兔在体左室肥厚心肌跨室壁电异质性的实验研究

目的：探讨兔在体左室肥厚心肌单相动作电位跨室壁的不均一性变化。方法：以腹主动脉缩窄术制备家兔高血压左室肥厚模型，并设假手术组（仅游离腹主动脉未缩窄）作为对照。采用自制复合式电极在兔左心室前壁同步记录心内膜、心肌中层、心外膜在体3层心肌单相动作电位（MAP），比较两组间跨室壁复极离散度(TDR)等各项参数的差异。结果：腹主动脉缩窄组平均动脉压、全心重量及其与体重比率、左心室游离壁厚度均大于假手术组。缩窄组3层心肌MAPD100［内膜：(191±19)ms；中层：(244±24)ms;外膜：(196±15)ms］均长于对照组［内膜：(170±18)ms ;中层：(172±15)ms;外膜：(168±16)ms，P<0.01］，以中层心肌MAPD100延长最为明显，缩窄组TDR（65±10)ms较对照组（4±3)ms明显增大（P<0.01）。结论：兔在体左室肥厚心肌跨室壁电不均一性明显增大，可能是肥厚心肌心律失常发生增多的原因之一。     

Cariporide对兔心房电重构的影响

目的：探讨钠氢交换体Ⅰ型(NHE-1)特异性抑制剂cariporide对快速起搏所致兔心房电重构的影响。 方法： 30只兔随机等分为3组：对照组、起搏组和cariporide组。起搏组和cariporide组给予6 h 600 beats/min的快速心房起搏。测定各组不同时点的心房有效不应期（AERP200，AERP150，AERP130），连续刺激6 h后取左右心耳组织，用Western blotting测定NHE-1的含量。 结果： 在快速起搏后1 h后，起搏组的AERP200较起搏前明显缩短，2 h时达高峰，相对缩短量为（15.63±9.04）ms，而对照组和cariporide组AERP未发生明显变化，起搏2h时相对缩短量为(1.43±2.44)ms和(1.43±6.90)ms（P<0.05，与起搏组相比），这些变化一直保持至快速起搏后6 h；起搏组的AERP频率适应性下降, 起搏前AERP130较AERP200缩短(11.88±15.57)ms，起搏后6 h只缩短(4.38±5.63)ms。而cariporide组的AERP频率适应性则未发生显著变化。起搏组右心耳组织的NHE-1含量显著少于对照组（P<0.05），cariporide组的右心耳组织NHE-1含量与对照组差异不显著。 结论： Cariporide可有效阻止快速心房起搏引起的AERP缩短，但不影响起搏引起的NHE-1含量的下降。     

高胆固醇血症对大鼠心室肌细胞离子电流的作用

目的：观察高胆固醇血症对大鼠心室肌细胞离子电流的作用。方法： 通过全细胞膜片钳技术记录用酶解法分离的正常和高胆固醇饮食的大鼠心室肌细胞离子电流。结果： 高胆固醇组（组Ⅱ）血清总胆固醇水平明显高于正常组（组Ⅰ）［（3.10±0.62)mmol·L-1 vs (1.18±0.37)mmol·L-1, P<0.01, n=20］。组Ⅱ血清甘油三酯也明显高于组Ⅰ［（1.51±0.30)mmol·L-1 vs (0.43±0.15)mmol·L-1, P<0.01, n=20］。组Ⅱ大鼠心室肌细胞动作电位时程（APD）与组I相比明显延长，APD50从(70.86±8.12)ms延长至(116.16±6.90)ms (n=10, P<0.01); APD90 从(95.10±7.27)ms延长至(144.04±7.39)ms (n=10, P<0.01)；在实验电压 -120 mV， Ik1从(-16.98±4.54) pA/pF（组I）增加到(-19.92±4.08) pA/pF（组Ⅱ）(n=12, P<0.05)；在实验电压 0 mV， ICa-L从(-8.56±1.29) pA/pF（组Ⅰ）减少到(-5.24±0.90) pA/pF（组Ⅱ）(n=10, P<0.01)；在实验电压 +60 mV，Ito从(13.20±1.97) pA/pF（组I）减少到(10.30±1.97) pA/pF（组Ⅱ）(n=8, P<0.05)。结论： 高胆固醇血症可显著改变心肌细胞离子电流密度的大小，对心脏具有毒性作用。     

瑞芬太尼对兔心肌动作电位及跨室壁复极离散度的影响

目的:观察瑞芬太尼对兔心肌动作电位及跨室壁复极离散度的影响。方法:成年家兔18只,体重2.0~2.5 kg,制备Langendorff离体心脏灌注模型,K-H液平衡灌注15 min后随机分为3组(n=6):正常对照组(C组)继续灌注37℃K-H液60 min;瑞芬太尼组(R组)灌注含12μg/L瑞芬太尼的K-H液60 min;瑞芬太尼+氨茶碱组(RA组)灌注含12μg/L瑞芬太尼+30 mg/L氨茶碱的K-H液60 min。记录平衡灌注15 min(T0)、继续灌注15 min(T1)、30 min(T2)和60 min(T3)时心率(HR)和左心室前壁3层心肌单相动作电位(MAP),计算单相动作电位复极90%的时程(MAPD90)和跨室壁复极离散度(TDR)。记录早期后除极、延迟后除极及心律失常的发生情况。结果:与T0比较,R组T1~T3时HR减慢,MAPD90延长,TDR增大(P0.05)。与C组和RA组比较,R组HR减慢时,MAPD90延长,TDR增大(P0.05)。结论:瑞芬太尼减慢HR时,MAPD90延长,TDR增大,折返激动易于发生;氨茶碱增快HR,缩短MAPD90,从而使TDR减小。     

人参对老年大鼠脑组织β受体的影响

<正> 研究表明人参可提高老年鼠心肌、肺等外周组织β受体含量,但对老年大鼠脑组织β受体的影响却较少报导.本研究目的观察人参对老年大鼠各脑区β受体含量的影响.实验选用SD老年大白鼠24只,分高浓度人参组(lg/500g体重/d)、低浓度人参组(0.25g/500g/d)、老年对照组.应用人参(吉林生晒参)水煎液灌服老年鼠,3周后用放射配基受体结合分析法测定大鼠大脑皮质、小海马、脑β受体含量,结果如下:大脑皮质、海马、小脑β受体 含量高浓度人参组分别为47.37±4.21、43.26±3.21和24.19±3.31;低浓度人参组分别为39.77± 3.68、39.26± 3.27和20.19±3.81;老年对照组分别为40.65±3.73、35.64±3.37和19.25±3.31.高浓度人参组的大脑皮质、海马β受体含量与老年对照组和低浓度人参组比较,P<0.05.本实验结果显示灌服高浓度人参大鼠大脑皮质、海马β受体含量有明显增高,而小脑组织β     

一氧化氮吸入对急性高浓度氧肺损伤新生大鼠肺水通道蛋白1和5表达的影响

目的：观察一氧化氮(NO)吸入对急性高浓度氧肺损伤新生大鼠肺上皮水转运体系的影响。方法：32只新生SD大鼠，随机分为：(1)空气组(C)：予空气48 h；（2）高浓度氧组(O)：予高浓度氧持续吸入48 h，维持FiO₂＞0.95；(3)高浓度氧+NO组(ONO)：予高浓度氧持续吸入48 h，维持FiO₂＞0．95，前24 h同时予1×10-5NO吸入；（4）空气 + NO组(CN)： 予空气48 h，前24 h同时予1×10^-5NO吸入。各组分别测肺组织湿重/干重比值(Q_W/Q_D)，行肺组织病理学检查，用RT-PCR方法测定肺组织AQP1、AQP5、α₁-NKA和α-ENaC mRNA含量。结果： 高浓度氧组肺湿重/干重比值明显高于正常对照组(5.81±1.01 vs 4.33±0.94，P<0.01)；而肺组织AQP1 mRNA含量明显低于正常对照组(0.68±0.38 vs 1.81±0.76， P<0.01)，AQP5mRNA含量无明显变化。1×10^-5 NO+高浓度氧组肺组织湿重/干重比值明显高于高浓度氧组(4.89±0.68 vs 5.81±1.01， P<0.05)；而肺组织AQP1 mRNA含量明显高于高浓度氧组(1.27±0.54 vs 0.68±0.38，P<0.05)，AQP5mRNA含量无明显变化。结论：1×10^-5NO吸入24 h能减轻急性高浓度氧肺损伤新生大鼠的肺水肿，提高肺内水通道蛋白1mRNA含量，水通道蛋白5的mRNA含量无明显改变，提示1×10^-5NO的吸入可能对急性高浓度氧肺损伤新生大鼠肺内水通道蛋白1有一定的保护作用。     

复方茯苓制剂对营养性肥胖大鼠体重、血糖、血脂及小肠肠系膜微循环的影响

目的：观察复方茯苓制剂(CPP)对肥胖大鼠体重、血流动力学、血糖、血脂、小肠肠系膜微循环的影响,探讨防治肥胖症的新途径。 方法： Wistar大鼠45只分为普通饲料喂养组（A组）、高能饲料喂养组（B组）、高能量饲料喂养+复方茯苓制剂组（C组），分别观测体重、血压、右心房压、血糖、血脂及肠系膜微循环的变化。 结果： B组用CPP治疗后平均体重由(313.00±17.29)g降至(217.50±17.50)g（P＜0.01);体动脉平均血压由(173.88±2.97)mmHg降至(101.73±3.35)mmHg（P<0.01）,右房平均压从（13.58±3.59）mmHg下降为（11.32±0.68）mmHg(P<0.05);大鼠肠系膜毛细血管管径由（7.93±0.90）μm降为（3.93±0.90）μm(P<0.05)；血流速度从（270.92±49.73）μm/s增至（410.13±76.54）μm/s（P<0.01）；血浆极低密度脂蛋白（VLDL）由（3.18±0.01）mmol/L增加至（4.55±0.01）mmol/L;总胆固醇（T-Chol）从（7.87±0.01）mmol/L降至（5.56±0.01）mmol/L（P<0.05），血糖由（12.87±0.04）mmol/L下降至（8.97±0.07）mmol/L(P<0.05)。上述指标参数与普通饲料喂养组相比无显著差异(P>0.05)。 结论： 复方茯苓制剂能使肥胖大鼠减肥及改善小肠肠系膜微循环。     

颈椎旋转手法对兔颈动脉粥样硬化血管 拉伸力学特性的影响

目的 研究颈椎旋转手法对兔颈动脉粥样硬化血管拉伸力学特性的影响,为颈椎旋转手法的安全性提供依据。方法 20只雄性新西兰兔随机分为2组,每组各10只,均饲高脂饮食12周建立动脉粥样硬化动物模型。12周后对实验组兔行颈椎旋转手法,每日左、右各旋转1次,共4周;对照组不作手法处理。手法结束后处死兔,取双侧颈动脉,利用生物组织材料力学试验机测定颈动脉拉伸最大载荷、最大形变、平均载荷、弹性模量和断裂延伸率等指标以及输出应力—应变曲线。结果 实验组颈动脉拉伸最大载荷(1.36±0.35) N,最大形变(6.84±2.08) mm,平均载荷(0.44±0.30) N,弹性模量(4.30±2.66) MPa,断裂延伸率(83.08±51.32)%;对照组颈动脉拉伸最大载荷(2.92±0.65) N,最大形变(9.23±2.62) mm,平均载荷(1.17±0.63) N,弹性模量(3.71±0.60) MPa,断裂延伸率(154.19±34.32)%。其中,实验组颈动脉拉伸的最大载荷、平均载荷和断裂延伸率明显小于对照组（P<0.05）;而最大形变以及弹性模量在两组中差异无统计学意义（P>0.05）。结论 经颈椎旋转手法后,颈动脉粥样硬化血管的拉伸力学特性下降,应注意颈椎旋转手法操作的力度和幅度,以免伤及颈动脉。     

N-乙酰半胱氨酸对慢性间歇缺氧大鼠海马神经元凋亡及氧化应激的影响

目的：探讨N-乙酰半胱氨酸(NAC)对慢性间歇缺氧(CIH)模型大鼠海马组织氧化应激及海马神经元凋亡的影响。方法:30只雄性Wistar大鼠随机分为慢性缺氧组、NAC治疗组及正常对照组3组，每组10只。采用化学比色法测定海马组织丙二醛(MDA)、超氧化物歧化酶(SOD)水平，同时应用免疫组化方法检测海马CA1 区磷酸化JNK(p-JNK)表达水平，应用TUNEL法检测海马CA1区神经元凋亡率。结果:NAC治疗组 MDA水平低于CIH组（1.71±0.43 vs 1.37±0.26，P＜0.05）、SOD活性高于CIH组（44.94±14.01 vs 57.66±14.07，P＜0.05），p-JNK表达水平低于CIH组 （0.53±0.10 vs 0.39±0.16，P＜0.05），海马神经元凋亡率显著低于CIH组（0.32±0.18 vs 0.20±0.11，P＜0.05）。结论:NAC能抑制慢性间歇缺氧导致的氧化应激，从而影响JNK信号转导通路，减少海马神经元凋亡。     

体位改变对兔急性肺损伤生理和病理的影响

目的：观察不同体位下兔油酸型急性肺损伤(ALI)模型肺生理功能和肺病理的改变。 方法： 采用油酸型ALI兔模型，分为正常对照组(Ⅰ组)、仰卧位油酸组(Ⅱ组)、俯卧位油酸组(Ⅲ组)、旋转体位油酸组(Ⅳ组)，观察各组兔实验过程中血压、心率和动脉血氧分压、呼吸力学、肿瘤坏死因子(TNF-α)和白细胞介素-6(IL-6)的变化以及病理的改变。 结果： 在实验结束时Ⅳ组的心率(176.13±26.55)beats/min低于Ⅲ组(217.75±14.44)beats/min, P<0.05；Ⅲ、Ⅳ组的动脉血氧分压(157.75±51.19和166.08±37.07)mmHg、肺的顺应性（2.75±0.89和2.63±0.74）mL/cmH2O高于Ⅱ组动脉血氧分压（86.59±23.82）mmHg和肺的顺应性(1.63±0.52)mL/cmH2O,P<0.05；Ⅲ、Ⅳ组的肺内分流（20.94±5.23和18.06±5.28）%低于Ⅱ组（29.30±7.54）%,P<0.05； Ⅳ组的气道峰压（19.63±2.45）cmH2O高于Ⅲ组（16.00±2.27）cmH2O，P<0.05；Ⅱ、Ⅳ组TNF-α(3.12±0.83和2.59±0.79)μg/L显著高于对照组(1.36±0.34)μg/L，P<0.05,而Ⅲ组(1.84±0.46)μg/L和对照组差别无显著；3个实验组的动脉血氧分压与肺的顺应性呈明显正相关，与肺内分流呈明显负相关。Ⅱ组光镜下见背侧水肿比腹侧重，Ⅲ组腹侧水肿比背侧重，Ⅳ组腹背侧病变大体一致。 结论： 俯卧位和旋转体位能改善ALI肺的顺应性、减少肺内分流，改善氧合；但俯卧位比旋转体位安全并能减少TNF-α的产生。体位改变可使肺水肿的分布发生变化。     

TNF‐α hyperpolarizes membrane potential and potentiates the response to nicotinic receptor stimulation in cultured rat myenteric neurones

Aim: Mechanically induced early afterdepolarization (EAD) is morphologically similar but different in the mechanisms with drug‐induced EAD, which lead to arrhythmia. Pacing suppresses the drug‐induced EAD and arrhythmia, however the effect of pacing on mechanically induced EAD and arrhythmia is not clear. This study addressed this issue in right ventricle (RV) of anaesthetized lambs. Methods: Six lambs were anaesthetized, and their hearts exposed. Nine monophasic action potential (MAP) electrodes were placed on RV apex, outflow and inflow regions, and recorded before, during, and after a 10 s occlusion of pulmonary artery at a number of pacing rates. Results: Pacing significantly reduced the baseline MAP duration at 90% repolarization (MAPD₉₀), decreased the reduction of MAPD at early repolarization at the peak of occlusion. Nonetheless, the percentage of reduction was not significantly different among them. Pacing was able to reduce the frequencies, size of mechanically induced EADs. MAPD₉₀ at the peak of occlusion was all shortened during pacing rather than some lengthened at intrinsic rate. Therefore, the dispersion of MAPD₉₀ at the peak of occlusion reduced from 86 ± 6 ms at intrinsic rate to 42 ± 4 ms at 120 beats min⁻¹ , 38 ± 3 ms at 150 beats min⁻¹ and 26 ± 3 ms at 170 beats min⁻¹. Ultimately, pacing reduced/suppressed mechanically induced premature ventricular beats. These alterations were inversely related to heart rates. Conclusion: Pacing reduces/suppresses both stretch‐induced EADs and arrhythmia. These modulations are remarkably similar to those on other EADs by the pacing.     

Rate dependence of mechanically induced electrophysiological changes in right ventricle of anaesthetized lambs during pulmonary artery occlusion

AIM: Mechanically induced early afterdepolarization (EAD) is morphologically similar but different in the mechanisms with drug-induced EAD, which lead to arrhythmia. Pacing suppresses the drug-induced EAD and arrhythmia, however the effect of pacing on mechanically induced EAD and arrhythmia is not clear. This study addressed this issue in right ventricle (RV) of anaesthetized lambs. METHODS: Six lambs were anaesthetized, and their hearts exposed. Nine monophasic action potential (MAP) electrodes were placed on RV apex, outflow and inflow regions, and recorded before, during, and after a 10 s occlusion of pulmonary artery at a number of pacing rates. RESULTS: Pacing significantly reduced the baseline MAP duration at 90% repolarization (MAPD90), decreased the reduction of MAPD at early repolarization at the peak of occlusion. Nonetheless, the percentage of reduction was not significantly different among them. Pacing was able to reduce the frequencies, size of mechanically induced EADs. MAPD90 at the peak of occlusion was all shortened during pacing rather than some lengthened at intrinsic rate. Therefore, the dispersion of MAPD90 at the peak of occlusion reduced from 86 +/- 6 ms at intrinsic rate to 42 +/- 4 ms at 120 beats min-1, 38 +/- 3 ms at 150 beats min-1 and 26 +/- 3 ms at 170 beats min-1. Ultimately, pacing reduced/suppressed mechanically induced premature ventricular beats. These alterations were inversely related to heart rates. CONCLUSION: Pacing reduces/suppresses both stretch-induced EADs and arrhythmia. These modulations are remarkably similar to those on other EADs by the pacing.     

The electrophysiological and mechanical effects of 2,3-butane-dione monoxime and cytochalasin-D in the Langendorff perfused rabbit heart

Procedures that reduce contraction are used to facilitate optical measurements of membrane potential, but it is unclear to what extent they affect the excitability of the heart. This study has examined the electrophysiological consequences of a range of extracellular [Ca2+] (0.7-2.5 mmol l(-1)), 2,3-butane-dione monoxime (BDM; 1-20 mmol l(-1)) and cytochalasin-D (Cyto-D; 1-5 micromol l(-1)). METHODS: Monophasic action potentials (MAPs) were recorded from the basal epicardial surface of the left ventricle of isolated rabbit hearts. Conduction delay (CD) and time to 90% repolarisation of the monophasic action potential (MAPD90) were measured. The effects of BDM and Cyto-D on restitution were studied at a [Ca2+] of 1.9 mmol l(-1). Restitution curves for MAPD90 were generated using a standard S1-S2 protocol. RESULTS: All manoeuvres decreased left ventricular developed pressure (LVDP): 0.7 mmol l(-1) Ca2+ to 74.0 +/- 6.1%, 20 mmol l(-1) BDM to 4.5 +/- 1.0%, and 5 micromol l(-1) Cyto-D to 12.8 +/- 3.5% of control value. CD decreased from a control value (33.3 +/- 1.0 ms, n= 16) to 93.0 +/- 2.2% in 0.7 mmol l(-1) Ca2+, but increased to 133.7 +/- 10.5% in 20 mmol l(-1) BDM and 127.4 +/- 10.6% in 5 micromol l(-1) Cyto-D. At 350 ms pacing cycle length, MAPD90 (control = 119.6 +/- 1.7 ms n= 16) was prolonged by reduced extracellular [Ca2+]. BDM had no effects on MAPD90 at control pacing rates. Cyto-D caused a significant prolongation (to 115.0 +/- 3.0% of control, n= 6) at the highest concentration studied (5 micromol l(-1)). Both BDM (20 mmol l(-1)) and Cyto-D (3 micromol l(-1)) flattened the restitution curves but neither agent altered maximum MAPD90. CONCLUSIONS: Extracellular [Ca2+] of 1.9 mmol l(-1) in conjunction with a moderate dose of Cyto-D (3 micromol l(-1)) reduced contractility with minimal effects on action potential duration and conduction at a fixed pacing cycle length. However, both BDM and Cyto-D had pronounced effects on electrical restitution.     

心力衰竭家兔心室动作电位时程整复性变化对室性心律失常的影响

 目的：探讨压力负荷诱导的兔慢性心力衰竭(CHF)模型离体心室动作电位时程整复性(APDR)变化对室性心律失常(VA)的影响。方法：雄性新西兰大耳兔20只,随机分为对照(CTL)组和CHF组,每组10只。CHF模型制备采用经腹主动脉缩窄术,造模结束4周后行心脏超声检查评价造模结果。在整体心脏Langendorff灌流条件下行离体电生理研究,分别记录和测量心室不同位点的单相动作电位(MAP)及有效不应期(ERP),并绘制APDR曲线;对2组心脏进行快速电刺激,观察室性心律失常（VA）的诱发。结果：与CTL组相比,CHF组心室相同部位90%单相动作电位时程(MAPD90)、ERP及APDR曲线最大斜率(Smax)均明显增大(均P<0.01),且VA更容易诱发(均P<0.05);此外,CHF组动物APDR曲线Smax的变异系数(COV-Smax)均较CTL组增大(均P<0.05)。结论：CHF时心室APDR曲线Smax及COV-Smax均增大,促进室性心律失常的发生。     

Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome

Aim: To perform an empirical, pharmacological, separation of early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in a genetically modified mouse heart modelling human long QT syndrome (LQT) 3. Methods: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Δ hearts perfused with 0.1 and 1 μm propranolol and paced from the right ventricular epicardium. Results: All spontaneously beating bradycardic Scn5a+/Δ hearts displayed EADs, triggered beats and ventricular tachycardia (VT; n = 7), events never seen in WT hearts (n = 5). Perfusion with 0.1 and 1 μm propranolol suppressed all EADs, triggered beats and episodes of VT. In contrast, triggering of VT persisted following programmed electrical stimulation in 6 of 12 (50%), one of eight (12.5%), but six of eight (75%) Scn5a+/Δ hearts perfused with 0, 0.1 and 1 μm propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (ΔAPD₉₀) values. Thus 0.1 μm propranolol reduced epicardial but not endocardial APD₉₀ from 54.7 ± 1.6 to 44.0 ± 2.0 ms, restoring ΔAPD₉₀ from ?3.8 ± 1.6 to 3.5 ± 2.5 ms (all n = 5), close to WT values. However, 1 μm propranolol increased epicardial APD₉₀ to 72.5 ± 1.2 ms and decreased endocardial APD₉₀ from 50.9 ± 1.0 to 24.5 ± 0.3 ms, increasing ΔAPD₉₀ to ?48.0 ± 1.2 ms. Conclusion: These findings empirically implicate EADs in potentially initiating spontaneous arrhythmogenic phenomena and transmural repolarization gradients in the re‐entrant substrate that would sustain such activity when provoked by extrasystolic activity in murine hearts modelling human LQT3 syndrome.     

Separation of early afterdepolarizations from arrhythmogenic substrate in the isolated perfused hypokalaemic murine heart through modifiers of calcium homeostasis

Aims: We resolved roles for early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in Langendorff‐perfused hypokalaemic murine hearts paced from the right ventricular epicardium. Methods: Left ventricular epicardial and endocardial monophasic action potentials (MAPs) and arrhythmogenic tendency were compared in the presence and absence of the L‐type Ca²⁺ channel blocker nifedipine (10 nm –1 μm ) and the calmodulin kinase type II inhibitor KN‐93 (2 μm ). Results: All the hypokalaemic hearts studied showed prolonged epicardial and endocardial MAPs, decreased epicardial‐endocardial APD₉₀ difference, EADs, triggered beats and ventricular tachycardia (VT) (n = 6). In all spontaneously beating hearts, 100 (but not 10) nm nifedipine reduced both the incidence of EADs and triggered beats from 66.9 ± 15.7% to 28.3 ± 8.7% and episodes of VT from 10.8 ± 6.3% to 1.2 ± 0.7% of MAPs (n = 6 hearts, P < 0.05); 1 μm nifedipine abolished all these phenomena (n = 6). In contrast programmed electrical stimulation (PES) still triggered VT in six of six hearts with 0, 10 and 100 nm but not 1 μm nifedipine. 1 μm nifedipine selectively reduced epicardial (from 66.1 ± 3.4 to 46.2 ± 2.5 ms) but not endocardial APD₉₀, thereby restoring ΔAPD₉₀ from ?5.9 ± 2.5 to 15.5 ± 3.2 ms, close to normokalaemic values. KN‐93 similarly reduced EADs, triggered beats and VT in spontaneously beating hearts to 29.6 ± 8.9% and 1.7 ± 1.1% respectively (n = 6) yet permitted PES‐induced VT (n = 6), in the presence of a persistently negative ΔAPD₉₀. Conclusions: These findings empirically implicate both EADs and triggered beats alongside arrhythmogenic substrate of ΔAPD₉₀ in VT pathogenesis at the whole heart level.     

Effects of potassium channel openers in the isolated perfused hypokalaemic murine heart

Aim: We explored the anti‐arrhythmic efficacy of K⁺ channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment I_Kr and I_KATP respectively. Methods: Left ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 μm ) and nicorandil (20 μm ). Results: Spontaneously beating hypokalaemic hearts (3 mm K⁺) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti‐arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD₉₀) and changes in the transmural gradient of repolarization, reflected in ΔAPD₉₀. NS1643 and nicorandil reduced epicardial APD₉₀ from 68.3 ± 1.1 to 56.5 ± 4.1 and 51.5 ± 1.5 ms, respectively, but preserved endocardial APD₉₀ in hypokalaemic hearts. NS1643 and nicorandil thus restored ΔAPD₉₀ from ?9.6 ± 4.3 ms under baseline hypokalaemic conditions to 3.9 ± 4.1 and 9.9 ± 2.1 ms, respectively, close to normokalaemic values. Conclusion: These findings demonstrate, for the first time, the anti‐arrhythmic efficacy of K⁺ channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti‐arrhythmic through the suppression of EADs, reductions in APD₉₀ and restorations of ΔAPD₉₀.     

The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts

The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K⁺) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 μM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD₉₀), ventricular effective refractory period (VERP), and transmural conduction time (Δlatency), where appropriate, were applied to normokalemic (5.2 mM K⁺) and hypokalemic hearts. Hypokalemia increased epicardial APD₉₀ from 46.6 ± 1.2 to 53.1 ± 0.7 ms yet decreased epicardial VERP from 41 ± 4 to 29 ± 1 ms, left endocardial APD₉₀ unchanged (58.2 ± 3.7 to 56.9 ± 4.0 ms) yet decreased endocardial VERP from 48 ± 4 to 29 ± 2 ms, and left Δlatency unchanged (1.6 ± 1.4 to 1.1 ± 1.1 ms; eight normokalemic and five hypokalemic hearts). These findings precisely matched computational predictions based on previous reports of altered ion channel gating and membrane hyperpolarization. Hypokalemia thus shifted all re-excitation criteria in the positive direction. In contrast, hypokalemia spared epicardial APD₉₀ (54.8 ± 2.7 to 60.6 ± 2.7 ms), epicardial VERP (84 ± 5 to 81 ± 7 ms), endocardial APD₉₀ (56.6 ± 4.2 to 63.7 ± 6.4 ms), endocardial VERP (80 ± 2 to 84 ± 4 ms), and Δlatency (12.5 ± 6.2 to 7.6 ± 3.4 ms; five hearts in each case) in lidocaine-treated hearts. Exposure to lidocaine thus consistently shifted all re-excitation criteria in the negative direction, again precisely agreeing with the arrhythmogenic findings. In contrast, established analyses invoking transmural dispersion of repolarization failed to account for any of these findings. We thus establish novel, more general, criteria predictive of arrhythmogenicity that may be particularly useful where APD₉₀ might diverge sharply from VERP.     

Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts

Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K⁺) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K⁺) hearts (P < 0.01): this was prevented by treatment with lidocaine (10 μM, P < 0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P < 0.05) maximal gradients (from 0.55 ± 0.14 to 2.35 ± 0.67 in the epicardium and from 0.67 ± 0.13 to 1.87 ± 0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from −2.14 ± 0.52 ms to 50.93 ± 14.45 ms in the epicardium and from 8.14 ± 1.49 ms to 44.64 ± 5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P > 0.05) on either maximal gradients (0.78 ± 0.27 in the epicardium and 0.83 ± 0.45 in the endocardium) or critical DIs (6.06 ± 2.10 ms and 7.04 ± 3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P < 0.05) both these parameters (1.05 ± 0.30 in the epicardium and 0.89 ± 0.36 in the endocardium and 30.38 ± 8.88 ms in the epicardium and 31.65 ± 4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings.