心室肌细胞膜Ik1和INa/Ca的影响。结果1～10μmol／LH-89可在大鼠离体心脏诱发明显的心律失常,室性期前收缩（PVB）数目,室速（VT）、室颤（VF）持续时间和发生率呈浓度依赖性增高（P〈O．05）。膜片钳记录结果显示,H-89可浓度依赖性抑制I。（P〈0．05）,在5μmol／L时即可完全阻断Ik1类似于0．5mmol／L氯化钡（BaCl2）的效应。但H-89（1-10μmol／L）对INa/Ca无明显作用（P〉O．05）。结论H-89对心肌细胞膜电流的异常扰动是其致心律失常风险的主要电生理．机制,可由PKA依赖性或非PKA依赖性药理学作用共同介导。     

心钠素对内皮素心脏效应的影响

在离体大鼠心脏灌流模型上,10~(-8)mol/L内皮素灌流导致平均灌流压和心室内压显著升高,±LVdp/dtmax严重降低等心功能损伤,而心钠素(10~7和2×10~7mol/L)能部分对抗内皮素引起的心功能损伤,提示心钠素可能是机体内源性的内皮素拮抗剂.     

5-HT4 受体部分激动剂RS67506可作为心肌IK1通道抑制剂

目的 验证5-HT4受体部分激动剂RS67506对心室肌内向整流钾通道（IK1）和动作电位（action potential，AP）的作用特征。方法 取成年雄性SD大鼠心脏经Langendorff离体灌流、胶原酶法急性分离单个左心室肌细胞，采用膜片钳技术检测1~30 μmol/L RS67506对心室肌静息电位（resting potential，RP）、动作电位（action potential，AP ）及IK1通道电流的影响。结果 1、10、30 μmol/L RS67506可剂量依赖性降低静息电位（由-75.2±0.4 mV 分别降低至-72.7±0.5 mV，-70.1±0.4 mV和-67.9±0.9 mV）（P<0.01），延长动作电位复极时间（APD）（APD90由31.1±1.1ms 分别延长至34.7±0.6 ms，40.4±1.2ms和45.0±0.5ms）（P<0.05 或P<0.01）；同时抑制IK1，30 μmol/L RS67506可使IK1外向电流密度（-60 mV）降低58.4%（P<0.05）；内向电流密度（-100 mV）降低53.2%（P<0.01）。结论 RS67506对大鼠心室肌IK1和AP的作用特征符合IK1抑制剂的特点，可能作为大鼠心肌IK1抑制剂，为临床防治心律失常提供新的药理学工具药。     

线粒体膜钾通道阻断剂在硫化氢对大鼠心功能调节的意义

目的 观察线粒体膜KATP通道特异性阻断剂5-羟基葵酸盐(5-hydroxydecanoate,5-HD)对硫化氢(H2S)灌流的大鼠离体心脏心功能的影响,以探讨线粒体膜KATP通道阻断剂在H2S调节心功能过程中的意义.方法 应用Langendorff灌流大鼠离体心脏,用生理浓度NaHS(100 μmol/L)持续灌流20 min,测最心率、左室内压差(△LVP=左室收缩压-左室舒张压)、左室内压变化速率(±dp、dtmax)、冠状动脉流量等指标,分别应用非特异性KATP通道阻断剂格列苯脲、线粒体膜KATP通道阻断剂5-HD预灌流,后给予生理剂量NaHS灌流,观察其是否可以阻断H2S的心功能效应.结果 生理剂量NaHS持续灌流20 min内,可以显著抑制±dp/dtmax及ALVP(P<0.05),而对心率、冠状动脉流量几乎没有影响.非特异性KATP通道阻断剂格列苯脲及线粒体膜KATP通道阻断剂5-HD均可以大部分阻断生理剂量NaHS对心功能的抑制效应.结论 内源性H2S可以通过开放线粒体膜KATP通道,产生对心肌的负性肌力调节作用.     

不同浓度曲美他嗪对缺血/再灌注大鼠离体心脏的保护作用

目的 明确曲美他嗪在缺血再灌注（I/R）大鼠离体心脏损伤中的保护作用,并寻找最佳的药物浓度。 方法 选取体质量介于（220～250） g的雄性健康SD大鼠,适应性喂养1周后,快速腹腔注射水合氯醛（100 mg/ml）和肝素（500 U/kg）。离体心脏正常灌注开始后,实验随机分为5组,正常对照组,I/R组,5 μmol/L,10 μmol/L和20 μmol/L曲美他嗪处理I/R组。实验全程采用Labchart软件记录左心室内压力的数值,左心室发展压(LVDP)和左心室舒张末压(LVEDP)评价左心室的收缩功能。检测各组心脏释放的乳酸脱氢酶（LDH）的含量,观察心肌梗死面积的变化,检测各组心肌组织中半胱氨酸蛋白酶3（caspase-3）的活性、细胞色素（cytochrome）C和有活性的半胱氨酸蛋白酶3（cleaved caspase-3）的蛋白表达水平。 结果 和I/R组比较,5 μmol/L TMZ处理 I/R组LVDP有升高,左室舒张末压有降低趋势;而10 μmol/L TMZ处理I/R组和20 μmol/L TMZ处理I/R组均能够明显增加LVDP,显著降低左室舒张末压（P<0.05）,但两组间比较无显著差异。和I/R组比较,5 μmol/L TMZ处理I/R组有降低心肌梗死面积、冠脉流出液中LDH的含量、caspase-3活性以及cytochrome c和cleaved caspase-3蛋白表达的趋势;而10 μmol/L TMZ处理I/R组和20 μmol/L TMZ处理I/R组均能够明显降低心肌梗死面积、冠脉流出液中LDH的含量、caspase-3活性以及cytochrome c和cleaved caspase-3的蛋白表达（P<0.05）,但两组间比较无显著差异。 结论 10 μmol/L和20 μmol/L曲美他嗪在I/R离体心脏中具有保护作用。     

抗钠-钙交换体α-2(807-844)抗体对Langendorff灌流大鼠离体心功能的影响

目的观察1～103 nmol/L抗钠-钙交换体(NCX)α-2(807-844)肽段抗体对离体大鼠心功能的影响。方法化学合成的NCXα-2(807-844)肽段主动免疫新西兰大耳白兔制备并纯化抗体,采用Langendorff离体心脏灌流系统观察对大鼠离体心功能的影响。结果主动免疫后兔体内抗α-2(807-844)抗血清滴度明显升高,经Protein A纯化后获得浓度为7.21mg/mL的抗体;与对照组比较,1～10nmol/Lα-2抗体可明显增加大鼠离体心脏左室发展压(LVDP)及左室压最大上升速率(+dP/dtmax,P<0.01),且使左室压最大下降速率(-dP/dtmax)减小(P<0.01);然而,102～103 nmol/Lα-2抗体则可不同程度地降低正常大鼠离体心脏LVDP、±dP/dtmax(P<0.01)。结论抗钠-钙交换体α-2(807-844)肽段抗体对离体大鼠心功能的作用与其浓度有关。在低浓度时,α-2抗体可使心肌收缩增强;而较高浓度的α-2抗体可同时抑制心肌收缩和舒张。     

Spectral and correlation analyses of the verapamil-induced conversion of ventricular fibrillation to tachycardia in isolated rat hearts

Ventricular tachycardia (VT) is considered to be the most common precursor of ventricular fibrillation (VF). However, the mechanisms underlying the transition from VT to VF remain unclear. Here, we investigated whether and how perfusion of the heart with verapamil, a blocker of L-type calcium channels, changed the macro-dynamics of the heart between VT and VF. The experiments were performed with Langendorff perfused isolated rat hearts, in which left ventricular pressure and left ventricular cardiomyogram were measured. Sustained VT or VF was induced by burst pacing of the left ventricular muscles. During sustained VF, verapamil perfusion resulted in the conversion of VF to VT. A cross-correlation analysis between left ventricular cardiomyogram and left ventricular pressure revealed that the correlation coefficient was small during VF, but became larger during VT. This study showed that inactivation of L-type Ca(2+) channels occurred during verapamil-induced conversion of pacing-induced sustained VF to VT, and characterized the changes in macro-dynamics of the heart associated with the transition.     

4-aminopyridine inhibits the occurrence of ventricular fibrillation but not ventricular tachycardia in the reperfused, P6olated rat heart

The 4-aminopyridine (4-AP)-sensitive transient outward current (Ito) has been reported to play an important role in the ischemia- or high [Ca2+]o-induced reentrant ventricular arrhythmias. However, the role of 4-AP sensitive Ito in reperfusion arrhythmia remains unknown. Rat hearts were perfused with Tyrode solution (control), and treated with 0.5 micromol/L verapamil, 1 micromol/L glibenclamide, 10 micromol/L E-4031 or 2 mmol/L 4-AP. After a 10-min perfusion, hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. The effects of the ion-channel blockers on the incidence of ventricular tachycardia (VT), torsades de pointes (Tdp) and ventricular fibrillation (VF) during the reperfusion period were investigated. Verapamil and 4-AP abolished VF and Tdp. The incidence of VT was also attenuated by verapamil, but not by 4-AP. Glibenclamide and E-4031 (a blocker of a rapidly activating component of delayed rectifier K+ current) did not affect the incidence of those tachyarrhythmias. Accordingly, (1) the underlying mechanism of VF or Tdp is different from that of VT, and (2) 4-AP sensitive Ito is required for the occurrence of reperfusion Tdp or VF in the present model.     

米诺环素预处理对大鼠缺血性室性心律失常的影响

目的观察米诺环素(MC)预处理对大鼠心肌缺血性室性心律失常的影响并探讨其可能机制。方法采用冠状动脉左前降支结扎法建立大鼠心肌梗死(MI)模型。将60只雄性SD大鼠随机分成6组:MI组,MI+MC组,MI+LY294002(LY)组,MI+5-羟基癸酸(5-HD)组,MI+MC+LY组及MI+MC+5-HD组。各组在制作MI模型前分别给予生理盐水、MC、LY、5-HD、MC+LY、MC+5-HD预处理。持续心电监护,观察缺血30 min内各组室性心动过速(VT)和心室颤动(VF)发生率、以及VT+VF持续时间、发生次数和室性心律失常的严重程度。缺血30min后迅速摘取心脏,用TTC法测心肌梗死面积。结果与MI组比较,MI+MC组的VT发生率无明显变化(P0.05),但VF发生率显著降低,VT+VF持续时间、发生次数和严重程度以及心肌梗死面积显著减少(P均0.05);而MI+MC+LY组及MI+MC+5-HD组上述指标与MI组无差异。结论 MC预处理可以减轻大鼠MI诱导的室性心律失常,这种作用可能与3-磷酸肌醇激酶/Akt信号通路和线粒体ATP敏感性钾离子通道的激活有关。     

The effect of heart rate on the termination of electrically induced ventricular fibrillation in the isolated perfused rat heart

Ventricular fibrillation (VF) which is normally sustained in large animals and humans, is transient in small animals. The purpose of the present study was to evaluate the possible effect of changing cardiac rate on spontaneous ventricular defibrillation. In isolated perfused rat heart, VF was electrically induced during normal spontaneous rhythm of the heart at normal rate and at various ventricular pacing rates. It was found that: 1) Electrically induced VF in isolated perfused, non-ischemic rat heart spontaneously terminated in 88% of the hearts; 2) Ventricular pacing rhythm of spontaneous rate plus 10% caused VF to be sustained in 26% of the hearts (which defibrillated spontaneously during normal rates); 3) Ventricular pacing at 200% of the basic rate led to sustained VF in about half the VF episodes (14 out of 33, p less than 0.005). In the remainder, which defibrillated spontaneously, a sustained VF could be achieved by further increase in ventricular pacing rate; 4) Slow pacing rate, as a result of the surgical production of atrioventricular (A-V) block, enhanced the probability of spontaneous defibrillation (21 of 21 episodes after slow pacing vs 24 of 34 episodes following pacing at previous normal sinus rhythm, p less than 0.05). Selective modulation of conduction velocity, refractory period or both, achieved by changes in ventricular pacing rate was assumed to play an important role in determining whether electrically-induced VF would be transient or sustained.     

射频导管消融治疗特发性室性期前收缩触发的心室颤动／多形性室性心动过速

目的：探讨特发性室性期前收缩（早搏,PVC）触发心室颤动和（或）多形性室性心动过速（VF／PVT）的临床特点及射频导管消融治疗效果。方法：313例无器质性心脏病接受射频导管消融治疗的特发性PVC患者,其中6例发生了由PVC触发的VF／PVT,分析该6例患者的临床资料及射频导管消融治疗效果。结果：该6例患者动态心电图可记录到频发PVC[（16303±5854）次／d],PVC联律间期及基础QT间期分别为（412±44）ms和（407±10）ms。这些参数值在另外307例特发性PVC患者中分别为（15570±4743）次／d、（419±36）ms和（404±8）ms,两组间无显著性差异。313例患者中,有88例记录到由PVC触发的单形态室性心动过速（VT）。PVC触发VF／PVT患者中晕厥发生率（3／6）高于由PVC触发的单形态VT患者（4／88,4．5％,P〈0．05）,PVT的周长[（235±22）ms]则短于单形态VT组[（324±29）ms,P〈0．05]。针对触发VF／PVT的PVC消融后随访的10～36个月期间,所有6例患者未再发生晕厥、VF及心脏骤停。结论：恶性VF／PVT可能由一些特发性PVC诱发,射频导管消融PVC治疗可作为一项有效的治疗选择。     

植入型心律转复除颤器治疗室性快速心律失常的临床应用

目的探讨植入型心律转复除颤器（ICD）对室性快速心律失常的治疗效果以及随访过程中所遇到的问题。方法48例植入ICD患者（其中8例为双腔ICD）,根据患者室性心动过速（VT）/心室颤动（VF）发作时的频率及对血流动力学的影响确定方法和参数,并对植入ICD患者定期随访。结果48例患者顺利植入ICD,无并发症,在随访1～38个月中,患者共发作VT/VF 1 025次（VT764次,占74.5%;VF 261次,占25.5%）,其中1 009次（98.4%）治疗成功,16次在ICD充电结束前自行终止。764次VT中,658次（86.1%）经抗心动过速起搏（ATP）终止,106次（13.9%）经低能量复律（CV）终止。261次VF中,经高能量除颤（DF）均终止。6例患者发生误放电19次,8例双腔ICD患者无误放电。结论ICD的疗效是确定的。但单腔ICD常会发生误识别、误放电,随访和及时调整参数可避免或减少此类情况发生。双腔ICD提高了对室上性心律失常的识别能力,从而减少误发电。同时应合理应用抗心律失常药物,高度重视ICD患者的心理治疗。     

链霉素对心肌梗死大鼠离体心脏牵张时心律失常的影响

目的探讨链霉素对心肌梗死(简称MI)大鼠离体心脏牵张时心律失常的影响。方法36只wistar大鼠随机分为正常对照组、链霉素组、MI组、MI+链霉素组。离体心脏经Langendorff灌流后,通过改变水囊容积,以△V=0.1,0.2,0.3ml对心室牵张5s,观察牵张效应30s,记录90%单相动作电位时程(MAPD90)、室性早搏(PVB)及室性心动过速(VT)的次数。结果牵张使正常对照组及MI组MAPD90显著延长(P<0.05或0.01),其中MI组在相应牵张幅度下其MAPD90增加更为显著(与正常对照组比较,P<0.01;如△V=0.3ml,从63.2±4.95ms到55.67±4.39ms)。链霉素对基础状态下MAPD90无影响(P>0.05),但可使牵张后已延长的MAPD90显著缩短(P均<0.05;如MI组与MI+链霉素组,△V=0.2ml,从58.09±4.27ms到53.1±3.64ms)。正常及MI组PVB和VT发生率随△V的增加而增加,且后者高于前者。链霉素使两组PVB发生率显著下降,并可显著抑制VT的发生(P<0.005)。结论MI后牵张更有助于恶性心律失常的产生和维持,链霉素可以明显抑制上述现象的发生。     

Ischemia-induced translocation of protein kinase C-epsilon mediates cardioprotection in the streptozotocin-induced diabetic rat.

The present study investigated the role of translocation of protein kinase C (PKC) during ischemia/reperfusion in cardioprotection in the streptozotocin (STZ)-induced diabetic rat. Twelve weeks after injection of STZ or vehicle, male Wister-King rat hearts were isolated and perfused in the presence or absence of 50 nmol/L staurosporine or 2 mumol/L chelerythrine using a Langendorff apparatus. Thirty minutes of global ischemia was followed by the same period of reperfusion. The time to onset of contracture was determined during ischemia. The recovery of left ventricular function, incidence of ventricular tachycardia/fibrillation (VT/VF), and amount of released creatine kinase (CK) were determined during the reperfusion period. Translocation of the PKC-alpha, -beta, -delta and -epsilon isoforms was determined by immunoblotting. Development of contracture was delayed, the recovery of left ventricular function was greater, and the incidence of VT/VF and amount of released CK were lower in diabetic than in control hearts. Ischemia caused an increase in the particulate/cytosolic fraction ratio of the PKC- epsilon isoform in the diabetic and control hearts. However, this translocation of PKC-epsilon during ischemia was transient in the control heart, but was persistent in the diabetic heart. The ischemia-induced translocation of PKC-epsilon was abolished by chelerythrine perfusion. These results suggest that persistent translocation of PKC-epsilon during ischemia plays a major role in cardioprotection against ischemia/reperfusion injury in STZ-induced diabetic rats.