【作者】 赵旭燕；

【导师】 王玉堂； 单兆亮； 李泱；

【作者基本信息】 中国人民解放军军医进修学院 ， 心血管病学， 2012， 博士

【摘要】 背景:应激是指机体在生存过程中遇到内外环境剧变时，机体出现的一种综合应答状态。强烈的应激或者是长时间的应激严重影响着人类的身心健康，轻者可表现为机体生理功能紊乱，重者可引发应激性疾病。军人作为一个特殊群体，经常处于特殊环境和特定事件之中，军人职业的特殊性决定其将比常人面对更多的应激源。军事应激所致损伤已被确定为部队非战斗减员的主要原因之一，因此军事应激损伤的防护已引起世界各国军事医学部门的高度重视。我国军事应激研究尚处起步阶段，对军事应激与心血管功能改变尤其是心律失常的研究报道尚少。因此，本课题从军事作业现场及实验室模拟应激状态，来探讨军事应激对军人心电生理的影响及机制。目的:本课题第一部分从军事作业现场探讨军事应激对我国现役军人心电生理的影响。通过对动态心电图的对比分析，了解心电变化尤其是心律失常发生的情况；通过分析心率变异性（HRV）、窦性心率震荡（HRT）和T波电交替（TWA）等反映自主神经功能的指标，探讨自主神经系统在应激性心律失常发生中的作用。第二部分是模拟军事应激中应激源多样性和多变性特点，建立急性复合刺激应激动物模型，通过比较炎症因子同型半胱氨酸（Hcy）和高敏C反应蛋白（hs-CRP）水平变化，结合心电图和心肌损伤因子肌钙蛋白I（TNI）变化，从氧化应激方面探讨应激性心律失常发生的机制。第三部分是利用全细胞膜片钳技术，研究异丙肾上腺素（ISO）状态下，豚鼠心室肌细胞动作电位（AP）、延迟后除极（DADs）和相关离子通道的改变，从细胞水平揭示军事应激状态下心律失常发生的机制。并应用β受体阻滞剂美托洛尔（MET）对ISO状态进行干预，探讨β受体阻滞剂在预防军事应激状态下心律失常发生的细胞电生理机制。第一部分急性应激对我国现役军人心电生理的影响课题实施时间：2006.03-2009.12。方案：对某驻京部队在执行维和任务或进行集中军事演练的103名现役军人进行动态心电图监测，作为应激组；同时对该部队在3个月内未参加重大集中军事训练的150名现役军人监测动态心电图，作为对照组，对两组动态心电图进行分析比较，研究军事应激状态下，参训军人心电变化尤其是心律失常发生情况及HRV、HRT、TWA等电生理指标变化。结果：1.所有动态心电图记录时间均为22h²4h，两组无统计学差异。2.心率：应激组的总心搏数、最高心率、最低心率及平均心率均高于对照组（P<0.05或P<0.01）。3.房性心律失常：房早发生率对照组稍高，但两组无统计学差异，但平均房早数应激组明显高于对照组（P<0.01）。应激组房速的发生率显著高于对照组（P<0.05），但由于两组房速发生率均较低，房速的平均阵数无统计学差异。4.室性心律失常：室性早搏的发生率两组无明显差异，但平均室性早搏数量应激组明显高于对照组（P<0.01）。应激组有3人出现短阵室速，而对照组无室速发生。5. HRV时域指标：应激组SDNN、SDANN、PNN50、HRVTI等均低于对照组（均P<0.05）。6. HRT：应激组TO高于对照组，而TS及TD均低于对照组（均P<0.05）。7. TWA：本研究比较了最高心率及早晨8：00连续30对窦性心律的TWA情况，结果显示：2个分析截断点，应激组TWA均明显高于对照组。（均P<0.05）。8.应激组有3人出现短阵室速，综合3人的心电生理指标可见，其中2人的总心搏、平均心率、最高心率及最低心率均明显高于本组相对应指标的均值，另1人的上述指标略高于均值。HRV各时域指标其中1人显著减低，另2人轻度减低。HRT指标中2人TO、TS及TD均为阳性，1人TS及TD阳性，TO阴性。3人的TWA均高于本组相对应指标的均值。结论：1.应激状态下，参训军人房早、室早发生的数量明显增加；房速、室速发生率和严重程度均增加。应激是我国军人心律失常产生或/和加重的原因之一。2.应激状态下，参训军人自主神经功能紊乱调节失衡，特别是迷走神经功能失常。3.应激状态下，自主神经调节失衡，致心肌细胞电活动不稳定，增加了心肌易损性，易诱发各种心律失常。军事应激与心律失常的发生有密切的关联。4.多个反映自主神经功能失衡的检测指标联合应用，将进一步提高对SCD高危人群的识别和预测。第二部分急性复合刺激对豚鼠的应激作用方法：采用噪声、夜间光照、足底电击以及束缚的复合刺激作为应激源，刺激豚鼠16h，制备急性应激模型。连接肢体导联心电图监测心率和心律失常情况。应用ELISA法检测急性应激状态下，豚鼠血清中神经内分泌因子促肾上腺皮质素释放激素（CRH）、促肾上腺皮质激素（ACTH）和皮质醇（CORT），炎症因子Hcy和心肌损伤指标TNI含量，用乳胶增强免疫比浊法测定炎症因子血清hs-CRP水平。在评估模型建立成功的同时，从应激因子和炎症因子角度分析应激性心电改变的机制。结果：1.一般行为改变：应激组豚鼠出现尖叫、全身肌肉收缩、乱跑乱钻、大小便增多、上下牙齿打架、毛乍起、易掉毛等现象，其中1只死亡。对照组豚鼠无行为学改变，精神状态良好，活动灵活，摄食摄水活跃，皮毛洁白有光泽，行为表现正常。2.心率变化：应激组豚鼠心率为503±16次/分，明显高于正常对照组337±18次/分（P<0.01）。3.心律失常发生情况：正常对照组在观察期间心电图未见心律失常出现；而应激组中有4只发生多种心律失常：房早（1只）、室早（1只）、短阵室速（1只），均为一过性，持续时间均不长，1只出现恶性心律失常室颤而死亡。4.血清CRH、ACTH及CORT水平：与正常对照组相比，应激组血清CRH、ACTH及CORT的水平均有显著升高（P<0.05或P<0.01）。5.血清Hcy和hs-CRP水平：应激后，豚鼠血清中Hcy为14.12±1.54umol/L显著升高，对照组Hcy为8.35±1.60umol/L（P<0.01）。血清中hs-CRP含量从对照组的2.27±1.52mg/L升高至应激组的6.01±1.74mg/L（P<0.01）。6.血清TNI水平：与正常对照组相比，应激组豚鼠血清TNI明显高于对照组。对照组的TNI为0.27±0.04ug/L应激组升至1.43±0.29ug/L （P<0.01）。结论：1.多重应激刺激成功建立了急性豚鼠应激模型，动物表现出与人类应激状态下相似的主要症状。2.应激状态下，应激动物出现了心电活动异常和心肌损伤。3.应激状态下，心律失常的发生可能与体内应激因子和炎症因子的水平变化有关。第三部分应激与心律失常细胞机制的研究方法：采用酶解法急性分离豚鼠心室肌细胞，成功分离出形态、状况良好，耐钙的单个豚鼠心室肌细胞。建立全细胞膜片钳模式。应用ISO30.0nmol/L为工具药，模拟高儿茶酚胺状态下的细胞模型。应用全细胞膜片钳技术记录ISO状态下，豚鼠单个心室肌细胞AP、DADs及L-型钙通道电流（ICa,L）、瞬时内向电流（Iti）等电流的变化，从细胞水平分析应激致心律失常的机制。并应用β受体阻滞剂MET对ISO状态进行干预，探讨β受体阻滞剂在预防军事应激状态下心律失常发生的细胞电生理机制。结果：1.豚鼠心室肌细胞的急性分离及全细胞膜片钳的建立：控制好心肌细胞分离中的各种实验条件、熟练的实验操作，可顺利得到适合膜片钳记录的单个心室肌细胞。2. ISO致豚鼠心室肌单细胞AP的改变及MET的干预：应用ISO后APD明显缩短，1相切迹降低，在同时灌流MET后这种变化得到缓解。ISO30.0nmol/L使APD₅₀显著缩短，从对照组的177.6±6.2ms缩短至130.3±9.9ms（P<0.01, n=10）；而APD₉₀由对照组的311.8±13.5ms缩短至262.1±11.6ms（P<0.01, n=10）；而动作电位幅度（APA）和静息膜电位（RMP）等参数均未发生改变。灌流ISO30.0nmol/L+MET1.0μmol/L后APD50恢复至145.7±8.8ms，APD₉₀恢复至297.5±15.5ms。APA和RMP仍然变化较小，均无统计学差异。3. ISO诱发豚鼠心室肌单细胞DADs和TAs作用：在1.0Hz频率刺激时，应用ISO30.0nmol/L后可以偶尔诱发出DADs，但无论是DADs的幅值还是发生的事件频率均较小。3.0Hz频率刺激时，应用ISO30.0nmol/L后可见诱发系列的DADs，最初DADs的幅值较高，之后逐渐降低，其发生的事件频率较多，几乎出现在整个静息电位期间。在5.0Hz频率刺激时，应用ISO30.0nmol/L后可见诱发出TAs，TAs呈现出明显的自动除极4相电位，但动作电位幅度较低，并未达到刺激诱发电位的幅值，同时，还伴随着较多的DADs出现。1.0-3.0-5.0Hz系列外向电流串刺激时，应用ISO30.0nmol/L后可见诱发出的DADs和TAs。在1.0Hz的刺激脉冲后，只出现了1个DADs，且幅值较小；在3.0Hz的刺激脉冲后，出现了数个DADs，幅值较1.0Hz时增加较多；而在5.0Hz时，则出现TAs和更多的DADs。4.1ISO对豚鼠心室肌单细胞ICa,L的作用及MET干预：应用ISO30.0nmol/L后，ICa,L（电流-电压） I-V曲线可见，电流密度显著增加，尤其是在0mV附近更甚，但其不改变通道的激活电压和峰值电压；也基本不改变I-V曲线的“倒钟”形状，随着电压的改变，电流密度也有所改变。在与MET合用后，各电压下电流密度降低明显，几乎与对照无差异。应用ISO30.0nmol/L后，稳态激活曲线右移，即向去极化方向移动，V_1/2从对照的-38.84±1.9mV移到-28.89±3.18mV（n=20, P<0.01）。应用MET后得以部分恢复，V_1/2变为-34.45±1.75mV。但无论是应用ISO或加用MET，k值变化不大，三组的k值分别为对照：5.88±0.54mV，ISO：5.18±0.16mV和MET+ISO:4.96±0.22mV。应用ISO30.0nmol/L后，稳态失活曲线右移，即向去极化方向移动，V_1/2从对照的-40.77±3.58mV移到-24.79±2.26mV（n=20, P<0.01）。应用MET后得以部分恢复，V_1/2变为-36.58±3.00mV。用ISO或加用MET，三组的k值分别为对照：7.11±0.52mV，ISO：5.30±0.22mV和MET+ISO：6.20±0.87mV，虽然三组有些差异，但差异无显著性意义。应用ISO30.0nmol/L后，虽然激活曲线也向右移，但由于失活曲线右移更加显著，致使窗口电流增加。应用MET后，增加的窗口电流得以恢复。无论是ISO30.0nmol/L还是同时灌流ISO+MET，均对通道失活后恢复影响不大。4.2ISO对豚鼠心室肌单细胞Iti的作用及MET干预：应用ISO30.0nmol/L后Iti显著增加，在-50mV时的峰电流密度从对照的-0.69±0.18pA/pF增加至-3.24±0.24pA/pF（n=18, P<0.01），而同时应用MET后，电流密度虽然也增加，但增加幅度显著降低，电流密度为-1.21±0.19pA/Pf。Iti的I-V曲线可见，对照组电流约在-70mV被激活，在-50mV达到峰值，之后内向电流降低（注本实验未对外向电流进行统计分析），ISO30.0nmol/L使各电压下电流密度增加，尤其是峰值电位附近增加更为明显，同时使通道激活提前至-100mV，并使曲线由“倒钟”形变为“三角”形，但其并未改变电流的峰值位置。应用MET后，Iti电流与单独应用ISO相比有明显的降低。应用ISO30.0nmol/L后稳态激活曲线显著负移，V_1/2从对照组的-61.02±3.09mV移至-89.76±7.58mV。而应用MET后虽然有所缓解，但V_1/2仍然左移至-72.96±7.69mV。结论:1.ISO对豚鼠心室肌单细胞APD50和APD90均有缩短作用，而对APA和RMP无明显影响。动作电位时程缩短，可引起折返性心律失常。2.MET可改善ISO对豚鼠心室肌单细胞AP时程缩短的影响，延长有效不应期，抑制折返环路的形成，减少心律失常发生。3.ISO可诱发豚鼠心室肌单细胞产生DADs和TAs，引起触发性心律失常，且此作用具有明显的频率依赖性。4.ISO对豚鼠心室肌单细胞L-型钙通道的激活和失活均有抑制作用，但程度不同，总效应表现为窗口电流增加。窗口电流是诱发DADs的重要原因。应用ISO+MET窗口电流被明显减弱，进而降低胞浆内的钙离子浓度，减轻钙超载，减少触发机制的形成。5. Iti是构成DADs的离子流。ISO改变了豚鼠心室肌单细胞Iti通道的激活特性，使Iti增加，且此作用存在电压依赖特征。MET在不同膜电位水平对Iti均有抑制作用，进而减少DADs及TAs发生。更多还原

【Abstract】 BACKGROUND: Stress is a comprehensive response status that’s created when wemeet with exterior and interior environment upheaval. Intensity or long-time of stresscould arouse severe influence on the mankind’s physical and mental health. The lightlevel of stress can lead to physiological function disorder. When the stress become tooseriously, it can cause stress diseases. Military personnel is a special community,usually be placed in special environment and particular affairs. Military stress hasbecome one of the main causes of non-combat attrition. Therefore, many countriesgreatly pay attention to prevent of damage related to military stress. China’s militarystress research is still on beginning stage. The reports about the mechanism thatmilitary stress can hurt cardiovascular function, particularly cause arrhythmia wererare.This research focuses on the influence on cardiac electrophysiology related toacute military stress by using some data collected from the scene of militaryoperations, and also focuses on the mechanisms how the stress lead to arrhythmias byusing laboratory data that mimic stress situation.PURPOSE:This eassy first part inquire into military stress influence on cardiac electrophysiologyof Chinese soldiers from the scene of military operations. We compare the Holter datato study the incidence and the type of stress-induced arrhythmia. We analyze HRV,HRT and TWA to investigate function of autonomic nervous system leading toarrhythmia related to stress.The second part is to imitate military stressor diversityand polytropy characteristics, build up acute guinea pig stress model. We measure theconcentrations of CRH, ACTH, CORT, Hcy, hs-CRP and TNI, combine the changesof electrocardiogram to explore the mechanism that stress factor and inflammatoryfactor which cause arrhythmias in acute stress situation.The third part we record thechanges of AP, DADs, ICa,Land Itiin ventricular myocytes of guinea pigs in ISO and normal situation by using patch clamp. From cellular level to reveal the mechanism ofacute military stress causing arrhythmias. Medicate with MET to make clearmolecular mechanism of β-blocker preventing arrhythmias.Part1The influence on cardiac electrophysiology of military personnel becauseof acute military stressTIME:2006Mar.-2009Dec.METHODS: Collected the Holter data of103soldiers in one Beijing military as atest group. At the same time, collected the Holter data of other150soldiers act as thecontrol group. By comparing the data of two groups, we studied the incidence andtype of arrhythmia, analyzed the changes of HRV, HRT and TWA.RESULT:1. All the soldiers’ Holter recording times were22h-24h. The recording times of thesetwo groups had no significant difference.2. The sum of heart rate, the average heart rate, the maximum heart rate and theminimum heart rate in the test group were all faster than those of the control group.They all had statistically different.3. The incidence of atrial premature in the test group was a litter lower than that of thecontrol group. But the average number of atrial premature was higher in the test group（P <0.01）. The incidence of paroxysmal atrial tachycardia in the test group was higherthan that of the control group （P <0.01）.4. There was no difference of the incidence of ventricular premature in two groups.But the average number of ventricular premature was higher in the test group （P<0.01）.In the test group,3soliders had attacked ventricular tachycardia. Fortunately,no people in the control group had this terrible thing.5. In the time domain indices of HRV, in the test group the SDNN, SDANN, PNN50,and HRVTI were all lower than those in the control group （all P <0.05）.6. We analyzed HRT of both groups. TO was higher in the test group, while otherindices such as TS and TD were lower than those in the control group （all P <0.05）.7. We compared TWA of30pair consecutive sinus rhythm at maximum heart rate andin the morning8:00in two groups. The results showed: the TWA of maximum heartrate and8:00Am in test group were significantly higher than those in the controlgroup （all P <0.01）.8. There were3soliders had attacked ventricular tachycardia in the test group.Combined these3men’s data, we found2soliders of these men had significantly higher in the sum heart rate, the average heart rate, the maximum heart rate and theminimum heart rate than the average level of the test group. The other man had a littlehigher. One solider’s HRV was obviously decreased. The other two men’s HRV wereslight decreased. Two of these men had positive all indices of HRT, one had positiveTS and TD. All these men’s TWA were higher than the average level of the test group.CONCLUSION:1. In stressful situations, military personnel have more atrial arrhythmia, ventriculararrhythmia than usual, and the severity of arrhythmia increased. Stress is one reasonfor arrhythmia happened or increased in our military personnel.2. Stress provoke misbalance of military personnel’s autonomic nervous system,especially vagus nerve malfunction.3. The disorder of military personnel’s autonomic nervous system may increaseunstable of cardiac myocytes’ electric activity and raise the risk of arrhythmia.4. Combined with several markers reflecting the function of autonomic nervoussystem may increase ability to identify high risk of SCD people.Part2Function of acute multiple stressors to the guinea pigMETHODS: Combined with noise, light, foot sole electric shock and constraint asthe stressors to stimulate guinea pigs for16hours to build up acute stress animalmodels. Recorded ECG, and measured the concentrations of guinea pigs’ serum CRH,ACTH, CORT, Hcy, hs-CRP and TNI.RESULT:1. Signs of Stress: guinea pigs which were experienced stress showed some of thefollowing signs, yelping, all over the body muscle contraction, hurried and confusedescaped, defecation increased, hair became upright and lost fur. One guinea pig wasdead.2. The average heart rate of stressed guinea pigs was faster than the control group （P<0.01）.3. During the observation period, in the control group there was no arrhythmia. Butfour guinea pigs in the test group had different types of arrhythmia. Every type ofarrhythmia did not last long time. One guinea pig was attacked ventricular fibrillationto dead.4. The concentrations of CRH, ACTH and CORT in serum of stressed guinea pigswere higher than those in the control group （P<0.01or P<0.05）. 5. The levels of Hcy and hs-CRP were significantly higher in the stress group thanthose in the control group （all P <0.01）.6. In the stress group, TNI was1.43±0.29ug/L higher than that in the control group0.27±0.04ug/L （P<0.01）.CONCLUSION:1. Multiple stressors successfully build up acute stress animal models. Animals showmain symptoms resemble to mankind in stressful situation.2. In stress state, animals manifest abnormality of electrocardio activity and damageof myocardium.3. The changes of stress factor and inflammatory factor are related to arrhythmias inacute stress situation.Part3Cellular mechanisms for stress-induced arrhythmiaMETHODS: Isolated guinea pigs ventricular myocytes by using enzymatic method.Selected guinea pigs’ single ventricular myocyte which was in good condition andcalcium-resistant to establish whole-cell patch clamp mode. Applicated ISO30.0nmol/L as a tool for medicine, to establish a cell model of hypercatecholamine state.Recorded AP, DADs, ICa,L, and Itiof guinea pig single ventricular myocyte by patch toanalyzed cellular mechanisms for stress-induced arrhythmia. Medicate with MET tomake clear molecular mechanisms of β-blocker preventing arrhythmias.RESULT:1. Guinea pig single ventricular cell was successfully isolated and established ofwhole-cell patch clamp mode.2. Recorded AP in stressed guinea pigs single ventricular myocytes and interferedwith MET.Using30.0nmol/L ISO to perfuse in the cell pool, the APD of single ventricularmyocyte shortened significantly. APD₅₀of guinea pig ventricular myocytes in thecontrol group were shorted from177.6±6.2ms to130.3±9.9ms（P<0.01, n=10）, andAPD₉₀of them were shorted from311.8±13.5ms to262.1±11.6ms （P <0.01, n=10）.No changes in APA and RMP. Used30.0nmol/L ISO+1.0μmol/L MET, APD₅₀recovered to145.7±8.8ms, and APD₉₀recovered to297.5±15.5ms. But APA andRMP had no significant changes.3. Effects on DADs of guinea pigs single ventricular myocytes by ISO. Using30.0nmol/L ISO to perfuse in the cell pool, given1.0Hz frequencystimulus may occasionly induce DADs. Both amplitude and incidence of DADs werelittle.3.0Hz frequency stimulus could induce a series of DADs. The amplitude ofDADs was high at the beginning, and then got short. The incidence of DADs wasincreased and nearly lasted for the whole resting potential.5.0Hz frequency stimulusinduced TAs. TAs took on apparent spontaneous depolarization of the4th phase. Butits amplitude of action potential was lower than stimulus-induced potential.Using30.0nmol/L ISO, given1.0-3.0-5.0Hz frequency train stimulus couldinduce DADs and TAs. After1.0Hz frequency stimulus, only one DADs emerged.Several DADs emerged after3.0Hz frequency stimulus and more DADs emergedafter5.0Hz frequency stimulus and then led to TAs.4. Effects on ICa,Lof guinea pigs single ventricular myocytes by ISO and interferedwith MET.ICa,Lincreased significantly after using30.0nmol/L ISO. ICa,Lcurrent density wasgreatly increased, especially at about0mV. No changes were detected in activationpotential, peak potential and the shape of I-V curve after given ISO. While perfusedwith30.0nmol/L ISO+1.0μmol/L MET, ICa,Lcurrent density at all voltages wasdecreased to nearly the control level.30.0nmol/L ISO made the steady-state activation curve of ICa,Lshift right. Thechannel half-inactivation voltage (V_1/2) shifted to depolarization, from-38.84±1.9mVmoved to-28.89±3.18mV （n=20, P <0.01）, but did not change the curve slope （k）.Used30.0nmol/L ISO+1.0μmol/L MET, V_1/2was partly recovered to-34.45±1.75mV,but k didn’t change.30.0nmol/L ISO made the steady-state inactivation curve of ICa,Lalso shift right.V_1/2shifted to depolarization, from-40.77±3.58mV moved to-24.79±2.26mV （n=20,P <0.01）. Interfered with MET, V_1/2was recovered to-36.58±3.00mV. Neither ISOnor ISO+MET, k changed notablely.Because the steady-state inactivation curve of ICa,Lshifted right more greatlythan the steady-state activation curve, window current was increased ultimately.Interfered with MET, window current was decreased to nearly control level.Both ISO and ISO+MET did not affect the recovery from inactivation curve ofICa,L.5. Effects on Itiof guinea pigs single ventricular myocytes by ISO and interfered withMET. Itiincreased significantly after using30.0nmol/L ISO. The current density at-50mV increased from-0.69±0.18pA/pF to-3.24±0.24pA/pF（P<0.01, n=18）.Perfused30.0nmol/L ISO+1.0μmol/L MET, the current density changed little to-1.21±0.19pA/pF.From the I-V curve of the current, we could see the current was activated at-70mV, reached peak potential at-50mV, and then inward current decreased. Using30.0nmol/L ISO, Iticurrent density was increased at every voltage, especially at aboutpeak potential, and the channel activation voltage moved early to-100mV. The shapeof curve changed from converse clock to triangle, but no change the location of peakcurrent. Interfered with MET, Iticurrent density was decreased slightly.30.0nmol/L ISO made the steady-state activation curve of Itishift left. V_1/2shifted from-61.02±3.09mV to-89.76±7.58mV. Used30.0nmol/L ISO+1.0μmol/LMET, V_1/2was partly recovered to-72.96±7.69mV.CONCLUSION:1. ISO shorts APD50and APD90in guinea pig single ventricular myocyte. Shortenof APD could induce reentry arrhythmias.2. MET may ameliorate the shorten of APD from ISO, extend effective refractoryperiod, inhibit formation of reentry loop to reduce arrhythmias.3. ISO could induce DADs and TAs in guinea pig single ventricular myocyte. Thisfunction shows frequency-depend.4. ISO inhibits both activation and inactivation of L-type calcium channel, and theinactivation is influenced greatly. So the final effect is window current is increased.Window current is the important reason for DADs. Interfered with MET, windowcurrent could recovery to nearly control level. Which decreases the concentration ofintracellular Ca2+, ameliorates Ca2+overload and lessens triggering mechanism.5. Itiis main component of DADs. ISO increases Itiof single guinea pig ventricularmyocyte by altering the activation characters of Iti. MET could inhibit Itiat differentmembrane potentials, which could reduce the incidence of DADs and TAs.更多还原