蝙蝠葛碱抗缺血/再灌注性室颤及其机制

目的：探讨蝙蝠葛碱抗缺血／再灌注性室颤的机理。方法：用高效液相色谱－电化学法测定豚鼠离体心脏灌注液中去甲肾上腺素（NE）含量。结果：蝙蝠葛碱组和维拉帕米组在停止灌注时心脏NE释放量明显低于对照组（P＜0．01），缺血／再灌注性室颤发生率显著低于对照组（P＜0．05）。发生缺血／再灌注性室颤的心脏NE释放量明显高于无缺血／再灌注性室颤心脏（P＜0．01）。停止灌注时心脏NE释放量和缺血／再灌注性室颤发生率，在蝙蝠葛碱组与维拉帕米组之间无显著差异（P＞0．05）。结论：蝙蝠葛碱抑制缺血心肌NE释放为其抗缺血／再灌注性室颤的机理之一。     

静脉注射美托洛尔对房颤快室率伴心衰患者心室率及无创心功能的影响

目的探讨静脉注射美托洛尔对房颤快速心室率(快室率)伴心力衰竭患者的疗效、安全性以及对无创心功能的影响。方法对房颤快室率伴心衰患者经常规治疗后观测0.5 h,如HR仍>100次·min~(-1)、BP≥100/60 mm Hg(1 mm Hg=0.133 kPa)以上的患者90例,随机分3组(每组30例),1组为美托洛尔注射液10 mg稀释后经微泵静注1h(微泵组);2组为美托洛尔注射液5mg,10min缓慢静脉推注(推注组),观察10min,如HR仍>100次·min~(-1),BP≥90/60mm Hg则再重复给药1次;3组为NS对照组。当HR≤60次·min~(-1)、BP<90/60 mm Hg时停止;各组用药物前及开始给美托洛尔注射液或NS后1 h,观察症状、体征、职、BP、肺部啰音、无创心功能指标。结果静脉注射美托洛尔后大多数患者症状、体征明显改善,心室率显著下降且比对照组明显(P<0.05),SBP、DBP有所降低但与对照组相比差异无统计学意义(P>0.05),无创心功能参数中CO、SI、SV、LVET显著增加且比对照组明显(P<0.05)。结论美托洛尔静脉注射能够安全有效地应用于房颤快室率伴心衰患者,能够明显改善临床症状、体征,减慢心室率,并改善无创心功能指标。     

槐果碱对犬室颤阈以及有效不应期的影响

目的：观察槐果碱静脉注射后对正常犬及急性心肌缺血犬心室有效不应期(ERP)、室颤阈(VFT)的影响。方法：测定犬静脉注射槐果碱(3 mg·kg~(-1))后5,20,40,60 min ERP和VFT,比较与氯化钠注射液对照组的差异。并且通过结扎犬左前降支冠脉(LAD)建立急性心肌缺血动物模型,比较对照组、槐果碱组用药前后ERP,VFT的变化。结果：正常犬用药后20 min及40 min,槐果碱组ERP较对照组有显著延长(P=0.028和P=0.02)；且VFT较对照组用药后有显著升高(P=0.013和P=0.026)。静脉注射槐果碱后20 min第2次结扎LAD,该组较对照组ERP有显著延长(P=0.043)；槐果碱组VFT较第1次结扎有提高,而对照组VFT有所下降,2组比较有显著差异(P=0.049)。结论：槐果碱用药后20,40 min能延长正常犬的ERP,提高VFT；用药后20 min槐果碱能提高急性心肌缺血犬的心室有效不应期和室颤阈。     

Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo

BACKGROUND AND PURPOSE: The mitochondrial permeability transition pore (mPTP), an energy-dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing the mitochondrial inner membrane potential. As mitochondrial Ca(2+) overload is a main inductor of mPTP opening, we examined the effect of Ru(360), a selective inhibitor of the mitochondrial calcium uptake system against myocardial damage induced by reperfusion in a rat model. EXPERIMENTAL APPROACH: Myocardial reperfusion injury was induced by a 5-min occlusion of the left anterior descending coronary artery, followed by a 5-min reperfusion in anaesthetized open-chest rats. We measured reperfusion-induced arrhythmias and functions indicative of unimpaired mitochondrial integrity to evaluate the effect of Ru(360) treatment. KEY RESULTS: Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru(360) (15-50 nmol kg(-1)), given 30-min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru(360)-treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter. CONCLUSIONS AND IMPLICATIONS: We showed that Ru(360) treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru(360) administration partially inhibits calcium uptake, preventing mitochondria from depolarization by the opening of the mPTP. We conclude that myocardial damage could be a consequence of failure of the mitochondrial network to maintain the membrane potential at reperfusion. Hence, it is plausible that Ru(360) could be used in reperfusion therapy to prevent the occurrence of arrhythmia.     

Attenuation of the ischaemia-induced fall of electrical ventricular fibrillation threshold by a calcium antagonist,diltiazem

Summary Calcium antagonists have been reported to decrease the incidence of sudden death in postinfarction management and vulnerability to fibrillation secondary to experimental coronary occlusion. In order to confirm such beneficial results regarding ischaemic ventricular fibrillation, the threshold intensity for fibrillation electrically induced with impulses of 100 ms and 180 beats · min^–1 was measured during the course of ischaemias obtained by total occlusion of the left anterior descending coronary artery near its origin in open-chest pigs. The variations of electrical fibrillation threshold with ischaemia duration (30, 60, 120, 180, 240, 360 s) were compared under control conditions and after i.v. diltiazem (0.50 mg · kg^–1 plus 0.02 mg · kg^–1 · min^–1 over 25 min). Electrical fibrillation threshold was not influenced by diltiazem before, but raised during ischaemia, particularly from the 60th s (1.7 to 4.0 mA), with delay in the triggering of fibrillation which occurs when the fibrillation threshold falls down to the pacing threshold (0.2 to 0.3 mA). In 6 pigs out of 8, fibrillation was even avoided in the longest of the ischaemic periods considered (360 s), for fibrillation threshold ceased falling before reaching the critical level. These experimental results obtained with diltiazem are consistent with the clinical effectiveness of calcium antagonists recently observed in the prevention of postinfarction sudden death, provided that myocardial contractility is not too much adversely affected. But, left ventricular dP/dt_max was not reduced by more than 6.8% in the present experiments. Correspondence to: Q. Timour at the above address     

内皮素-1对急性心肌缺血大鼠室颤阈的影响

在麻醉大鼠急性心肌缺血前5 min iv内皮素-1 1.5—3.0μg·kg~(-1)导致室颤阈呈剂量和时间依赖性降低,其作用持续至少60min。当内皮素-1剂量在3.0μg·kg~(-1)时,自发性室速显著增加,心肌梗死范围明显扩大,动脉血压处于较高水平。钙拮抗剂地尔硫(艹卓)能部分地预防内皮素-1引起的室颤阈下降,完全对抗其加压反应且有效限制心肌坏死的扩展。     

Effect of osmotic stress on spontaneous calcium sparks in rat ventricular myocytes

AIM: To study whether the volume of cardiomyocytes and their functions would change under severe pathological conditions or osmotic stress. To clarify the role of ryanodine receptors/calcium release channels (RyRs) in the functional change, the effect of osmotic stress on spontaneous Ca2+ sparks in rat ventricular myocytes was investigated. METHODS: A laser scanning confocal microscope was used to detect spontaneous Ca2+ sparks of intact or saponin permeabilized myocytes loaded with Fluo-4. High and low tonicity was obtained by adding sucrose and reducing NaCl concentration in the external medium, respectively. RESULTS: In intact myocytes the frequency of Ca2+ sparks was increased and decreased by hyperosmotic (1.5 T) and hyposmotic (0.6 T) exposure, respectively. In addition, hyperosmotic exposure increased the temporal parameters and decreased the spatial parameter of Ca2+ sparks, while opposite changes occurred with hyposmotic exposure. The spatio-temporal properties of Ca2+ sparks were slightly affected by altering [K+]i (50-200 mmol/L) in saponin permeabilized myocytes in the presence of 8% dextran. It was observed that the spatio-temporal parameters of the Ca2+ sparks in permeabilized myocytes were dose-dependently altered by dextran. The propagating velocity of Ca2+ waves in intact and permeabilized myocyte was also affected by osmotic pressure or dextran. CONCLUSION: The effect of osmotic stress on the frequency of spontaneous Ca2+ sparks might be ascribed to the change of myoplasmic Ca2+ and Ca2+ content in the sarcoplasmic reticulum, while the effect on the spatio-temporal properties is caused by the alteration of Ca2+ diffusion mainly resulting from the morphological change of the myocytes.     

胺碘酮联合阿托伐他汀钙与单用胺碘酮治疗房颤的 Meta分析

目的：系统评价胺碘酮联合阿托伐他汀钙与单用胺碘酮治疗房颤的临床疗效和对患者血清CRP、左房内径的影响。方法检索PubMed、Elsvier、CNKI数据库2000－2012年的所有文献,尽可能全面地收集相关临床试验资料,并在严格评价文献质量的基础上,利用RevMan5．0进行Meta分析。用Mantel-Haensze法对其结果进行检验并证实其同质性,若具有同质性则选择固定效应模型,否则选择随机效应模型。用漏斗图分析文献的发表偏倚。结果10个胺碘酮联合阿托伐他汀钙治疗房颤窦性心律维持情况的分析研究具有同质性（P＝0．96,I2＝0％）,选择固定效应模型分析,OR＝2．42,95％CI（1．75,3.35）。6个胺碘酮联合阿托伐他汀钙治疗房颤CRP水平变化的分析研究不具有同质性（P＝0．006,I2＝69％）,选择随机效应模型分析,OR＝－1．60,95％CI（－1．97,－1．23）。结论胺碘酮联合阿托伐他汀钙比单用胺碘酮能更有效地降低CRP的水平,更好地维持窦性心律,在治疗前后左房内径的改变和不良反应发生率方面两组间差异无统计学意义（P＞0．05）。     

芍药苷对大鼠心肌细胞L钙通道的阻断作用

目的　在单个大鼠心肌细胞上 ,研究芍药苷对L型钙通道的阻断作用。方法　采用全细胞膜片钳技术。结果　芍药苷浓度依赖性阻断ICa ,L,其IC50 为 387μmol·L- 1 。应用 40 0 μmol·L- 1 芍药苷后 ,ICa,L最大电流幅度下降 51 % ,但I U曲线的形态和反转电位没有变化 ,激活曲线也没有明显的改变 ;失活曲线向较负电压的方向偏移约 8 3mV ,通道从失活中恢复的时间明显延长 ,由给药前的 (96± 1 7)ms增至 (1 85± 2 8)ms ;芍药苷的阻断作用没有显示出频率依赖性。结论　芍药苷对心肌细胞ICa ,L有阻断作用     

慢性心房颤动患者心室率变化的临床意义

目的探讨慢性心房颤动患者心室率变化的临床意义。方法住院和门诊收治的病程超过一年的慢性心房颤动患者分为脑栓塞组（34例）和非脑栓塞组（32例）,用24h动态心电图记录两组患者最大心室率、最小心室率、平均心室率;用彩色多普勒心动图仪测定两组患者左房内径、左室射血分数。结果两组患者的一般临床特征、左房内径差异无统计学意义（P〉0．05）。脑栓塞组最大心室率、最小心室率、平均心室率明显快于非脑栓塞组（P〈0．05）,左室射血分数明显低于非脑栓塞组（P〈0．05）。结论慢性心房颤动患者降低心室率对预防脑栓塞、左心功能降低有重要临床意义。     

Effect of methamphetamine on potassium and L-type calcium currents in rat ventricular myocytes

The mechanisms of cardiac toxicity caused by methamphetamine (MA) are poorly understood at present. This study was designed to investigate the effects of MA on ionic currents in myocardial cells. The effects of MA on transient outward potassium current (I_to), inward rectifying potassium current (I_K1), and L-type calcium current (I_Ca-L) in isolated rat ventricular myocytes were studied using the whole-cell patch clamp technique. It was demonstrated that MA inhibited the I_to, I_K1, and I_Ca-L in the rat ventricular myocytes concentration-dependently. MA shifted left the I_to steady-state inactivation curve and shifted down the recovery curve, but had no influence on the steady-state activation curve. MA did not affect the I_Ca-L steady-state activation curve or steady-state inactivation curve, but shifted down the recovery curve. We concluded that MA had inhibitory effects on the I_to, I_K1, and I_Ca-L in ventricular myocytes, which might be one of the possible electrophysiological mechanisms of cardiac damage caused by MA.     

三七皂甙Rg_1对犬心电生理特性及心室纤颤阈值的影响(英文)

目的:研究三七皂甙Rg_1对心肌电生理特性及室颤阈值(VFT)的影响.方法:17只正常犬被随机分为生理盐水对照组和Rg_1组(20 mgkg~(-1),iv).麻醉后沿正中开胸,暴露心脏.应用心脏电刺激及单相动作电位(MAP)记录技术,测量心肌电生理参数及VFT.结果:Rg_1延长窦房结恢复时间19.1％;延长房室传导文氏阻滞周长7.1％;延长心室有效不应期7.9％;延长心室MAP时程(MAPD),其中MAPD_(30)延长25.5％,MAPD_(50)延长24.2％,MAPD_(90)延长13.5％;提高VFT 19.2％.结论:Rg_1延长心室不应性及复极化时程,提高VFT,提示Rg_1的作用与胺碘酮的效应类似.     

HMR 1883, a cardioselective KATP channel blocker, inhibits ischaemia- and reperfusion-induced ventricular fibrillation in rats

Ventricular fibrillation (VF) is a major cause of sudden cardiac death in which myocardial ischemia plays a leading role. During ischaemia activation of ATP-sensitive potassium channels (K(ATP)) occurs, leading to potassium efflux from cardiomyocytes and shortening of the action potential favoring the genesis of ventricular fibrillation. In confirmation of this concept the sulfonylurea glibenclamide, which stimulates insulin release by inhibition of pancreatic K(ATP) channels, has been shown to inhibit VF in different models of ischaemia by inhibition of myocardial K(ATP) channels. HMR 1883 (1-[15-12-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective K(ATP) channel blocker. The aim of this study was to show that with this compound it is possible to separate the antifibrillatory from the insulin-releasing effect for the treatment of patients at risk of ischaemia-induced arrhythmias and sudden death. In the present study HMR 1883 reduced VF in Sprague-Dawley rats during prolonged ischaemia and also diminished mortality and the duration of VF in a separate reperfusion experiment at 3 mg/kg and 10 mg/kg with no effect on blood glucose or insulin. Glibenclamide, which was antifibrillatory at 0.3 mg/kg and 1 mg/kg, increased plasma insulin and lowered blood glucose already at a dose as low as 0.01 mg/kg. In conclusion, based on its antifibrillatory action and the absence of significant pancreatic effects at therapeutic doses, HMR 1883 is of potential clinical utility for the prevention of severe arrhythmias in patients with ischaemic heart disease.     

Advances in the pharmacologic treatment of ventricular arrhythmias

Introduction: Despite many advances in nonpharmacologic management of ventricular arrhythmias, antiarrhythmic drugs remain important in both the acute conversion and chronic prevention of ventricular arrhythmias.

Areas covered: Key trials related to antiarrhythmic drug use are reviewed, emphasizing the impact of recent discoveries. Sodium channel blockers are discussed with an emphasis on recently identified specialized uses. Beta blockers, amiodarone, sotalol, and dofetilide are discussed together in the context of structural heart disease, because they do not increase mortality in this group of patients. Other medications found to reduce ventricular arrhythmia burden are discussed last.

Expert opinion: Since most patients with ventricular arrhythmias have structural heart disease, pharmacologic treatment is limited to amiodarone, d-,l-sotalol, and dofetilide (off-label indication), in conjunction with defibrillator implantation. While amiodarone has superior reduction in arrhythmias, its long-term extracardiac toxicities can cause significant morbidity. A trial of sotalol is reasonable if there are no contraindications, recognizing that over 20% of patients have to discontinue it because of adverse effects. Beta blockers are first line therapy for most patients. Genetic testing is particularly informative regarding treatment approach in long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Research should continue to focus on developing more effective antiarrhythmic medications with less long-term toxicity.     

Relationships between the severity of myocardial ischaemia, reperfusion-induced ventricular fibrillation, and the late administration of dazmegrel or nifedipine

We examined the effects of late administration of the thromboxane synthetase inhibitor dazmegrel (UK 38485) and the calcium channel blocker nifedipine in anaesthetised greyhounds subject to occlusion of the left anterior descending coronary artery with reperfusion after 40 min of ischaemia. Administration of dazmegrel, 3 mg/kg i.v., or nifedipine, 5 micrograms/kg + 1 microgram kg-1 min-1 i.v., 25 min after coronary artery occlusion failed to reduce the incidence of reperfusion-induced ventricular fibrillation (controls, 70%; dazmegrel, 50%; nifedipine, 70%; n = 10). Measurement of plasma prostanoid concentrations indicated that within 5 min of receiving dazmegrel there was a significant reduction in thromboxane B2 concentrations in the local coronary vein draining the ischaemic myocardium. The results suggest that the occurrence of reperfusion-induced ventricular fibrillation depends upon the severity of changes occurring during ischaemia. Analysis of various factors suggested that the number of ischaemia-induced arrhythmias, heart rate, and the magnitude of changes in local coronary venous PO2 may be important predictors of reperfusion-induced ventricular fibrillation.     

前胡丙素对分离的成年鼠正常及肥厚心室肌细胞内游离钙的影响(英文)

目的:研究分离的成年大鼠正常及肥厚左室肌细胞[Ca~(2 )]_i及前胡丙素的作用.方法:用Fura 2-AM测定单细胞[Ca~(2 )]_i.结果:外钙为1.0mmol·L~(-1)时,正常左室肌细胞静息钙87±4 nmol·L~(-1),肥厚细胞123±7 nmol·L~(-1).肥厚心肌细胞中,加入KCl 20,40,60 mmol·L~(-1),[Ca~(2 )]_i增加29％,78％和185％,幅度高于正常细胞.前胡丙素1,10,100 μmol·L~(-1)浓度依赖地抑制KCl及去甲肾上腺素诱导[Ca~(2 )]_i增加.作用与硝苯啶相似.结论:肥厚心肌细胞静息钙高于正常细胞;前胡丙素抑制激动剂引起的[Ca~(2 )]_i升高源于其钙通道阻断作用.     

选择性冠状动脉造影术中并发心室颤动的原因及防止对策

目的分析选择性冠状动脉造影(SCA)术中发生心室颤动(VF)的原因及其预防措施。方法回顾性分析3 028例SCA术中发生VF病例。结果用5F Terumo TIG造影导管VF发生率1.26%,高于使用其它造影导管VF的发生率。SCA术中,23例发生VF,三支CA病变5例、双支CA病变2例、RCA近端重度狭窄4例、左主干单支病变5例、RCA发育细小2例、CA无异常1例、前降支重度狭窄并AMI 2例、RCA单支完全闭塞2例。导管超选择进入圆锥支8例、导管插入过深4例、导管在RCA口操作时间较长2例、左主干病变导管在左主干操作时间过长2例、无诱因6例,RCA单支重度狭窄、前降支注入气泡1例。16患者发生VF前首先表现为CA内压力下降,7例发生VF前无CA内压力下降。结论冠脉病变特点器材选择及操作不当是SCA中VF发生的主要原因,充分认识并避免之可防止VF发生。     

Characteristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes

1. The Ca²⁺-antagonistic properties of lacidipine were investigated in patch-clamp guinea-pig ventricular myocytes.
2. In basal conditions, 0.1 μM lacidipine reduced the action potential duration, associated with a decrease in the L-type calcium current (I_Ca,L) to 66±4% of the control value, without a change in the current-voltage relationship. Sodium current and background potassium currents were not affected. All the effects reached a steady state within 2 min.
3. The Ca²⁺-antagonistic effect of lacidipine was voltage-dependent: a marked negative shift (about 20 mV) of the steady-state inactivation curve was observed with long (10 s) conditioning prepulses, but not with short (350 ms) prepulses.
4. The onset of and recovery from the voltage-dependent effect caused by 0.1 μM lacidipine were significantly slower when compared to those of equiactive concentrations of nimodipine (0.5 μM) and nisoldipine (0.1 μM). I_Ca,L measured after prepulses at −40 mV lasting 500 ms or less was unchanged (95±5% of maximum current value) while it was reduced to 49±10% by nimodipine and 43±9% by nisoldipine (P<0.05 vs lacidipine for both).
5. Similarly, the recovery from block in the presence of lacidipine was slower than with nimodipine and nisoldipine. After a prepulse of 1 s at −80 mV, I_Ca,L recovered up to 54±2% of the maximum current value in the presence of lacidipine, and up to 91±3% and 93±5% in the presence of nimodipine and nisoldipine, respectively (P<0.05 vs lacidipine).
6. Blockade of I_Ca,L by lacidipine was use-dependent. After ten 200 ms long pulses (1 Hz) from −80 mV, I_Ca,L was reduced to 55±7% of the current measured at the first pulse. In the presence of nimodipine and nisoldipine, I_Ca,L elicited by the tenth pulse amounted to 93±3% and 80±6% of the first pulse value, respectively (P<0.05 vs lacidipine). Lacidipine did not cause use-dependent blockade of I_Ca,L in cells stimulated with 10 ms long pulses.
7. These results demonstrate that lacidipine selectively inhibits I_Ca,L in isolated cardiomyocytes and suggest that this effect occurs mainly through binding to the inactivated Ca²⁺ channels.

     

丹参素对大鼠心室肌动作电位、L-型钙电流和ATP敏感性钾电流的作用

目的研究丹参素对单个大鼠心室肌细胞动作电位、L-型钙电流和ATP敏感性钾电流（IKAVP）的影响,探讨丹参素在离子通道水平的药理机制。方法胶原酶急性酶解法分离单个大鼠心室肌细胞,采用全细胞膜片钳的方法,记录丹参素对动作电位、L-型钙电流和IKATP的影响。结果丹参素可影响心室肌细胞动作电位时程（APD）,并能使APD25、APD50和APD90显著缩短;丹参素能够抑制三．型钙电流;丹参素可使IKA卯外向电流增大,此效应呈浓度依赖性。结论丹参素的心肌保护作用机制与抑制L-型钙电流和部分激活IKA口外向电流有关。     

心房颤动的控制心室率治疗进展

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