慢性间歇性低压低氧对发育大鼠抗心律失常作用的电生理学研究
|
摘要
大量研究表明,慢性间歇性低压低氧(chronic intermittent hypobaric hypoxia, CIHH)对成年动物具有明显的心脏保护作用,可有效对抗急性缺血/再灌注或急性缺氧/复氧对心肌的损伤、减少心肌梗死面积、限制心肌超微结构的损伤,以及抗心律失常。其机制可能涉及心肌抗氧化能力增强、心肌毛细血管密度及冠脉血流量增加、热休克蛋白表达增加、NO产生增加、抗心肌细胞凋亡、稳定线粒体及钙处理功能、延长心肌动作电位时程及有效不应期等。但有关CIHH对幼年动物发育心脏的作用尚未明了。本研究旨在应用功能学及电生理学方法探讨CIHH对幼年发育大鼠的抗心律失常作用,及其电生理学机制。
本研究分为四部分:(1)应用模拟高原低氧处理方法制备发育大鼠间歇性低氧心脏保护动物模型;(2)应用在体冠脉结扎方法诱发心律失常,观察CIHH对发育大鼠的抗心律失常作用;(3)应用细胞内记录方法观察CIHH对发育大鼠心室乳头肌动作电位的影响,探讨CIHH抗心律失常作用的电生理学机制;(4)应用全细胞膜片钳方法观察CIHH对发育大鼠心室肌细胞钾离子通道电流的影响,探讨CIHH抗心律失常的离子机制。
Ⅰ发育大鼠慢性间歇性低压低氧心脏保护模型的制备
目的:通过应用不同间歇性低氧方式,制备发育大鼠CIHH心脏保护模型。
方法:雄性新生SD大鼠按年龄及体重相匹配分成三组:间歇性低压低氧3000米组(CIHH3000)、间歇性低压低氧5000米组(CIHH5000)和对照组(CON)。间歇性低氧处理动物置于低压氧舱,分别接受28天、42天和56天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)或5000米(PB = 404 mmHg, PO2 = 84 mmHg, 6小时/天)的减压低氧处理。应用langendorff离体心脏灌流技术描记大鼠离体心脏左室功能,给予30分钟全心缺血和60分钟复灌处理。分别记录大鼠心脏缺血前及复灌后不同时间的左室发展压(LVDP)、左室舒张末压(LVEDP)、最大压力变化速率(±LV dp/dt)等心功能参数和冠脉流量(CF)。并测定冠脉流出液的乳酸脱氢酶(LDH)活性。实验结束后,分别测量全心、左心室及右心室重量。
结果:
(1) CIHH3000组大鼠体重增长与对照组无明显差异;CIHH5000组大鼠体重增长明显慢于对照组及CIHH3000组大鼠(P < 0.01)。
(2)对照组28天、42天及56天的大鼠在基础状态及缺血/复灌后心功能分别相比无显著差异(P > 0.05)。
(3) CIHH3000组大鼠表现明显的心脏保护效应。与对照组相比较,基础状态下灌脉流量明显增加,在心脏停灌/再灌注60 min时,心功能恢复增强(P < 0.05)、冠状动脉流量增多(P < 0.05)、LDH活性降低(P < 0.05);心脏重量与对照组大鼠无差异;CIHH 42天处理的大鼠心功能恢复明显好于CIHH 28天处理的大鼠(P < 0.05)。
(4) CIHH5000组大鼠表现出明显的心脏损伤效应,与对照组相比,心功能的恢复降低(P < 0.05),冠脉流量减少(P < 0.05),复灌过程中LDH活性明显升高(P < 0.05)。右心室重量明显高于对照组大鼠(P < 0.05)。小结:适度的CIHH可保护发育大鼠心脏对抗缺血/再灌注损伤,其保护作用与冠脉流量增加有关;间歇性低氧方式影响其心脏保护作用。
Ⅱ慢性间歇性低压低氧对发育大鼠缺血性心律失常的影响
目的:利用在体结扎冠脉诱发心律失常的方法,研究CIHH对发育大鼠的抗缺血性心律失常作用。
方法:雄性新生SD大鼠,根据年龄及体重相匹配分成四组:28天间歇性低压低氧组(CIHH28)、42天间歇性低压低氧组(CIHH42)和28天对照组(CON28)、42天对照组(CON42)。CIHH动物置于低压氧舱,分别接受28天和42天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)的减压低氧处理。动物麻醉下,描记动脉血压和心电图。通过在体结扎冠状动脉左前降支造成急性心肌缺血,观察室性早搏(VE)、室性心动过速(VT)及心室纤颤(VF)的发生情况。心律失常评分(arrhythmia score, AC)根据Johnston标准。
结果:
(1)冠脉阻断后引起的心律失常主要集中在3~8分钟。CON28组与CIHH28组动物相比较,AC无明显差别,分别为0.25±0.11和0.20±0.15(P > 0.05);
(2) CON42组与CIHH42组大鼠的AC明显不同。CON42组的AC(2.13±0.74)明显高于CIHH42组(0.38±0.24)大鼠(P < 0.05)。
(3)经CIHH处理后,CIHH28组与CIHH42组动物的AC无明显差别,分别为0.20±0.15, 0.38±0.24(P > 0.05)。
小结:本研究结果显示CIHH对发育大鼠具有明显的抗心律失常作用,其作用与动物年龄密切相关。发育大鼠缺血性心律失常的发生在一定范围随年龄而增加。
Ⅲ慢性间歇性低压低氧对发育大鼠心室乳头肌动作电位的影响
目的:利用CIHH动物模型和记录乳头肌动作电位(AP)的方法,研究CIHH对发育大鼠乳头肌AP的影响。
方法:雄性新生SD大鼠,按年龄及体重相匹配分成四组:28天间歇性低压低氧组(CIHH28)、42天间歇性低压低氧组(CIHH42)和28天对照组(CON28)、42天对照组(CON42)。CIHH动物置于低压氧舱,分别接受28天和42天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)的减压低氧处理。以台氏液及模拟缺血液灌流左室乳头肌标本,利用细胞内微电极技术描记动物乳头肌AP以及缺血前后AP的变化。
结果:
(1)在台氏液灌流的基础状态下,CON动物与CIHH动物相比,AP各参数无明显差异(P > 0.05)。
(2)以模拟缺血液灌流乳头肌标本5分钟后, CON42组与CIHH42组动物乳头肌AP的APA、OS、Vmax及APD90均明显降低(P < 0.05)。但CIHH42组AP的APD90的缩短程度明显小于CON42组(P < 0.05);模拟缺血液灌流时,CON28与CIHH28组动物APD缩短无明显差别(P > 0.05)。
(3)在台氏液灌流的基础状态下,CON28组与CON42组大鼠AP相比较无明显差异(P > 0.05)。以模拟缺血液灌流乳头肌标本5分钟后,CON42组大鼠APD90的缩短程度明显大于CON28组大鼠(P < 0.05)。
(4)在台氏液灌流的基础状态下,CIHH28组与CIHH42组大鼠AP相比较无明显差异(P > 0.05)。以模拟缺血液灌流乳头肌标本5分钟后,两组大鼠AP缩短的程度相比无明显差异(P > 0.05)。
小结:我们的研究显示, CIHH处理不影响基础状态下发育大鼠乳头肌的AP。但随年龄增长,CIHH可显著延缓APD90在缺血时的缩短,稳定膜的复极化。
Ⅳ慢性间歇性低压低氧对发育大鼠心室肌细胞钾通道的影响
目的:通过全细胞膜片钳方法观察CIHH对发育大鼠心室肌细胞钾离子通道电流的影响,探讨CIHH抗心律失常的离子机制。
方法:雄性新生SD大鼠,按年龄及体重相匹配分成四组:28天间歇性低压低氧组(CIHH28)、42天间歇性低压低氧组(CIHH42)和28天对照组(CON28)、42天对照组(CON42)。CIHH动物置于低压氧舱,分别接受28天和42天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)的减压低氧处理。通过酶解法得到单个心肌细胞,利用全细胞膜片钳技术记录瞬时外向钾电流(Ito),延迟整流钾电流(IK)和内向整流钾电流,观察CON和CIHH大鼠心肌细胞在模拟缺血液灌流前后上述钾通道电流的变化。
结果:
(1) CON28组与CIHH28组大鼠心室肌细胞IK密度在模拟缺血液前后无明显变化(P > 0.05); CON42组与CIHH42组大鼠心室肌细胞IK密度在模拟缺血前相比无差异(P > 0.05),但在模拟缺血灌流5分钟后,CON42组大鼠心室肌细胞IK密度较CIHH42组明显增大(P < 0.05)。
(2) CON28组与CIHH28组大鼠心室肌细胞IK1密度在模拟缺血液前后无明显变化(P > 0.05);CON42组与CIHH42组大鼠心室肌细胞IK1密度在模拟缺血前相比无差异(P > 0.05),但在模拟缺血灌流5分钟后,CON42组心室肌细胞IK1密度较CIHH42组明显增大(P < 0.05)。
(3) CON与CIHH大鼠心室肌细胞Ito密度在模拟缺血前后相比无明显差别(P > 0.05)。在模拟缺血时,心室肌细胞Ito密度降低,稳态激活和失活曲线向负电压方向移位而且复活时间常数延长(P < 0.05)。
小结:研究结果显示CIHH对生后发育大鼠心脏复极化电流产生复杂的影响。CIHH不影响基础状态下的IK、IK1和Ito,但CIHH可显著减轻IK,IK1在模拟缺血状态下的增强。
A lot of researches have demonstrated that chronic intermittent hypobaric hypoxia (CIHH) confers significant cardioprotetive effects on adult heart, such as enchancing the resistance of heart against acute hypoxia/re-oxygen or acute ischemia/reperfusion injury, reducing infarct size, limiting cardiac ultrastruc- ture damage and anti-arrhythmia. The candidate mechanisms involved enhancement of antioxidation, increase of myocardium capillary desity and coronary flow, overexpression of heat shock protein, increase of NO production, anti-apoptosis, stabilization of mitochondria and function of handling calcium, prolongation of action potential duration and effective refractory period. However, it was not clear about the role of CIHH on postnatal developing hearts. The objective of the study was to explore the anti-arrhythmic effects of CIHH and underling electrophysiological mechanism on postnatal developing rat using functional and electro- physiological methods。
Our study consists of four parts: (1) To make an animal model of CIHH cardioprotection through exposing the developing rat to simulated high altitude hypoxia. (2) To examine anti-arrhythmic effects of CIHH on developing rat via analysis of arrhythmia induced by ligation of coronary artery in vivo. (3) To examine effects of CIHH on action potential in papillary muscle from developing rat through intracellular recording, and to explore electrophysiological mechanism of CIHH against arrhythmias. (4) To examine of effects of CIHH on potassium currents in ventricular myocytes of developing rat by using whole-cell patch clamp techenique, and to explore the ionic mechanism of CIHH against arrhythmias.
I Preparation of animal mode for cardioprotection of CIHH in developing rat
Objective: to make animal model for cardioprotection of CIHH in developing rat by using different modes of CIHH.
Methods: Age- and body weight- matched postnatal male rats were divided into three groups: 3000m chronic intermittent hypoxia (CIHH3000) group, 5000m chronic intermittent hypoxia (CIHH5000) group and control (CON) group. For CIHH groups, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) or 5000 m altitude (PB = 404 mmHg, PO2 = 84 mmHg, 6 hrs/day) for 28, 42 and 56days, respectively. The isolated hearts were perfused in the langendorff apparatus, undergoing 30min global ischemia and 60min reperfusion. Parameters of cardiac function including left ventricular developing pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximal velocity of left ventricular pressure (LVdp/dtmax), coronary flow (CF) and lactate dehydrogenase (LDH) activity were recorded respectively. The total heart weight, right ventricular weight and left ventricular plus inter-ventricular septum weight were measured at the end of the experiment.
Results:
(1) There was no difference of body weight gaining between CIHH3000 and CON rats. The gain of body weight in CIHH5000 rats was much lower than that in CIHH3000 and CON (P < 0.01).
(2) There were no significant differences of cardiac function among 28-day, 42-day and 56-day of control rats under basic condition and during ischemia/reperfusion.
(3) Compared with CON, CF in CIHH rats was increased under basic condition, the recovery of cardiac function in CIHH3000 rats was enhanced at 60 min after ischemia/reperfusion (P < 0.05), coronary flow was increased (P < 0.05), and LDH activity was decreased (P < 0.05), which means a cardioprotective effect occurred. There was no significant difference of heart weight between CIHH3000 and CON. In addition, cardiac function restored better in CIHH3000 rat after 42 days CIHH than that after 28 days CIHH (P < 0.05).
(4) Compared with CON, the recovery of cardiac function in CIHH5000 rats was lower (P < 0.05), coronary flow was decreased (P < 0.05), and LDH activity was increased (P < 0.05). Right ventricular weight was higher in CIHH5000 than that in CON rats (P < 0.05).
Conclusion: The result of the study suggests that moderate CIHH can protect developing rat heart against ischemia/reperfusion injury, which was affected by mode of CIHH exposure and related with CF increase.
ⅡEffects of CIHH on ischemic arrhythmia in developing rats
Objective: To examine anti-arrhythmic effects of CIHH on developing rat via analysis of arrhythmia induced by ligation of coronary artery in vivo.
Methods: In this part of experiment, age- and body weight-matched postnatal male rats were divided into four groups: 28-day CIHH group (CIHH28), 42-day CIHH group (CIHH42), 28-day control group (CON28) and 42-day control group (CON42). For CIHH group, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) for 28days and 42days, respectively. Arterial blood pressure and electrocardiogram (ECG) were recorded under anesthetized state. Acute myocardial ischemia was produced by ligating left anterior descending coronary artery in anesthetized postnatal male rats. Ventricular extrasystole (VE), tachycardia (VT) and fibrillation (VF) were analyzed from ECG. Arrhythmia scores (AC) were used according to Johnston’s Standards.
Results:
(1) The arrhythmia was mainly occurred between 3 and 8 min after coronary artery occlusion. There was no significant difference in ACs between CON28 (0.25±0.11) and CIHH28 (0.20±0.15) rats (P > 0.05).
(2) There was a significant difference of AC between CON42 and CIHH42 rats. The AC was 2.13±0.74 in CON42 rats, much higher than 0.38±0.24 in CIHH42 rats (P < 0.05).
(3) In CIHH group, there was no significant difference of AC between CIHH 28 (0.20±0.15) and CIHH42 (0.38±0.24) rats (P > 0.05).
Conclusion: The result of the study demonstrates that CIHH has a significant anti-arrhythmic effect in developing rat, which is closely related with animals’age. The incidence of ischemic arrhythmia in developing rat increases along with rat growing in a certain age range.
ⅢEffects of CIHH on action potential in ventricular papillary muscle of developing rat
Objective: to investigate the effects of CIHH on action potential (AP) in ventricular papillary muscle of developing rats by using CIHH animal model and intracelluar recording method. Methods: In this part of experiment, age- and body weight-matched postnatal male rats were divided into four groups: 28-day CIHH group (CIHH28), 42-day CIHH group (CIHH42), 28-day control group (CON28) and 42-day control group (CON42). For CIHH group, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) for 28days, 42days, respectively. The left vetricullar papillary muslces were perfused with Tyrodes solution and simulated ischemic solution. AP in papillary muscle was recorded before and during simulated ischemia by using intracellular microelectrode technique.
Results:
(1) There was no difference in any parameters of basic AP between CON and CIHH rats during Tyrodes solution perfusion (P > 0.05).
(2) APA, OS, Vmax and APD90 of AP in papillary muscle were decreased significantly (P < 0.05) after 5minutes of simulated ischemia solution perfusion, but the decreasing of AP90 in CIHH42 rats was much smaller than than in CON42 rats (P < 0.05). There was no significant difference of AP decreasing during simulated ischemia between CON28 and CIHH28 rats (P > 0.05).
(3) In CON groups, there was no difference of AP between CON28 and CON42 rats during Tyrodes solution perfusion (P > 0.05). The decreasing of APD90 of AP after 5minutes of simulated ischemia solution perfusion was more severe in CON 42 rats than that in CON28 rats (P < 0.05).
(4) In CIHH groups, there was no difference of AP between CIHH28 and CIHH42 rats during Tyrodes solution perfusion (P > 0.05). Also there was no significant difference of AP decreasing after 5minutes of simulated ischemia solution perfusion between CIHH28 and CIHH42 rats (P > 0.05).
Conclusion: The result of the study shows that CIHH does not affect basic AP in papillary muscle of developing rats. CIHH, however, can significantly alleviate the decreasing of APD90 induced by simulated ischemia, stabilizing the membrane repolarization during ischemia.
ⅣEffect of CIHH on potassium currents in ventricular myocytes of developing rat
Objective: to explore the effect of CIHH on cardiac potassium currents in developing rat heart by using whole-cell patch clamp technique, and the ionic mechanism of CIHH against arrhythmias.
Methods: In this part of experiment, age- and body weight-matched postnatal male rats were divided into four groups: 28-day CIHH group (CIHH28), 42-day CIHH group (CIHH42), 28-day control group (CON28) and 42-day control group (CON42). For CIHH group, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) for 28days, 42days, respectively. Isolated myocytes were obtained from ventricles by acute enzymic digestion method. Transient ourward potassium current (Ito), delayed rectifier potassium current (IK), inwardly rectifier potassium (IK1) and ATP-sensitive potassium current (IKATP) from myocytes were recorded before and during simulated ischemic solution perfusion.
Results:
(1) There was no difference of IK density between CON28 and CIHH28 rats before and during simulated ischemia. There was no difference of IK density between CON42 and CIHH42 rats before simulated ischemia, but IK density was increased significantly after 5minutes of simulated ischemia in CON42 rats compared with CIHH42 rats (P < 0.05).
(2) There was no difference of IK1 density between CON28 and CIHH28 rats before and during simulated ischemia. There was no difference of IK1 density between CON42 and CIHH42 rats before simulated ischemia, but IK1 density was increased significantly after 5minutes of simulated ischemia in CON42 rats compared with CIHH42 rats (P < 0.05).
(3) There was no difference of Ito density between CON and CIHH groups before or during simulated ischemia (P > 0.05). During simulated ischemia, Ito density was decreased, steady-state activation and inactivation curves of Ito were shifted negatively, and the time constant of recovery was prolonged (P < 0.05).
Conclusion: The result of the study shows that CIHH has complicated effects on repolarization currents in cardiomyocytes of developing rats. CIHH has no effects on the basic IK, IK1 and Ito, but can significantly alliviate the increase of IK, IK1 during simulated ischemia.
本研究分为四部分:(1)应用模拟高原低氧处理方法制备发育大鼠间歇性低氧心脏保护动物模型;(2)应用在体冠脉结扎方法诱发心律失常,观察CIHH对发育大鼠的抗心律失常作用;(3)应用细胞内记录方法观察CIHH对发育大鼠心室乳头肌动作电位的影响,探讨CIHH抗心律失常作用的电生理学机制;(4)应用全细胞膜片钳方法观察CIHH对发育大鼠心室肌细胞钾离子通道电流的影响,探讨CIHH抗心律失常的离子机制。
Ⅰ发育大鼠慢性间歇性低压低氧心脏保护模型的制备
目的:通过应用不同间歇性低氧方式,制备发育大鼠CIHH心脏保护模型。
方法:雄性新生SD大鼠按年龄及体重相匹配分成三组:间歇性低压低氧3000米组(CIHH3000)、间歇性低压低氧5000米组(CIHH5000)和对照组(CON)。间歇性低氧处理动物置于低压氧舱,分别接受28天、42天和56天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)或5000米(PB = 404 mmHg, PO2 = 84 mmHg, 6小时/天)的减压低氧处理。应用langendorff离体心脏灌流技术描记大鼠离体心脏左室功能,给予30分钟全心缺血和60分钟复灌处理。分别记录大鼠心脏缺血前及复灌后不同时间的左室发展压(LVDP)、左室舒张末压(LVEDP)、最大压力变化速率(±LV dp/dt)等心功能参数和冠脉流量(CF)。并测定冠脉流出液的乳酸脱氢酶(LDH)活性。实验结束后,分别测量全心、左心室及右心室重量。
结果:
(1) CIHH3000组大鼠体重增长与对照组无明显差异;CIHH5000组大鼠体重增长明显慢于对照组及CIHH3000组大鼠(P < 0.01)。
(2)对照组28天、42天及56天的大鼠在基础状态及缺血/复灌后心功能分别相比无显著差异(P > 0.05)。
(3) CIHH3000组大鼠表现明显的心脏保护效应。与对照组相比较,基础状态下灌脉流量明显增加,在心脏停灌/再灌注60 min时,心功能恢复增强(P < 0.05)、冠状动脉流量增多(P < 0.05)、LDH活性降低(P < 0.05);心脏重量与对照组大鼠无差异;CIHH 42天处理的大鼠心功能恢复明显好于CIHH 28天处理的大鼠(P < 0.05)。
(4) CIHH5000组大鼠表现出明显的心脏损伤效应,与对照组相比,心功能的恢复降低(P < 0.05),冠脉流量减少(P < 0.05),复灌过程中LDH活性明显升高(P < 0.05)。右心室重量明显高于对照组大鼠(P < 0.05)。小结:适度的CIHH可保护发育大鼠心脏对抗缺血/再灌注损伤,其保护作用与冠脉流量增加有关;间歇性低氧方式影响其心脏保护作用。
Ⅱ慢性间歇性低压低氧对发育大鼠缺血性心律失常的影响
目的:利用在体结扎冠脉诱发心律失常的方法,研究CIHH对发育大鼠的抗缺血性心律失常作用。
方法:雄性新生SD大鼠,根据年龄及体重相匹配分成四组:28天间歇性低压低氧组(CIHH28)、42天间歇性低压低氧组(CIHH42)和28天对照组(CON28)、42天对照组(CON42)。CIHH动物置于低压氧舱,分别接受28天和42天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)的减压低氧处理。动物麻醉下,描记动脉血压和心电图。通过在体结扎冠状动脉左前降支造成急性心肌缺血,观察室性早搏(VE)、室性心动过速(VT)及心室纤颤(VF)的发生情况。心律失常评分(arrhythmia score, AC)根据Johnston标准。
结果:
(1)冠脉阻断后引起的心律失常主要集中在3~8分钟。CON28组与CIHH28组动物相比较,AC无明显差别,分别为0.25±0.11和0.20±0.15(P > 0.05);
(2) CON42组与CIHH42组大鼠的AC明显不同。CON42组的AC(2.13±0.74)明显高于CIHH42组(0.38±0.24)大鼠(P < 0.05)。
(3)经CIHH处理后,CIHH28组与CIHH42组动物的AC无明显差别,分别为0.20±0.15, 0.38±0.24(P > 0.05)。
小结:本研究结果显示CIHH对发育大鼠具有明显的抗心律失常作用,其作用与动物年龄密切相关。发育大鼠缺血性心律失常的发生在一定范围随年龄而增加。
Ⅲ慢性间歇性低压低氧对发育大鼠心室乳头肌动作电位的影响
目的:利用CIHH动物模型和记录乳头肌动作电位(AP)的方法,研究CIHH对发育大鼠乳头肌AP的影响。
方法:雄性新生SD大鼠,按年龄及体重相匹配分成四组:28天间歇性低压低氧组(CIHH28)、42天间歇性低压低氧组(CIHH42)和28天对照组(CON28)、42天对照组(CON42)。CIHH动物置于低压氧舱,分别接受28天和42天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)的减压低氧处理。以台氏液及模拟缺血液灌流左室乳头肌标本,利用细胞内微电极技术描记动物乳头肌AP以及缺血前后AP的变化。
结果:
(1)在台氏液灌流的基础状态下,CON动物与CIHH动物相比,AP各参数无明显差异(P > 0.05)。
(2)以模拟缺血液灌流乳头肌标本5分钟后, CON42组与CIHH42组动物乳头肌AP的APA、OS、Vmax及APD90均明显降低(P < 0.05)。但CIHH42组AP的APD90的缩短程度明显小于CON42组(P < 0.05);模拟缺血液灌流时,CON28与CIHH28组动物APD缩短无明显差别(P > 0.05)。
(3)在台氏液灌流的基础状态下,CON28组与CON42组大鼠AP相比较无明显差异(P > 0.05)。以模拟缺血液灌流乳头肌标本5分钟后,CON42组大鼠APD90的缩短程度明显大于CON28组大鼠(P < 0.05)。
(4)在台氏液灌流的基础状态下,CIHH28组与CIHH42组大鼠AP相比较无明显差异(P > 0.05)。以模拟缺血液灌流乳头肌标本5分钟后,两组大鼠AP缩短的程度相比无明显差异(P > 0.05)。
小结:我们的研究显示, CIHH处理不影响基础状态下发育大鼠乳头肌的AP。但随年龄增长,CIHH可显著延缓APD90在缺血时的缩短,稳定膜的复极化。
Ⅳ慢性间歇性低压低氧对发育大鼠心室肌细胞钾通道的影响
目的:通过全细胞膜片钳方法观察CIHH对发育大鼠心室肌细胞钾离子通道电流的影响,探讨CIHH抗心律失常的离子机制。
方法:雄性新生SD大鼠,按年龄及体重相匹配分成四组:28天间歇性低压低氧组(CIHH28)、42天间歇性低压低氧组(CIHH42)和28天对照组(CON28)、42天对照组(CON42)。CIHH动物置于低压氧舱,分别接受28天和42天模拟高原3000米(PB = 525 mmHg, PO2 = 108.8 mmHg, 5小时/天)的减压低氧处理。通过酶解法得到单个心肌细胞,利用全细胞膜片钳技术记录瞬时外向钾电流(Ito),延迟整流钾电流(IK)和内向整流钾电流,观察CON和CIHH大鼠心肌细胞在模拟缺血液灌流前后上述钾通道电流的变化。
结果:
(1) CON28组与CIHH28组大鼠心室肌细胞IK密度在模拟缺血液前后无明显变化(P > 0.05); CON42组与CIHH42组大鼠心室肌细胞IK密度在模拟缺血前相比无差异(P > 0.05),但在模拟缺血灌流5分钟后,CON42组大鼠心室肌细胞IK密度较CIHH42组明显增大(P < 0.05)。
(2) CON28组与CIHH28组大鼠心室肌细胞IK1密度在模拟缺血液前后无明显变化(P > 0.05);CON42组与CIHH42组大鼠心室肌细胞IK1密度在模拟缺血前相比无差异(P > 0.05),但在模拟缺血灌流5分钟后,CON42组心室肌细胞IK1密度较CIHH42组明显增大(P < 0.05)。
(3) CON与CIHH大鼠心室肌细胞Ito密度在模拟缺血前后相比无明显差别(P > 0.05)。在模拟缺血时,心室肌细胞Ito密度降低,稳态激活和失活曲线向负电压方向移位而且复活时间常数延长(P < 0.05)。
小结:研究结果显示CIHH对生后发育大鼠心脏复极化电流产生复杂的影响。CIHH不影响基础状态下的IK、IK1和Ito,但CIHH可显著减轻IK,IK1在模拟缺血状态下的增强。
A lot of researches have demonstrated that chronic intermittent hypobaric hypoxia (CIHH) confers significant cardioprotetive effects on adult heart, such as enchancing the resistance of heart against acute hypoxia/re-oxygen or acute ischemia/reperfusion injury, reducing infarct size, limiting cardiac ultrastruc- ture damage and anti-arrhythmia. The candidate mechanisms involved enhancement of antioxidation, increase of myocardium capillary desity and coronary flow, overexpression of heat shock protein, increase of NO production, anti-apoptosis, stabilization of mitochondria and function of handling calcium, prolongation of action potential duration and effective refractory period. However, it was not clear about the role of CIHH on postnatal developing hearts. The objective of the study was to explore the anti-arrhythmic effects of CIHH and underling electrophysiological mechanism on postnatal developing rat using functional and electro- physiological methods。
Our study consists of four parts: (1) To make an animal model of CIHH cardioprotection through exposing the developing rat to simulated high altitude hypoxia. (2) To examine anti-arrhythmic effects of CIHH on developing rat via analysis of arrhythmia induced by ligation of coronary artery in vivo. (3) To examine effects of CIHH on action potential in papillary muscle from developing rat through intracellular recording, and to explore electrophysiological mechanism of CIHH against arrhythmias. (4) To examine of effects of CIHH on potassium currents in ventricular myocytes of developing rat by using whole-cell patch clamp techenique, and to explore the ionic mechanism of CIHH against arrhythmias.
I Preparation of animal mode for cardioprotection of CIHH in developing rat
Objective: to make animal model for cardioprotection of CIHH in developing rat by using different modes of CIHH.
Methods: Age- and body weight- matched postnatal male rats were divided into three groups: 3000m chronic intermittent hypoxia (CIHH3000) group, 5000m chronic intermittent hypoxia (CIHH5000) group and control (CON) group. For CIHH groups, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) or 5000 m altitude (PB = 404 mmHg, PO2 = 84 mmHg, 6 hrs/day) for 28, 42 and 56days, respectively. The isolated hearts were perfused in the langendorff apparatus, undergoing 30min global ischemia and 60min reperfusion. Parameters of cardiac function including left ventricular developing pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximal velocity of left ventricular pressure (LVdp/dtmax), coronary flow (CF) and lactate dehydrogenase (LDH) activity were recorded respectively. The total heart weight, right ventricular weight and left ventricular plus inter-ventricular septum weight were measured at the end of the experiment.
Results:
(1) There was no difference of body weight gaining between CIHH3000 and CON rats. The gain of body weight in CIHH5000 rats was much lower than that in CIHH3000 and CON (P < 0.01).
(2) There were no significant differences of cardiac function among 28-day, 42-day and 56-day of control rats under basic condition and during ischemia/reperfusion.
(3) Compared with CON, CF in CIHH rats was increased under basic condition, the recovery of cardiac function in CIHH3000 rats was enhanced at 60 min after ischemia/reperfusion (P < 0.05), coronary flow was increased (P < 0.05), and LDH activity was decreased (P < 0.05), which means a cardioprotective effect occurred. There was no significant difference of heart weight between CIHH3000 and CON. In addition, cardiac function restored better in CIHH3000 rat after 42 days CIHH than that after 28 days CIHH (P < 0.05).
(4) Compared with CON, the recovery of cardiac function in CIHH5000 rats was lower (P < 0.05), coronary flow was decreased (P < 0.05), and LDH activity was increased (P < 0.05). Right ventricular weight was higher in CIHH5000 than that in CON rats (P < 0.05).
Conclusion: The result of the study suggests that moderate CIHH can protect developing rat heart against ischemia/reperfusion injury, which was affected by mode of CIHH exposure and related with CF increase.
ⅡEffects of CIHH on ischemic arrhythmia in developing rats
Objective: To examine anti-arrhythmic effects of CIHH on developing rat via analysis of arrhythmia induced by ligation of coronary artery in vivo.
Methods: In this part of experiment, age- and body weight-matched postnatal male rats were divided into four groups: 28-day CIHH group (CIHH28), 42-day CIHH group (CIHH42), 28-day control group (CON28) and 42-day control group (CON42). For CIHH group, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) for 28days and 42days, respectively. Arterial blood pressure and electrocardiogram (ECG) were recorded under anesthetized state. Acute myocardial ischemia was produced by ligating left anterior descending coronary artery in anesthetized postnatal male rats. Ventricular extrasystole (VE), tachycardia (VT) and fibrillation (VF) were analyzed from ECG. Arrhythmia scores (AC) were used according to Johnston’s Standards.
Results:
(1) The arrhythmia was mainly occurred between 3 and 8 min after coronary artery occlusion. There was no significant difference in ACs between CON28 (0.25±0.11) and CIHH28 (0.20±0.15) rats (P > 0.05).
(2) There was a significant difference of AC between CON42 and CIHH42 rats. The AC was 2.13±0.74 in CON42 rats, much higher than 0.38±0.24 in CIHH42 rats (P < 0.05).
(3) In CIHH group, there was no significant difference of AC between CIHH 28 (0.20±0.15) and CIHH42 (0.38±0.24) rats (P > 0.05).
Conclusion: The result of the study demonstrates that CIHH has a significant anti-arrhythmic effect in developing rat, which is closely related with animals’age. The incidence of ischemic arrhythmia in developing rat increases along with rat growing in a certain age range.
ⅢEffects of CIHH on action potential in ventricular papillary muscle of developing rat
Objective: to investigate the effects of CIHH on action potential (AP) in ventricular papillary muscle of developing rats by using CIHH animal model and intracelluar recording method. Methods: In this part of experiment, age- and body weight-matched postnatal male rats were divided into four groups: 28-day CIHH group (CIHH28), 42-day CIHH group (CIHH42), 28-day control group (CON28) and 42-day control group (CON42). For CIHH group, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) for 28days, 42days, respectively. The left vetricullar papillary muslces were perfused with Tyrodes solution and simulated ischemic solution. AP in papillary muscle was recorded before and during simulated ischemia by using intracellular microelectrode technique.
Results:
(1) There was no difference in any parameters of basic AP between CON and CIHH rats during Tyrodes solution perfusion (P > 0.05).
(2) APA, OS, Vmax and APD90 of AP in papillary muscle were decreased significantly (P < 0.05) after 5minutes of simulated ischemia solution perfusion, but the decreasing of AP90 in CIHH42 rats was much smaller than than in CON42 rats (P < 0.05). There was no significant difference of AP decreasing during simulated ischemia between CON28 and CIHH28 rats (P > 0.05).
(3) In CON groups, there was no difference of AP between CON28 and CON42 rats during Tyrodes solution perfusion (P > 0.05). The decreasing of APD90 of AP after 5minutes of simulated ischemia solution perfusion was more severe in CON 42 rats than that in CON28 rats (P < 0.05).
(4) In CIHH groups, there was no difference of AP between CIHH28 and CIHH42 rats during Tyrodes solution perfusion (P > 0.05). Also there was no significant difference of AP decreasing after 5minutes of simulated ischemia solution perfusion between CIHH28 and CIHH42 rats (P > 0.05).
Conclusion: The result of the study shows that CIHH does not affect basic AP in papillary muscle of developing rats. CIHH, however, can significantly alleviate the decreasing of APD90 induced by simulated ischemia, stabilizing the membrane repolarization during ischemia.
ⅣEffect of CIHH on potassium currents in ventricular myocytes of developing rat
Objective: to explore the effect of CIHH on cardiac potassium currents in developing rat heart by using whole-cell patch clamp technique, and the ionic mechanism of CIHH against arrhythmias.
Methods: In this part of experiment, age- and body weight-matched postnatal male rats were divided into four groups: 28-day CIHH group (CIHH28), 42-day CIHH group (CIHH42), 28-day control group (CON28) and 42-day control group (CON42). For CIHH group, neonatal rats with the maternals were exposed to a hypobaric chamber, enduring CIHH mimicking 3000 m altitude (PB = 525 mmHg, PO2 = 108.8 mmHg, 5 hrs/day) for 28days, 42days, respectively. Isolated myocytes were obtained from ventricles by acute enzymic digestion method. Transient ourward potassium current (Ito), delayed rectifier potassium current (IK), inwardly rectifier potassium (IK1) and ATP-sensitive potassium current (IKATP) from myocytes were recorded before and during simulated ischemic solution perfusion.
Results:
(1) There was no difference of IK density between CON28 and CIHH28 rats before and during simulated ischemia. There was no difference of IK density between CON42 and CIHH42 rats before simulated ischemia, but IK density was increased significantly after 5minutes of simulated ischemia in CON42 rats compared with CIHH42 rats (P < 0.05).
(2) There was no difference of IK1 density between CON28 and CIHH28 rats before and during simulated ischemia. There was no difference of IK1 density between CON42 and CIHH42 rats before simulated ischemia, but IK1 density was increased significantly after 5minutes of simulated ischemia in CON42 rats compared with CIHH42 rats (P < 0.05).
(3) There was no difference of Ito density between CON and CIHH groups before or during simulated ischemia (P > 0.05). During simulated ischemia, Ito density was decreased, steady-state activation and inactivation curves of Ito were shifted negatively, and the time constant of recovery was prolonged (P < 0.05).
Conclusion: The result of the study shows that CIHH has complicated effects on repolarization currents in cardiomyocytes of developing rats. CIHH has no effects on the basic IK, IK1 and Ito, but can significantly alliviate the increase of IK, IK1 during simulated ischemia.
引文
1 Hurtado A. Some clinical aspects of life at high altitudes. Ann Intern Med, 1960, 53: 247~258
2 Zhu HF, Dong JW, Zhu WZ, Ding HL, and Zhou ZN. ATP-dependent potassium channels involved in the cardiac protection induced by intermittent hypoxia against ischemia/reperfusion injury. Life Sci, 2003, 73 (10): 1275~1287
3 Zhu WZ, Xie Y, Zhou ZN, et al. Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury. J Mol Cell Cardiol, 2006, 40(1): 96~106
4 Béguin PC, Belaidi E, Godin-Ribuot D, et al. Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2. J Mol Cell Cardiol, 2007, 42(2):343~351
5 Zhuang J, Zhou Z. Protective effects of intermittent hypoxic adaptation on myocardium and its mechanisms. Biol Signals Recept, 1999, 8(45): 316~322
6 Zhang Y, Zhong N, Zhou ZN, et al. Antiarrhythmic and antioxidative effects of intermittent hypoxia exposure on rat myocardium. Sheng Li Xue Bao, 2000, 52(2): 89~92
7 Zhong N, Zhang Y, Zhou ZN, et al. Intermittent hypoxia exposure-induced heat-shock protein 70 expression increases resistance of rat heart to ischemic injury. Acta Pharmacol Sin 2000, 21(5): 467~472
8 Dong JW, Zhu HF, Zhou ZN, et al. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression. Cell research 2003, 13(5): 385~391
9 Zhang Y, Zhong N, Gia J, Zhou Z. Effects of chronic intermittent hypoxia on the hemodynamics of systemic circulation in rats. Jpn J Physiol, 2004, 54(2): 171~174
10 O??áDALOVáI, O??áDAL B, JARKOVSKáD, et al. Ischemic preconditioning in chronically hypoxic neonatal rat heart. Pediatr Res,2002, 52(4): 561~567
11 O??áDALOVáI, O??áDAL B, KOLá? F, et al. Tolerance to ischaemia and ischaemic preconditioning in neonatal rat heart. J Mol Cell Cardiol, 1998, 30(4): 857~865
12 Béguin PC, Joyeux-Faure M, Godin-Ribuot D, et ak. Acute intermittent hypoxia improves rat myocardium tolerance to ischemia. Appl Physiol, 2005, 99(3): 1064~1069
13 Zhu WZ, Dong JW, Zhou ZN, et al. Postnatal development in intermittent hypoxia enhances resistance to myocardial ischemia/reperfusion in male rats. Eur J Appl Physiol 2004, 91 (5-6) : 716~722
14 La Padula P, Costa LE. Effect of sustained hypobaric hypoxia during maturation and aging on rat myocardium. I. Mechanical activity. J Appl Physiol 2005, 98(6): 2363~2369
15 Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev, 1999, 79(3): 635~659
16 Poupa O, Krofta K, Prochazka J,et al. Acclimatization to simulated high altitude and acute cardiac necrosis. Federation Proc, 1966, 25(4):1243~1246
17 McGrath JJ, Bullard RW. Altered myocardial performance in response to anoxia after high-altitude exposure. J Appl Physiol, 1968, 25(6): 761~764
18 Widimsky J, Urbanova D, Ressl J, et al. Effect of intermittent altitude hypoxia on the myocardium and lesser circulation in the rat. Cardiovasc Res, 1973, 7(6): 798~808
19 Meerson F.Z. Adaptative protection of the heart: protecting against stress and ischemic damage. Boston: CRC Press, Inc. 1991:pp 249~281
20 Zong P, Setty S, Sun W, et al. Intermittent hypoxic training protects canine myocardium from infarction. Exp Biol Med (Maywood), 2004, 229(8): 806~812
21 Joyeux-Faure M, Stanke-Labesque F, Lefebvre B,et al. Chronic intermittenthypoxia increases infarction in the isolated rat heart. J ApplPhysiol, 2005, 98(5): 1691~1696
22 Kolar, F, Ostada B, Prochazka J, et al. Comparison of cardiopulmonary response to intermittent high-altitude hypoxia in young and adult rats. Respiration, 1989, 56(1-2): 57~62
23 Lemler MS, Bies RD, Frid MG, et al. Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension. Am J Physiol 2000, 279(3): H1365~H1376
24 Bae S, Xiao YH, Li GH, et al.. Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. Am J Physiol Heart Circ Physiol, 2003, 285(3): H983~H990
1 Meerson FZ, Ustinova EE, Orlova EH. Prevention and elimination of heart arrhythmias by adaptation to intermittent high altitude hypoxia. Clin Cardiol, 1987, 10(12): 783~789
2 Meerson FZ, Ustinova EE, Manukhina EB. Prevention of cardiac arrhythmias by adaptation to hypoxia: regulatory mechanisms and cardiotropic effect. Biomed Biochim Acta, 1989, 48(2-3): S83~S88
3 Vovc E. The antiarrhythmic effect of adaptation to intermittent hypoxia. Folia Med (Plovdiv ), 1998, 40(3B Suppl 3): 51~54
4 Asemu G, Papousek F, Ostadal B et al. Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K(ATP) channel. J Mol Cell Cardiol, 1999, 31(10):1821~1831
5 Asemu G, Neckar J, Szarszoi O et al. Effects of adaptation to intermittent high altitude hypoxia on ischemic ventricular arrhythmias in rats. Physiol Res, 2000, 49(5): 597~606
6 Zhang Y, Zhong N, Zhu HF et al. [Antiarrhythmic and antioxidative effects of intermittent hypoxia exposure on rat myocardium]. Sheng Li Xue Bao, 2000,52(2): 89~92
7 Beguin PC, Joyeux-Faure M, Godin-Ribuot D et al. Acute intermittent hypoxia improves rat myocardium tolerance to ischemia. J Appl Physiol, 2005, 99(3): 1064~1069
8 Zhang H, Yang CY, Wang YP et al. Effects of different modes of intermittent hypobaric hypoxia on ischemia/reperfusion injury in developing rat hearts. Sheng Li Xue Bao, 2007, 59(5): 660~666
9 Zhong N, Zhang Y, Fang QZ et al. Intermittent hypoxia exposure-induced heat-shock protein 70 expression increases resistance of rat heart to ischemic injury. Acta Pharmacol Sin. 2000;21:467~472
10 Dong JW, Zhu HF, Zhu WZ et al. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulatingBcl-2/Bax expression, Cell Res, 2003, 13(5): 385-391
11 Zhang Y, Zhong N, Gia J et al. Effects of chronic intermittent hypoxia on the hemodynamics of systemic circulation in rats. Jpn J Physiol, 2004, 54(2): 171~174
12 Zhang Y, Zhong N, Zhou ZN. Estradiol potentiates antiarrhythmic and antioxidative effects of intermittent hypoxic rat heart. Acta Pharmacol Sin, 2000, 21(7): 609-612
13 Walker MJ, Curtis MJ, Hearse DJ et al. The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion. Cardiovasc Res, 1988, 22(7): 447~455
14 Johnston KM, MacLeod BA, Walker MJ. Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics. Can J Physiol Pharmacol, 1983, 61(11): 1340-1353
15 Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev, 1999, 79(3):635~659
16 Riva E, Hearse DJ. Age-dependent changes in myocardial susceptibility to ischemic injury. Cardioscience, 1993, 4(2): 85~92
17 Hoerter J. Changes in the sensitivity to hypoxia and glucose deprivation in the isolated perfused rabbit heart during perinatal development. Pflugers Arch, 1976, 363(1): 1~6
18 Young HH, Shimizu T, Nishioka K et al. Effect of hypoxia and reoxygenation on mitochondrial function in neonatal myocardium. Am J Physiol, 1983, 245(6): H998~1006
19 Billman GE. The cardiac sarcolemmal ATP-sensitive potassium channel as a novel target for anti-arrhythmic therapy. Pharmacol Ther, 2008, 120(1): 54~70
20 Willems L, Zatta A, Holmgren K et al. Age-related changes in ischemic tolerance in male and female mouse hearts. J Mol Cell Cardiol, 2005, 38(2): 245~256
21 Silverman HS, Wei S, Haigney MC et al. Myocyte adaptation to chronichypoxia and development of tolerance to subsequent acute severe hypoxia. Circ Res, 1997, 80(5): 699~707
1 Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev, 1989, 69(4):1049~1169
2 Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev, 1999, 79(3):917~1017
3 Cascio WE, Johnson TA, Gettes LS. Electrophysiologic changes in ischemic ventricular myocardium: I. Influence of ionic, metabolic, and energetic changes. J Cardiovasc Electrophysiol, 1995, 6(11):1039~1062
4 Meerson FZ, Ustinova EE, Orlova EH. Prevention and elimination of heart arrhythmias by adaptation to intermittent high altitude hypoxia. Clin Cardiol, 1987, 10(12):783~789
5 Vovc E. The antiarrhythmic effect of adaptation to intermittent hypoxia. Folia Med (Plovdiv ), 1998, (3B Suppl 3), 40: 51~54
6 Zhang Y, Zhong N, Zhou ZN. Effects of intermittent hypoxia on action potential and contraction in non-ischemic and ischemic rat papillary muscle. Life Sci, 2000, 67(20): 2465~2471
7 Saito T, Sato T, Miki T et al. Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice. Am J Physiol Heart Circ Physiol, 2005, 288(1): H352~H357
8 Riva E, Hearse DJ. Age-dependent changes in myocardial susceptibility to ischemic injury. Cardioscience, 1993, 4(2): 85~92
9 Noma A. ATP-regulated K+ channels in cardiac muscle. Nature, 1983, 305(5930): 147~148
10 Muramatsu H, Sato R, Okumura H. Early increase in K+ conductance during metabolic inhibition by cyanide in guinea pig ventricular myocytes. Nippon Ika Daigaku Zasshi, 1990, 57(4): 308~321
11 Piao L, Li J, McLerie M et al. Cardiac IK1 underlies early action potential shortening during hypoxia in the mouse heart. J Mol Cell Cardiol, 2007,43(1): 27~38
12 Meerson FZ, Vovk VI. [Effects of adaptation to stress exposure and periodic hypoxia on bioelectric activity of cardiomyocytes of isolated heart in ischemia and reperfusion]. Biull Eksp Biol Med, 1991,112(12): 573~575
13 Lebkova NP, Chizhov AI, Bobkov I. [The adaptational intracellular mechanisms regulating energy homeostasis during intermittent normobaric hypoxia]. Ross Fiziol Zh Im I M Sechenova, 1999, 85 (3): 403~411
1 Schulze-Bahr E, Wedekind H, Haverkamp W et al. The LQT syndromes--current status of molecular mechanisms. Z Kardiol, 1999, 88(4): 245~254
2 Qin D, Zhang ZH, Caref EB et al. Cellular and ionic basis of arrhythmias in postinfarction remodeled ventricular myocardium. Circ Res, 1996, 79(3): 461~473
3 De Ambroggi L. [Heterogeneities of ventricular repolarization and vulnerability to arrhythmia. How to detect them with noninvasive methods?]. Cardiologia, 1999, 44(4): 355~360
4 You B, Pu J, Liu N et al. Effect of lidocaine and amiodarone on transmural heterogeneity of ventricular repolarization in isolated rabbit hearts model of sustained global ischemia. J Huazhong Univ Sci Technolog Med Sci, 2005, 25(4): 400~403
5 Billman GE, Kukielka M. Novel transient outward and ultra-rapid delayed rectifier current antagonist, AVE0118, protects against ventricular fibrillation induced by myocardial ischemia. J Cardiovasc Pharmacol, 2008, 51(4): 352~358
6 Zhang LP, Yin JX, Liu Z et al. Effect of resveratrol on L-type calcium current in rat ventricular myocytes. Acta Pharmacol Sin, 2006, 27(2): 179~183
7 Apkon M, Nerbonne JM. Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes. J Gen Physiol, 1991, 97(5): 973~1011
8 Freyss-Beguin M, Millanvoye-van Brussel E, Duval D. Effect of oxygen deprivation on metabolism of arachidonic acid by cultures of rat heart cells. Am J Physiol, 1989, 257(2 Pt 2): H444~H451
9 Colbert CM, Pan E. Arachidonic acid reciprocally alters the availability of transient and sustained dendritic K(+) channels in hippocampal CA1 pyramidal neurons. J Neurosci, 1999, 19(19): 8163~8171
10 Zhu M, Natarajan R, Nadler JL et al. Angiotensin II increases neuronal delayed rectifier K(+) current: role of 12-lipoxygenase metabolites of arachidonic acid. J Neurophysiol, 2000, 84(5): 2494~2501
11 Jezkova J, Novakova O, Kolar F et al. Chronic hypoxia alters fatty acid composition of phospholipids in right and left ventricular myocardium. Mol Cell Biochem, 2002, 232(1-2): 49~56
12 Hashimoto M, Shahdat MH, Shimada T et al. Relationship between age-related increases in rat liver lipid peroxidation and bile canalicular plasma membrane fluidity. Exp Gerontol, 2001, 37(1): 89~97
13 Noma A. ATP-regulated K+ channels in cardiac muscle. Nature, 1983, 305(5930): 147~148
14 Nichols CG, Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system. Am J Physiol, 1991, 261(6 Pt 2): H1675~H1686
15 Henry P, Popescu A, Puceat M et al. Acute simulated ischaemia produces both inhibition and activation of K+ currents in isolated ventricular myocytes. Cardiovasc Res, 1996, 32(5): 930~939
16 Nichols CG, Ripoll C, Lederer WJ. ATP-sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ Res, 1991, 68(1): 280~287
17 Ruiz-Petrich E, de Lorenzi F, Chartier D. Role of the inward rectifier IK1 in the myocardial response to hypoxia. Cardiovasc Res, 1991, 25(1): 17~26
18 Piao L, Li J, McLerie M et al. Cardiac IK1 underlies early action potential shortening during hypoxia in the mouse heart. J Mol Cell Cardiol, 2007, 43(1): 27~38
19 Liu Y, Liu D, Heath L et al. Direct activation of an inwardly rectifying potassium channel by arachidonic acid. Mol Pharmacol, 2001, 59(5): 1061~1068
20 Xu Z, Rozanski GJ. Proton inhibition of transient outward potassium current in rat ventricular myocytes. J Mol Cell Cardiol, 1997, 29(2): 481~490
21 Du Z, Chaoqian X, Shan H et al. Functional impairment of cardiac transient outward K+ current as a result of abnormally altered cellular environment. Clin Exp Pharmacol Physiol, 2007, 34(3): 148~152
22 Colbert CM, Pan E. Arachidonic acid reciprocally alters the availability of transient and sustained dendritic K(+) channels in hippocampal CA1 pyramidal neurons. J Neurosci, 1999, 19(19): 8163~8171
23 Pike GK, Bretag AH, Roberts ML. Modification of the transient outward current of rat atrial myocytes by metabolic inhibition and oxidant stress. J Physiol, 1993, 470(1): 365~382
24 Zhou J, Tian M, Zhang Y, et al. Effects of intermittent hypoxia on transient outward current in rat ventricular myocytes. Acta Physiol Sin. 1999,51(2):187~192
1 Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev, 1999, 79(3): 917~1017
2 Taylor AJ, Burke AP, O'Malley PG et al. A comparison of the Framingham risk index, coronary artery calcification, and culprit plaque morphology in sudden cardiac death. Circulation, 2000, 101(11): 1243~1248
3 Smith WT, Fleet WF, Johnson TA et al. The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Experimental Cardiology Group, University of North Carolina. Circulation, 1995, 92(10): 3051~3060
4 Kaplinsky E, Ogawa S, Balke CW et al. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation, 1979, 60(2): 397~403
5 Coronel R, Wilms-Schopman FJ, deGroot JR. Origin of ischemia-induced phase 1b ventricular arrhythmias in pig hearts. J Am Coll Cardiol, 2002, 39(1): 166~176
6 Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res, 2002, 53(1): 31~47
7 Engler RL, Dahlgren MD, Peterson MA et al. Accumulation of polymorphonuclear leukocytes during 3-h experimental myocardial ischemia. Am J Physiol, 1986, 251(1 Pt 2): H93~100
8 Sasaki K, Ueno A, Katori M et al. Detection of leukotriene B4 in cardiac tissue and its role in infarct extension through leucocyte migration. Cardiovasc Res, 1988, 22(2): 142~148
9 Clements-Jewery H, Hearse DJ, Curtis MJ. Neutrophil ablation with anti-serum does not protect against phase 2 ventricular arrhythmias in anaesthetised rats with myocardial infarction. Cardiovasc Res, 2007, 73(4): 761~769
10 Clements-Jewery H, Andrag E, Hearse DJ et al. Complex adrenergic and inflammatory mechanisms contribute to phase 2 ventricular arrhythmias in anaesthetized rats. Br J Pharmacol, 2009;156(3): 444~453
11 Weiss JN, Venkatesh N, Lamp ST. ATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J Physiol, 1992, 447(1): 649~673
12 Weiss JN, Lamp ST, Shine KI. Cellular K+ loss and anion efflux during myocardial ischemia and metabolic inhibition. Am J Physiol, 1989, 256(4 Pt 2): H1165~H1175
13 Scirica BM, Morrow DA, Hod H et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation, 2007, 116(15): 1647~1652
14 Maier LS. A Novel Mechanism for the Treatment of Angina, Arrhythmias, and Diastolic Dysfunction: Inhibition of Late INa Using Ranolazine. J Cardiovasc Pharmacol, 2009. [Epub ahead of print]
15 Tani M, Neely JR. Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange. Circ Res, 1989, 65(4): 1045~1056
16 Saffitz JE, Schuessler RB, Yamada KA. Mechanisms of remodeling of gapjunction distributions and the development of anatomic substrates of arrhythmias. Cardiovasc Res, 1999, 42(2): 309~317
17 Lerner DL, Beardslee MA, Saffitz JE. The role of altered intercellular coupling in arrhythmias induced by acute myocardial ischemia. Cardiovasc Res, 2001, 50(2): 263~269
18 Beardslee MA, Lerner DL, Tadros PN et al. Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res, 2000, 87(8): 656~662
19 Gutstein DE, Morley GE, Tamaddon H et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res, 2001, 88(3): 333~339
20 Jiang H, Lu Z, Yu Y et al. Relationship between sympathetic nerve sprouting and repolarization dispersion at peri-infarct zone after myocardial infarction. Auton Neurosci, 2007, 134(1-2): 18~25
21 Jardine DL, Charles CJ, Forrester MD et al. A neural mechanism for sudden death after myocardial infarction. Clin Auton Res, 2003, 13(5): 339~341
22 Jardine DL, Charles CJ, Ashton RK et al. Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model. J Physiol, 2005, 565(Pt 1): 325~333
23 Kurz T, Offner B, Schreieck J et al. Nonexocytotic noradrenaline release and ventricular fibrillation in ischemic rat hearts. Naunyn Schmiedebergs Arch Pharmacol, 1995;352(5): 491~496
24 Du XJ, Cox HS, Dart AM et al. Sympathetic activation triggers ventricular arrhythmias in rat heart with chronic infarction and failure. Cardiovasc Res, 1999;43(4): 919~929
25 Vanoli E, De Ferrari GM, Stramba-Badiale M et al. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res, 1991, 68(5): 1471~1481
26 Kawada T, Yamazaki T, Akiyama T et al. Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release. Life Sci,2006, 78(8): 882~887
27 Ando M, Katare RG, Kakinuma Y et al. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation, 2005, 112(2): 164~170
28 Jiang H, Hu X, Lu Z et al. Effects of sympathetic nerve stimulation on ischemia-induced ventricular arrhythmias by modulating connexin43 in rats. Arch Med Res, 2008, 39(7): 647~654
29 Vetterlein F, Muhlfeld C, Cetegen C et al. Redistribution of connexin43 in regional acute ischemic myocardium: influence of ischemic preconditioning. Am J Physiol Heart Circ Physiol, 2006, 291(2): H813~H819
30 Papp R, Gonczi M, Kovacs M et al. Gap junctional uncoupling plays a trigger role in the antiarrhythmic effect of ischaemic preconditioning. Cardiovasc Res, 2007, 74(3): 396~405
31 Verkerk AO, Veldkamp MW, Coronel R et al. Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias. Cardiovasc Res, 2001, 51(1): 30~40
32 de Groot JR, Wilms-Schopman FJ, Opthof T et al. Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling. Cardiovasc Res, 2001, 50(2): 362~372
33 Jie X, Rodriguez B, de Groot JR et al. Reentry in survived subepicardium coupled to depolarized and inexcitable midmyocardium: insights into arrhythmogenesis in ischemia phase 1B. Heart Rhythm, 2008, 5(7): 1036~1044
34 Anderson ME, Braun AP, Wu Y et al. KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart. J Pharmacol Exp Ther, 1998, 287(3): 996~1006
35 Sato D, Xie LH, Sovari AA et al. Synchronization of chaotic earlyafterdepolarizations in the genesis of cardiac arrhythmias. Proc Natl Acad Sci U S A, 2009, 106(9): 2983~2988
36 Pogwizd SM, Schlotthauer K, Li L et al. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res, 2001, 88(11): 1159~1167
37 Said M, Becerra R, Palomeque J et al. Increased intracellular Ca2+ and SR Ca2+ load contribute to arrhythmias after acidosis in rat heart. Role of Ca2+/calmodulin-dependent protein kinase II. Am J Physiol Heart Circ Physiol, 2008, 295(4): H1669~H1683
38 DeSantiago J, Maier LS, Bers DM. Phospholamban is required for CaMKII-dependent recovery of Ca transients and SR Ca reuptake during acidosis in cardiac myocytes. J Mol Cell Cardiol, 2004, 36(1): 67~74
39 Franz MR, Cima R, Wang D et al. Electrophysiological effects of myocardial stretch and mechanical determinants of stretch-activated arrhythmias. Circulation, 1992, 86(3): 968~978
40 Livingston JZ, Resar JR, Yin FC. Effect of tetanic myocardial contraction on coronary pressure-flow relationships. Am J Physiol, 1993, 265(4 Pt 2): H1215~H1226
41 Parker KK, Lavelle JA, Taylor LK et al. Stretch-induced ventricular arrhythmias during acute ischemia and reperfusion. J Appl Physiol, 2004, 97(1): 377~383
42 Barrabes JA, Garcia-Dorado D, Agullo L et al. Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine. Am J Physiol Heart Circ Physiol, 2006, 290(6): H2344~H2350
43 Saito T, Sato T, Miki T et al. Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice. Am J Physiol Heart Circ Physiol, 2005, 288(1): H352~H357
44 Wilde AA. Role of ATP-sensitive K+ channel current in ischemicarrhythmias. Cardiovasc Drugs Ther, 1993, 7 Suppl 3: 521~526
45 Nichols CG, Lederer WJ. The regulation of ATP-sensitive K+ channel activity in intact and permeabilized rat ventricular myocytes. J Physiol, 1990, 423(1): 91~110
46 Nichols CG. KATP channels as molecular sensors of cellular metabolism. Nature, 2006, 440(7083): 470~476
47 Faivre JF, Findlay I. Action potential duration and activation of ATP-sensitive potassium current in isolated guinea-pig ventricular myocytes. Biochim Biophys Acta, 1990, 1029(1): 167~172
48 Kubota I, Yamaki M, Shibata T et al. Role of ATP-sensitive K+ channel on ECG ST segment elevation during a bout of myocardial ischemia. A study on epicardial mapping in dogs. Circulation, 1993, 88(4 Pt 1): 1845~1851
49 Kondo T, Kubota I, Tachibana H et al. Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia. Cardiovasc Res, 1996, 31(5): 683~687
50 Billman GE, Englert HC, Scholkens BA. HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part II: effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs. J Pharmacol Exp Ther, 1998, 286(3): 1465~1473
51 Suzuki M, Li RA, Miki T et al. Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ Res, 2001, 88(6): 570-577
52 Das B, Sarkar C. Is the sarcolemmal or mitochondrial K(ATP) channel activation important in the antiarrhythmic and cardioprotective effects during acute ischemia/reperfusion in the intact anesthetized rabbit model? Life Sci, 2005, 77(11): 1226~1248
53 Asemu G, Papousek F, Ostadal B et al. Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K(ATP) channel. J Mol Cell Cardiol, 1999, 31(10): 1821~1831
54 Yamada KA, Kanter EM, Green KG et al. Transmural distribution of connexins in rodent hearts. J Cardiovasc Electrophysiol, 2004, 15(6): 710~715
55 Tribulova N, Novakova S, Macsaliova A et al. Histochemical and ultrastructural characterisation of an arrhythmogenic substrate in ischemic pig heart. Acta Histochem, 2002, 104(4): 393~397
56 Aon MA, Cortassa S, Marban E et al. Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem, 2003, 278(45): 44735~44744
57 Akar FG, Aon MA, Tomaselli GF et al. The mitochondrial origin of postischemic arrhythmias. J Clin Invest, 2005, 115(12): 3527~3535
58 Morad M, Javaheri A, Risius T et al. Multimodality of Ca2+ signaling in rat atrial myocytes. Ann N Y Acad Sci. 2005, 1047: 112~121
59 Woo SH, Risius T, Morad M. Modulation of local Ca2+ release sites by rapid fluid puffing in rat atrial myocytes. Cell Calcium, 2007, 41(4): 397~403
60 Belmonte S, Morad M. 'Pressure-flow'-triggered intracellular Ca2+ transients in rat cardiac myocytes: possible mechanisms and role of mitochondria. J Physiol, 2008, 586(5): 1379~1397
61 Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med, 1991, 324(12): 781~788
62 Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: a 3-phase time-sensitive model. JAMA, 2002, 288(23): 3035~3038
2 Zhu HF, Dong JW, Zhu WZ, Ding HL, and Zhou ZN. ATP-dependent potassium channels involved in the cardiac protection induced by intermittent hypoxia against ischemia/reperfusion injury. Life Sci, 2003, 73 (10): 1275~1287
3 Zhu WZ, Xie Y, Zhou ZN, et al. Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury. J Mol Cell Cardiol, 2006, 40(1): 96~106
4 Béguin PC, Belaidi E, Godin-Ribuot D, et al. Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2. J Mol Cell Cardiol, 2007, 42(2):343~351
5 Zhuang J, Zhou Z. Protective effects of intermittent hypoxic adaptation on myocardium and its mechanisms. Biol Signals Recept, 1999, 8(45): 316~322
6 Zhang Y, Zhong N, Zhou ZN, et al. Antiarrhythmic and antioxidative effects of intermittent hypoxia exposure on rat myocardium. Sheng Li Xue Bao, 2000, 52(2): 89~92
7 Zhong N, Zhang Y, Zhou ZN, et al. Intermittent hypoxia exposure-induced heat-shock protein 70 expression increases resistance of rat heart to ischemic injury. Acta Pharmacol Sin 2000, 21(5): 467~472
8 Dong JW, Zhu HF, Zhou ZN, et al. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression. Cell research 2003, 13(5): 385~391
9 Zhang Y, Zhong N, Gia J, Zhou Z. Effects of chronic intermittent hypoxia on the hemodynamics of systemic circulation in rats. Jpn J Physiol, 2004, 54(2): 171~174
10 O??áDALOVáI, O??áDAL B, JARKOVSKáD, et al. Ischemic preconditioning in chronically hypoxic neonatal rat heart. Pediatr Res,2002, 52(4): 561~567
11 O??áDALOVáI, O??áDAL B, KOLá? F, et al. Tolerance to ischaemia and ischaemic preconditioning in neonatal rat heart. J Mol Cell Cardiol, 1998, 30(4): 857~865
12 Béguin PC, Joyeux-Faure M, Godin-Ribuot D, et ak. Acute intermittent hypoxia improves rat myocardium tolerance to ischemia. Appl Physiol, 2005, 99(3): 1064~1069
13 Zhu WZ, Dong JW, Zhou ZN, et al. Postnatal development in intermittent hypoxia enhances resistance to myocardial ischemia/reperfusion in male rats. Eur J Appl Physiol 2004, 91 (5-6) : 716~722
14 La Padula P, Costa LE. Effect of sustained hypobaric hypoxia during maturation and aging on rat myocardium. I. Mechanical activity. J Appl Physiol 2005, 98(6): 2363~2369
15 Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev, 1999, 79(3): 635~659
16 Poupa O, Krofta K, Prochazka J,et al. Acclimatization to simulated high altitude and acute cardiac necrosis. Federation Proc, 1966, 25(4):1243~1246
17 McGrath JJ, Bullard RW. Altered myocardial performance in response to anoxia after high-altitude exposure. J Appl Physiol, 1968, 25(6): 761~764
18 Widimsky J, Urbanova D, Ressl J, et al. Effect of intermittent altitude hypoxia on the myocardium and lesser circulation in the rat. Cardiovasc Res, 1973, 7(6): 798~808
19 Meerson F.Z. Adaptative protection of the heart: protecting against stress and ischemic damage. Boston: CRC Press, Inc. 1991:pp 249~281
20 Zong P, Setty S, Sun W, et al. Intermittent hypoxic training protects canine myocardium from infarction. Exp Biol Med (Maywood), 2004, 229(8): 806~812
21 Joyeux-Faure M, Stanke-Labesque F, Lefebvre B,et al. Chronic intermittenthypoxia increases infarction in the isolated rat heart. J ApplPhysiol, 2005, 98(5): 1691~1696
22 Kolar, F, Ostada B, Prochazka J, et al. Comparison of cardiopulmonary response to intermittent high-altitude hypoxia in young and adult rats. Respiration, 1989, 56(1-2): 57~62
23 Lemler MS, Bies RD, Frid MG, et al. Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension. Am J Physiol 2000, 279(3): H1365~H1376
24 Bae S, Xiao YH, Li GH, et al.. Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. Am J Physiol Heart Circ Physiol, 2003, 285(3): H983~H990
1 Meerson FZ, Ustinova EE, Orlova EH. Prevention and elimination of heart arrhythmias by adaptation to intermittent high altitude hypoxia. Clin Cardiol, 1987, 10(12): 783~789
2 Meerson FZ, Ustinova EE, Manukhina EB. Prevention of cardiac arrhythmias by adaptation to hypoxia: regulatory mechanisms and cardiotropic effect. Biomed Biochim Acta, 1989, 48(2-3): S83~S88
3 Vovc E. The antiarrhythmic effect of adaptation to intermittent hypoxia. Folia Med (Plovdiv ), 1998, 40(3B Suppl 3): 51~54
4 Asemu G, Papousek F, Ostadal B et al. Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K(ATP) channel. J Mol Cell Cardiol, 1999, 31(10):1821~1831
5 Asemu G, Neckar J, Szarszoi O et al. Effects of adaptation to intermittent high altitude hypoxia on ischemic ventricular arrhythmias in rats. Physiol Res, 2000, 49(5): 597~606
6 Zhang Y, Zhong N, Zhu HF et al. [Antiarrhythmic and antioxidative effects of intermittent hypoxia exposure on rat myocardium]. Sheng Li Xue Bao, 2000,52(2): 89~92
7 Beguin PC, Joyeux-Faure M, Godin-Ribuot D et al. Acute intermittent hypoxia improves rat myocardium tolerance to ischemia. J Appl Physiol, 2005, 99(3): 1064~1069
8 Zhang H, Yang CY, Wang YP et al. Effects of different modes of intermittent hypobaric hypoxia on ischemia/reperfusion injury in developing rat hearts. Sheng Li Xue Bao, 2007, 59(5): 660~666
9 Zhong N, Zhang Y, Fang QZ et al. Intermittent hypoxia exposure-induced heat-shock protein 70 expression increases resistance of rat heart to ischemic injury. Acta Pharmacol Sin. 2000;21:467~472
10 Dong JW, Zhu HF, Zhu WZ et al. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulatingBcl-2/Bax expression, Cell Res, 2003, 13(5): 385-391
11 Zhang Y, Zhong N, Gia J et al. Effects of chronic intermittent hypoxia on the hemodynamics of systemic circulation in rats. Jpn J Physiol, 2004, 54(2): 171~174
12 Zhang Y, Zhong N, Zhou ZN. Estradiol potentiates antiarrhythmic and antioxidative effects of intermittent hypoxic rat heart. Acta Pharmacol Sin, 2000, 21(7): 609-612
13 Walker MJ, Curtis MJ, Hearse DJ et al. The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion. Cardiovasc Res, 1988, 22(7): 447~455
14 Johnston KM, MacLeod BA, Walker MJ. Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics. Can J Physiol Pharmacol, 1983, 61(11): 1340-1353
15 Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev, 1999, 79(3):635~659
16 Riva E, Hearse DJ. Age-dependent changes in myocardial susceptibility to ischemic injury. Cardioscience, 1993, 4(2): 85~92
17 Hoerter J. Changes in the sensitivity to hypoxia and glucose deprivation in the isolated perfused rabbit heart during perinatal development. Pflugers Arch, 1976, 363(1): 1~6
18 Young HH, Shimizu T, Nishioka K et al. Effect of hypoxia and reoxygenation on mitochondrial function in neonatal myocardium. Am J Physiol, 1983, 245(6): H998~1006
19 Billman GE. The cardiac sarcolemmal ATP-sensitive potassium channel as a novel target for anti-arrhythmic therapy. Pharmacol Ther, 2008, 120(1): 54~70
20 Willems L, Zatta A, Holmgren K et al. Age-related changes in ischemic tolerance in male and female mouse hearts. J Mol Cell Cardiol, 2005, 38(2): 245~256
21 Silverman HS, Wei S, Haigney MC et al. Myocyte adaptation to chronichypoxia and development of tolerance to subsequent acute severe hypoxia. Circ Res, 1997, 80(5): 699~707
1 Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev, 1989, 69(4):1049~1169
2 Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev, 1999, 79(3):917~1017
3 Cascio WE, Johnson TA, Gettes LS. Electrophysiologic changes in ischemic ventricular myocardium: I. Influence of ionic, metabolic, and energetic changes. J Cardiovasc Electrophysiol, 1995, 6(11):1039~1062
4 Meerson FZ, Ustinova EE, Orlova EH. Prevention and elimination of heart arrhythmias by adaptation to intermittent high altitude hypoxia. Clin Cardiol, 1987, 10(12):783~789
5 Vovc E. The antiarrhythmic effect of adaptation to intermittent hypoxia. Folia Med (Plovdiv ), 1998, (3B Suppl 3), 40: 51~54
6 Zhang Y, Zhong N, Zhou ZN. Effects of intermittent hypoxia on action potential and contraction in non-ischemic and ischemic rat papillary muscle. Life Sci, 2000, 67(20): 2465~2471
7 Saito T, Sato T, Miki T et al. Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice. Am J Physiol Heart Circ Physiol, 2005, 288(1): H352~H357
8 Riva E, Hearse DJ. Age-dependent changes in myocardial susceptibility to ischemic injury. Cardioscience, 1993, 4(2): 85~92
9 Noma A. ATP-regulated K+ channels in cardiac muscle. Nature, 1983, 305(5930): 147~148
10 Muramatsu H, Sato R, Okumura H. Early increase in K+ conductance during metabolic inhibition by cyanide in guinea pig ventricular myocytes. Nippon Ika Daigaku Zasshi, 1990, 57(4): 308~321
11 Piao L, Li J, McLerie M et al. Cardiac IK1 underlies early action potential shortening during hypoxia in the mouse heart. J Mol Cell Cardiol, 2007,43(1): 27~38
12 Meerson FZ, Vovk VI. [Effects of adaptation to stress exposure and periodic hypoxia on bioelectric activity of cardiomyocytes of isolated heart in ischemia and reperfusion]. Biull Eksp Biol Med, 1991,112(12): 573~575
13 Lebkova NP, Chizhov AI, Bobkov I. [The adaptational intracellular mechanisms regulating energy homeostasis during intermittent normobaric hypoxia]. Ross Fiziol Zh Im I M Sechenova, 1999, 85 (3): 403~411
1 Schulze-Bahr E, Wedekind H, Haverkamp W et al. The LQT syndromes--current status of molecular mechanisms. Z Kardiol, 1999, 88(4): 245~254
2 Qin D, Zhang ZH, Caref EB et al. Cellular and ionic basis of arrhythmias in postinfarction remodeled ventricular myocardium. Circ Res, 1996, 79(3): 461~473
3 De Ambroggi L. [Heterogeneities of ventricular repolarization and vulnerability to arrhythmia. How to detect them with noninvasive methods?]. Cardiologia, 1999, 44(4): 355~360
4 You B, Pu J, Liu N et al. Effect of lidocaine and amiodarone on transmural heterogeneity of ventricular repolarization in isolated rabbit hearts model of sustained global ischemia. J Huazhong Univ Sci Technolog Med Sci, 2005, 25(4): 400~403
5 Billman GE, Kukielka M. Novel transient outward and ultra-rapid delayed rectifier current antagonist, AVE0118, protects against ventricular fibrillation induced by myocardial ischemia. J Cardiovasc Pharmacol, 2008, 51(4): 352~358
6 Zhang LP, Yin JX, Liu Z et al. Effect of resveratrol on L-type calcium current in rat ventricular myocytes. Acta Pharmacol Sin, 2006, 27(2): 179~183
7 Apkon M, Nerbonne JM. Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes. J Gen Physiol, 1991, 97(5): 973~1011
8 Freyss-Beguin M, Millanvoye-van Brussel E, Duval D. Effect of oxygen deprivation on metabolism of arachidonic acid by cultures of rat heart cells. Am J Physiol, 1989, 257(2 Pt 2): H444~H451
9 Colbert CM, Pan E. Arachidonic acid reciprocally alters the availability of transient and sustained dendritic K(+) channels in hippocampal CA1 pyramidal neurons. J Neurosci, 1999, 19(19): 8163~8171
10 Zhu M, Natarajan R, Nadler JL et al. Angiotensin II increases neuronal delayed rectifier K(+) current: role of 12-lipoxygenase metabolites of arachidonic acid. J Neurophysiol, 2000, 84(5): 2494~2501
11 Jezkova J, Novakova O, Kolar F et al. Chronic hypoxia alters fatty acid composition of phospholipids in right and left ventricular myocardium. Mol Cell Biochem, 2002, 232(1-2): 49~56
12 Hashimoto M, Shahdat MH, Shimada T et al. Relationship between age-related increases in rat liver lipid peroxidation and bile canalicular plasma membrane fluidity. Exp Gerontol, 2001, 37(1): 89~97
13 Noma A. ATP-regulated K+ channels in cardiac muscle. Nature, 1983, 305(5930): 147~148
14 Nichols CG, Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system. Am J Physiol, 1991, 261(6 Pt 2): H1675~H1686
15 Henry P, Popescu A, Puceat M et al. Acute simulated ischaemia produces both inhibition and activation of K+ currents in isolated ventricular myocytes. Cardiovasc Res, 1996, 32(5): 930~939
16 Nichols CG, Ripoll C, Lederer WJ. ATP-sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ Res, 1991, 68(1): 280~287
17 Ruiz-Petrich E, de Lorenzi F, Chartier D. Role of the inward rectifier IK1 in the myocardial response to hypoxia. Cardiovasc Res, 1991, 25(1): 17~26
18 Piao L, Li J, McLerie M et al. Cardiac IK1 underlies early action potential shortening during hypoxia in the mouse heart. J Mol Cell Cardiol, 2007, 43(1): 27~38
19 Liu Y, Liu D, Heath L et al. Direct activation of an inwardly rectifying potassium channel by arachidonic acid. Mol Pharmacol, 2001, 59(5): 1061~1068
20 Xu Z, Rozanski GJ. Proton inhibition of transient outward potassium current in rat ventricular myocytes. J Mol Cell Cardiol, 1997, 29(2): 481~490
21 Du Z, Chaoqian X, Shan H et al. Functional impairment of cardiac transient outward K+ current as a result of abnormally altered cellular environment. Clin Exp Pharmacol Physiol, 2007, 34(3): 148~152
22 Colbert CM, Pan E. Arachidonic acid reciprocally alters the availability of transient and sustained dendritic K(+) channels in hippocampal CA1 pyramidal neurons. J Neurosci, 1999, 19(19): 8163~8171
23 Pike GK, Bretag AH, Roberts ML. Modification of the transient outward current of rat atrial myocytes by metabolic inhibition and oxidant stress. J Physiol, 1993, 470(1): 365~382
24 Zhou J, Tian M, Zhang Y, et al. Effects of intermittent hypoxia on transient outward current in rat ventricular myocytes. Acta Physiol Sin. 1999,51(2):187~192
1 Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev, 1999, 79(3): 917~1017
2 Taylor AJ, Burke AP, O'Malley PG et al. A comparison of the Framingham risk index, coronary artery calcification, and culprit plaque morphology in sudden cardiac death. Circulation, 2000, 101(11): 1243~1248
3 Smith WT, Fleet WF, Johnson TA et al. The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Experimental Cardiology Group, University of North Carolina. Circulation, 1995, 92(10): 3051~3060
4 Kaplinsky E, Ogawa S, Balke CW et al. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation, 1979, 60(2): 397~403
5 Coronel R, Wilms-Schopman FJ, deGroot JR. Origin of ischemia-induced phase 1b ventricular arrhythmias in pig hearts. J Am Coll Cardiol, 2002, 39(1): 166~176
6 Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res, 2002, 53(1): 31~47
7 Engler RL, Dahlgren MD, Peterson MA et al. Accumulation of polymorphonuclear leukocytes during 3-h experimental myocardial ischemia. Am J Physiol, 1986, 251(1 Pt 2): H93~100
8 Sasaki K, Ueno A, Katori M et al. Detection of leukotriene B4 in cardiac tissue and its role in infarct extension through leucocyte migration. Cardiovasc Res, 1988, 22(2): 142~148
9 Clements-Jewery H, Hearse DJ, Curtis MJ. Neutrophil ablation with anti-serum does not protect against phase 2 ventricular arrhythmias in anaesthetised rats with myocardial infarction. Cardiovasc Res, 2007, 73(4): 761~769
10 Clements-Jewery H, Andrag E, Hearse DJ et al. Complex adrenergic and inflammatory mechanisms contribute to phase 2 ventricular arrhythmias in anaesthetized rats. Br J Pharmacol, 2009;156(3): 444~453
11 Weiss JN, Venkatesh N, Lamp ST. ATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J Physiol, 1992, 447(1): 649~673
12 Weiss JN, Lamp ST, Shine KI. Cellular K+ loss and anion efflux during myocardial ischemia and metabolic inhibition. Am J Physiol, 1989, 256(4 Pt 2): H1165~H1175
13 Scirica BM, Morrow DA, Hod H et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation, 2007, 116(15): 1647~1652
14 Maier LS. A Novel Mechanism for the Treatment of Angina, Arrhythmias, and Diastolic Dysfunction: Inhibition of Late INa Using Ranolazine. J Cardiovasc Pharmacol, 2009. [Epub ahead of print]
15 Tani M, Neely JR. Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange. Circ Res, 1989, 65(4): 1045~1056
16 Saffitz JE, Schuessler RB, Yamada KA. Mechanisms of remodeling of gapjunction distributions and the development of anatomic substrates of arrhythmias. Cardiovasc Res, 1999, 42(2): 309~317
17 Lerner DL, Beardslee MA, Saffitz JE. The role of altered intercellular coupling in arrhythmias induced by acute myocardial ischemia. Cardiovasc Res, 2001, 50(2): 263~269
18 Beardslee MA, Lerner DL, Tadros PN et al. Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res, 2000, 87(8): 656~662
19 Gutstein DE, Morley GE, Tamaddon H et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res, 2001, 88(3): 333~339
20 Jiang H, Lu Z, Yu Y et al. Relationship between sympathetic nerve sprouting and repolarization dispersion at peri-infarct zone after myocardial infarction. Auton Neurosci, 2007, 134(1-2): 18~25
21 Jardine DL, Charles CJ, Forrester MD et al. A neural mechanism for sudden death after myocardial infarction. Clin Auton Res, 2003, 13(5): 339~341
22 Jardine DL, Charles CJ, Ashton RK et al. Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model. J Physiol, 2005, 565(Pt 1): 325~333
23 Kurz T, Offner B, Schreieck J et al. Nonexocytotic noradrenaline release and ventricular fibrillation in ischemic rat hearts. Naunyn Schmiedebergs Arch Pharmacol, 1995;352(5): 491~496
24 Du XJ, Cox HS, Dart AM et al. Sympathetic activation triggers ventricular arrhythmias in rat heart with chronic infarction and failure. Cardiovasc Res, 1999;43(4): 919~929
25 Vanoli E, De Ferrari GM, Stramba-Badiale M et al. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res, 1991, 68(5): 1471~1481
26 Kawada T, Yamazaki T, Akiyama T et al. Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release. Life Sci,2006, 78(8): 882~887
27 Ando M, Katare RG, Kakinuma Y et al. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation, 2005, 112(2): 164~170
28 Jiang H, Hu X, Lu Z et al. Effects of sympathetic nerve stimulation on ischemia-induced ventricular arrhythmias by modulating connexin43 in rats. Arch Med Res, 2008, 39(7): 647~654
29 Vetterlein F, Muhlfeld C, Cetegen C et al. Redistribution of connexin43 in regional acute ischemic myocardium: influence of ischemic preconditioning. Am J Physiol Heart Circ Physiol, 2006, 291(2): H813~H819
30 Papp R, Gonczi M, Kovacs M et al. Gap junctional uncoupling plays a trigger role in the antiarrhythmic effect of ischaemic preconditioning. Cardiovasc Res, 2007, 74(3): 396~405
31 Verkerk AO, Veldkamp MW, Coronel R et al. Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias. Cardiovasc Res, 2001, 51(1): 30~40
32 de Groot JR, Wilms-Schopman FJ, Opthof T et al. Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling. Cardiovasc Res, 2001, 50(2): 362~372
33 Jie X, Rodriguez B, de Groot JR et al. Reentry in survived subepicardium coupled to depolarized and inexcitable midmyocardium: insights into arrhythmogenesis in ischemia phase 1B. Heart Rhythm, 2008, 5(7): 1036~1044
34 Anderson ME, Braun AP, Wu Y et al. KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart. J Pharmacol Exp Ther, 1998, 287(3): 996~1006
35 Sato D, Xie LH, Sovari AA et al. Synchronization of chaotic earlyafterdepolarizations in the genesis of cardiac arrhythmias. Proc Natl Acad Sci U S A, 2009, 106(9): 2983~2988
36 Pogwizd SM, Schlotthauer K, Li L et al. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res, 2001, 88(11): 1159~1167
37 Said M, Becerra R, Palomeque J et al. Increased intracellular Ca2+ and SR Ca2+ load contribute to arrhythmias after acidosis in rat heart. Role of Ca2+/calmodulin-dependent protein kinase II. Am J Physiol Heart Circ Physiol, 2008, 295(4): H1669~H1683
38 DeSantiago J, Maier LS, Bers DM. Phospholamban is required for CaMKII-dependent recovery of Ca transients and SR Ca reuptake during acidosis in cardiac myocytes. J Mol Cell Cardiol, 2004, 36(1): 67~74
39 Franz MR, Cima R, Wang D et al. Electrophysiological effects of myocardial stretch and mechanical determinants of stretch-activated arrhythmias. Circulation, 1992, 86(3): 968~978
40 Livingston JZ, Resar JR, Yin FC. Effect of tetanic myocardial contraction on coronary pressure-flow relationships. Am J Physiol, 1993, 265(4 Pt 2): H1215~H1226
41 Parker KK, Lavelle JA, Taylor LK et al. Stretch-induced ventricular arrhythmias during acute ischemia and reperfusion. J Appl Physiol, 2004, 97(1): 377~383
42 Barrabes JA, Garcia-Dorado D, Agullo L et al. Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine. Am J Physiol Heart Circ Physiol, 2006, 290(6): H2344~H2350
43 Saito T, Sato T, Miki T et al. Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice. Am J Physiol Heart Circ Physiol, 2005, 288(1): H352~H357
44 Wilde AA. Role of ATP-sensitive K+ channel current in ischemicarrhythmias. Cardiovasc Drugs Ther, 1993, 7 Suppl 3: 521~526
45 Nichols CG, Lederer WJ. The regulation of ATP-sensitive K+ channel activity in intact and permeabilized rat ventricular myocytes. J Physiol, 1990, 423(1): 91~110
46 Nichols CG. KATP channels as molecular sensors of cellular metabolism. Nature, 2006, 440(7083): 470~476
47 Faivre JF, Findlay I. Action potential duration and activation of ATP-sensitive potassium current in isolated guinea-pig ventricular myocytes. Biochim Biophys Acta, 1990, 1029(1): 167~172
48 Kubota I, Yamaki M, Shibata T et al. Role of ATP-sensitive K+ channel on ECG ST segment elevation during a bout of myocardial ischemia. A study on epicardial mapping in dogs. Circulation, 1993, 88(4 Pt 1): 1845~1851
49 Kondo T, Kubota I, Tachibana H et al. Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia. Cardiovasc Res, 1996, 31(5): 683~687
50 Billman GE, Englert HC, Scholkens BA. HMR 1883, a novel cardioselective inhibitor of the ATP-sensitive potassium channel. Part II: effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs. J Pharmacol Exp Ther, 1998, 286(3): 1465~1473
51 Suzuki M, Li RA, Miki T et al. Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ Res, 2001, 88(6): 570-577
52 Das B, Sarkar C. Is the sarcolemmal or mitochondrial K(ATP) channel activation important in the antiarrhythmic and cardioprotective effects during acute ischemia/reperfusion in the intact anesthetized rabbit model? Life Sci, 2005, 77(11): 1226~1248
53 Asemu G, Papousek F, Ostadal B et al. Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K(ATP) channel. J Mol Cell Cardiol, 1999, 31(10): 1821~1831
54 Yamada KA, Kanter EM, Green KG et al. Transmural distribution of connexins in rodent hearts. J Cardiovasc Electrophysiol, 2004, 15(6): 710~715
55 Tribulova N, Novakova S, Macsaliova A et al. Histochemical and ultrastructural characterisation of an arrhythmogenic substrate in ischemic pig heart. Acta Histochem, 2002, 104(4): 393~397
56 Aon MA, Cortassa S, Marban E et al. Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem, 2003, 278(45): 44735~44744
57 Akar FG, Aon MA, Tomaselli GF et al. The mitochondrial origin of postischemic arrhythmias. J Clin Invest, 2005, 115(12): 3527~3535
58 Morad M, Javaheri A, Risius T et al. Multimodality of Ca2+ signaling in rat atrial myocytes. Ann N Y Acad Sci. 2005, 1047: 112~121
59 Woo SH, Risius T, Morad M. Modulation of local Ca2+ release sites by rapid fluid puffing in rat atrial myocytes. Cell Calcium, 2007, 41(4): 397~403
60 Belmonte S, Morad M. 'Pressure-flow'-triggered intracellular Ca2+ transients in rat cardiac myocytes: possible mechanisms and role of mitochondria. J Physiol, 2008, 586(5): 1379~1397
61 Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med, 1991, 324(12): 781~788
62 Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: a 3-phase time-sensitive model. JAMA, 2002, 288(23): 3035~3038