Broad sensitivity of rodent arrhythmia models to class I, II, III, and IV antiarrhythmic agents

To determine specificity of rodent models of arrhythmia for different Vaughan Williams classes of antiarrhythmic drugs, we tested 17 drugs from the four classes in one in vitro and four in vivo models. In the mouse chloroform-induced ventricular fibrillation model and in the guinea pig ouabain-induced arrhythmia model, drugs of classes I (amefalone, aprindine, lidocaine, mexiletine, phenytoin, procainamide, or quinidine), II (metoprolol or propranolol), and IV (bepridil) were active. Class III drugs (bretylium, clofilium, or melperone did not suppress ouabain arrhythmias, but were active in the mouse chloroform model. In the rat coronary artery ligation model, disopyramide (class I), amefalone and melperone significantly (P less than 0.05) reduced the number of extrasystoles. Propranolol, sotalol, and verapamil (class IV) were less effective. In the rat coronary artery ligation/reperfusion model, all four classes of antiarrhythmic agents were active in vitro (isolated heart) and in vivo (anesthetized rat). Thus, one model of automaticity, the guinea pig ouabain model, detected class I, II, and IV drugs, whereas another automaticity model, the mouse chloroform model, also detected class III agents. The model of reentry induced by ischemia plus reperfusion (rat coronary artery ligation reperfusion) can be recommended as a screen for new antiarrhythmic agents based on its sensitivity to all four classes of antiarrhythmic drugs. The Vaughan Williams class of an antiarrhythmic agent must be determined, however, by additional mechanism studies.     

牛磺酸镁对哇巴因致豚鼠心肌细胞心律失常模型钙离子通道的作用机制分析

摘要目的：研究牛磺酸镁（TMCC）对哇巴因致豚鼠心肌细胞心律失常模型钙离子通道的作用机制。方法：运用全细胞膜片钳技术分别记录TMCC和胺碘酮对正常心肌细胞和哇巴因导致的心律失常心肌细胞模型钙离子通道的作用。结果：5bμmol／L哇巴因使心肌细胞钙离子通道电流（ICa-L）减小。200和400μmol／L可以明显使Ic}L恢复。24．26μmol／L胺碘酮使IM进一步减少（P〉0．05）。结论：400μmol／LTMCC可以明显加大正常细胞的b。,起到促进钙内流的作用,并且增强哇巴因致豚鼠心律失常心肌细胞异常减少的电流。     

Antiarrhythmic effect of magnesium sulfate against occlusion-induced arrhythmias

The antiarrhythmic effect of magnesium sulfate (Mg) as well as the hemodynamics were studied using the coronary ligation and reperfusion models in rats.In the study on coronary ligation arrhythmia, i.v. administration of Mg (0.6, 2, 6, 20 and 60 \sgmaelig;mol) was conducted at 5 min after coronary ligation. Mg had an action to decrease the total number of premature ventricular contraction (PVC), the duration of ventricular tachycardia (VT), the frequency of VT and ventricular fibrillation (Vf) and the mortality ratio for 30 min after coronary ligation. In the 6-60 \sgmaelig;mol groups, significant antiarrhythmic action (p < 0.01 vs. control) was attained.In the study on reperfusion arrhythmia, i.v. administration of Mg (20, 60 and 200 \sgmaelig;mol) was conducted at 4 min after coronary ligation, and at 1 min after ligation, the coronary artery was reperfused. Mg had an action to decrease the frequency of Vf, the mortality ratio and the duration of VT and Vf and to extend the interval between the initiation of reperfusion and the occurrence of VT and Vf for 10 min after reperfusion. In the 200 \sgmaelig;mol group, significant antiarrhythmic action (p < 0.05 vs. control) was attained. Administration of Mg decreased the heart rate and blood pressure.We concluded that Mg can control myocardial ischemia-induced and reperfusion-induced arrhythmia and that sudden cardiac death which occurs as a result of arrhythmia can be prevented.     

白藜芦醇对哇巴因所致豚鼠乳头状肌迟后去极化及触发活动的效应

研究旨在应用标准玻璃微电极技术,观察白藜芦醇对哇巴因所引起的离体豚鼠乳头状肌迟后去极化(delayed after depolarization,DAD)及触发活动(triggered activity,TA)的效应。结果显示：(1)预先给予白藜芦醇(30、60、120μmol／L)可剂量依赖性地抑制哇巴因所引起的乳头状肌DAD及TA;(2)预先应用L型钙通道开放剂Bay K8644(0．25μmol／L),可取消白藜芦醇的上述效应;(3)预先应用一氧化氮合酶抑制剂L-NAME(1mmol／L),对白藜芦醇的上述效应无影响;(4)单独应用17β-雌二醇(E2,5μmol／1．0或白藜芦醇(30μmol／L)对DAD及TA无明显影响,而联合应用相同剂量的E2和白藜芦醇则对DAD及TA产生明显的抑制效应;(5)预先应用雌激素受体拮抗剂他莫昔芬(10μmol／L)不能取消白藜芦醇对DAD及TA的抑制作用。以上结果表明,白藜芦醇具有抑制乳头状肌DAD及TA的作用,这一效应可能与其抑制钙离子内流有关,但此作用机制中NO和雌激素受体的作用并不显著。白藜芦醇这种抗心律失常作用对于心血管系统具有一定的保护意义。     

Effects of Taurine–Magnesium Coordination Compound on Ionic Channels in Rat Ventricular Myocytes of Arrhythmia Induced by Ouabain

Taurine-magnesium coordination compound (TMCC) has anti-arrhythmic effects. The aim of the present study was to explore the targets of the anti-arrhythmic effect of TMCC and the electrophysiological effects of TMCC on ouabain-induced arrhythmias in rat ventricular myocytes. Sodium current (I(Na)), L-type calcium current (I(ca, L)), and transient outward potassium current (I(to)) were measured and analyzed using whole-cell patch-clamp recording technique in normal rat cardiac myocytes and rat ventricular myocytes of arrhythmia induced by ouabain. In isolated ventricular myocytes, I(Na) and I(to) were blocked by TMCC (100, 200, 400 μM) in a concentration-dependent manner, and the effects of TMCC (400 μM) were equal to that of amiodarone. However, I (ca, L) was moderately increased by TMCC (400 μM) while significantly decreased by amiodarone. Ouabain (5 μM) significantly decreased sodium, L-type calcium, and transient outward potassium currents. TMCC (100 μM) relieved abnormal sodium currents induced by ouabain through facilitation of steady-state inactivation. TMCC (200 and 400 μM) relieved abnormal L-type calcium currents induced by ouabain through facilitation of steady-state activation and retardation of steady-state inactivation. TMCC failed to further inhibit abnormal transient outward potassium currents induced by ouabain. However, amiodarone inhibited the decreasing sodium, L-type calcium, and transient outward potassium currents further. These data suggest that I(Na), I(ca, L), and I(to) may be the targets of the antiarrhythmic effect of TMCC, which can antagonize ouabain-induced changes of ionic currents in rat ventricular myocytes.     

Anti-arrhythmic activity of the beta2-adrenoblockader alpheprol]

Experiments were conducted on dogs, cats and rats in which various disturbances of the cardiac rhythm were induced. Beta2-adrenoblocker alpheprol proved to produce a marked antiarrhythmic action. The preparation arrested the auricular arrhythmias caused by electric stimulation of the auricles or by aconitine application, eliminated the auricular arrhythmias resulting from occlusion of a branch of the coronary artery or oubaine intoxication, prevented lethal auricular fibrillation in rats after the calcium chloride intoxication. It is supposed that along with the beta-adrenoreceptor block the antiarrhythmic effect of alpheprol was also caused by quinidine-like action of the preparation.     

Chlorpromazine: cardiac arrhythmogenicity in the cat

To determine the effect of chlorpromazine on ouabain-induced arrhythmia and death, dial-urethane anesthetized cats were pretreated with chlorpromazine (5, 10, 20, 30, 40, or 60 mg/kg, i.v.) and then administered ouabain (2 microgram/kg/min, i.v.). Blood pressure, heart rate and lead II electrocardiogram (ECG) were monitored. The dosages of ouabain necessary to induce premature ventricular contractions, ventricular tachycardia and death were determined. No significant correlation between the dose of chlorpromazine given and the dose of ouabain required to produce arrhythmia or death was found. These doses of chlorpromazine could, therefore, be considered neither arrhythmogenic nor antiarrhythmic in the ouabain model. To determine whether chlorpromazine produced arrhythmia in the dial-urethane anesthetized cat model, the drug was infused at a rate of 1 mg/kg/min, i.v. Chlorpromazine produced arrhythmia at 185 +/- 4.3 minutes and death via cardiovascular collapse at 128 +/- 4.7 minutes. Bilateral adrenal vein ligation, employed to eliminate the influence of adrenal catecholamines, decreased the dosage of chlorpromazine necessary to produce arrhythmia and death to 67.8 +/- 17.7 and 84.7 +/- 15.7 mg/kg, respectively. Thus, adrenal catecholamines did not appear to contribute to chlorpromazine-induced arrhythmia, although the procedure of bilateral adrenal vein ligation appeared to be deleterious in combination with chlorpromazine. In all experiments, chlorpromazine depressed blood pressure without producing the reflex tachycardia normally seen with hypotension. This suggests that the drug may be interfering with the baroreceptor reflex arc. As chlorpromazine modifies the autonomic parameters of blood pressure, heart rate, and cardiac electrophysiology, sudden unexplained death in patients managed with this agent may be due to drug-induced arrhythmia.     

间歇性低氧处理大鼠心肌的抗心律失常与抗氧化效应

利用结扎在体大鼠冠脉方法研究不同时间间歇性低氧处理对血、再灌注心律失常以及心肌超氧化物歧化酶（ＳＯＤ）、丙二醛（ＭＤＡ）的影响,并与连续性低氧相比较。实验结果如下：⑴间歇性低氧（ｉｎｔｅｒｍｉｔｔｅｎｔ ｈｙｐｏｘｉａ ｅｘｐｏｓｕｒｅ）２８ｄ（ＩＨ２８）、４２ｄ（ＩＨ４２）、间歇性低氧２８ｄ后１周（ＰＩＨ２８－２Ｗ）和连续性低氧（ｃｏｍｔｉｎｕｅｄ ｈｙｐｏｘｉａ ｅｘｐｏｓｕｒｅ）２８ｄ（ＣＨ     

Antiarrhythmic activity of 4,6-di(het)aryl-5-nitro-3,4-dihydropyrimidin-(1H)-2-ones and its effects on arterial pressure in rats

The antiarrhythmic activity of 4,6-di(het)aryl-5-nitro-3,4-dihydropyrimidin-(1H)-2-ones toward two types of experimental rat arrhythmia has been studied. With CaCl(2) induced arrhythmia model, several agents have demonstrated high antiarrhythmic activity and the lack of influence on arterial pressure of rats.     

Effect of B-HT 920 on cardiotoxic effects of ouabain in guinea pigs.

Effect of B-HT 920, a selective alpha 2 adrenoceptor agonist, was studied on ouabain induced cardiac arrhythmias and cardiac arrest in guinea pigs. Ventricular premature beats, ventricular tachyarrhythmias and cardiac arrest were induced in anaesthetized guinea pigs by slow infusion of ouabain. B-HT 920 accorded significant protection to guinea pigs against ouabain induced arrhythmias. Yohimbine inhibited the antiarrhythmic effect of B-HT 920 significantly. It is concluded that the protective effect of B-HT 920 against ouabain induced cardiac arrhythmias and cardiac arrest is mediated through the stimulation of alpha 2 adrenoceptors.     

降钙素基因相关肽拮抗内皮素的致心律失常作用

本工作在麻醉大鼠冠状动脉口注射内皮素１（ＥＴ１）９００ｐｍｏｌ／ｋｇ能引起室性早搏（ＰＶＣ）、室速（ＶＴ）、室颤（ＶＦ）等严重心律失常,心律失常评分（ＡＳ）为５．６±１．０;冠状动脉口单独注射降钙素基因相关肽（ＣＧＲＰ）３００－１２００ｐｍｏｌ／ｋｇ仅引起血压一过性下降,此后逐渐恢复,无心律失常发生,心律失常评分为０。用ＣＧＲＰ３００ｐｍｏｌ／ｋｇ预处理后再注射ＥＴ１９００ｐｍｏｌ／ｋｇ,心律失常发生率减少,严重程度降低,ＡＳ为１．６±１．６。ＣＧＲＰ１２００ｐｍｏｌ／ｋｇ＋ＥＴ１组心律失常评分显著低于ＥＴ１对照组（Ｐ＜０．０１）。本实验结果表明,ＣＧＲＰ的抗心律失常作用很可能有部分是通过拮抗内皮素的致心律失常作用来实现的。     

Prevention of reperfusion-induced ventricular arrhythmias in isolated rat heart with magnesium

The effects of magnesium (from 1.2 to 7.2 mM) were investigated in isolated perfused rat heart subjected to coronary artery ligation and reperfusion. Increasing magnesium concentrations, of the medium containing 3.00 mM of calcium, induced a significant bradycardia and a protective effect towards reperfusion arrhythmias. A significant correlation was found between the heart rate and the antiarrhythmic activity of increasing magnesium concentrations. The effects of high magnesium concentration (4.8 mM) were also investigated after labelling of internal stores of noradrenaline with [3H]noradrenaline. Without any marked change in the pattern of release of radioactivity, a significant reduction of the sudden release of radioactivity was observed during the reperfusion. However, magnesium did not change the uptake of noradrenaline by the heart. Our results suggest that the antiarrhythmic effect of magnesium might be of importance in the clinical treatment of myocardial ischemia.     

The antiarrhythmic action of prostacyclin (PGI2) on aconitine induced arrhythmias in rats.

Prostacyclin (PGI2) produces an antiarrhythmic effect on aconitine induced arrhythmias in rats. The ED50 of PGI2 was 0.7 microgram/kg and the maximum antiarrhythmic effect 54 per cent. The equi-effective doses of PGE2 and PGF2alpha were higher (ED50 of PGF2alpha = 1.2 microgram/kg, ED50 of PGE2 = 2.7 microgram/kg). However, PGF2alpha and PGE2 had a maximum antiarrhythmic effect of 80 per cent in this model.     

Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms

We previously showed that resveratrol (3,4',5-trihydroxystilbene) stimulates NO production and is cardioprotective in rat heart subjected to ischemia-reperfusion (I/R rat heart). We now show that in I/R rat heart, inducible nitric oxide synthase (iNOS) expression is markedly induced, while expression of endothelial nitric oxide synthase (eNOS) and nueronal nitric oxide synthase (nNOS) is unchanged. In animals preconditioned with resveratrol (0.5 to 1 mg/kg body wt), I/R-induced iNOS induction is abrogated; however, expression of eNOS and nNOS is greatly upregulated. The protective effects of resveratrol on I/R rat heart include reduced rhythm disturbances, reduced cardiac infarct size, and decreased plasma levels of lactate dehydrogenase (LDH) and creatine kinase (CK). Among these, the reductions in LDH/CK levels and infarct size are NO-dependent as the coadministration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg body wt) with resveratrol abolishes the resveratrol effect. In contrast, the reductions in the severity of ventricular arrhythmia and mortality rate are not affected by L-NAME coadministration, suggesting that a NO-independent mechanism is involved.     

Anti-arrhythmia action of the antioxidant SD-6 in the development of ischemic and reperfusion rhythm disorders of the isolated rat heart

An antiarrhythmic action of water-soluble antioxidant SD-6 from 3-hydroxypyridine class and its effect on the transmembrane potentials were studied using the isolated rat heart and papillary muscle. Ischemia was induced by the occlusion of the left anterior descending coronary artery. 10 minutes later the ligation was removed and reperfusion was achieved. In the control, ischemia induced premature ventricular complexes, tachycardia and, in some cases, fibrillation. During perfusion total fibrillation occurred in 100% of the experiments. SD-6 in the doses of 10(-6) g/ml and 5 X 10(-6) g/ml significantly reduced the incidence of fibrillation and tachycardia. In the experiments on the papillary muscle SD-6 during reperfusion completely normalized the action potential duration and removed depolarization developed in hypoxia, which suggests the ability of the antioxidant to block reperfusion-induced arrhythmias by normalization of the parameters of electrical heterogeneity. These data show that the origin of reperfusion-induced arrhythmias is connected with the activation of free radical metabolites and that their scavengers--synthetic antioxidants from 3-hydroxypyridine class--can be used as new antiarrhythmic agents.     

Influence of 15-keto-metabolites and 13,14-dihydro-15-keto-metabolites of PGE2 and PGF2 alpha as well as of 6-keto-PGF1 alpha as a metabolite of PGI2 on aconitine induced cardiac arrhythmia in rats

The 15-keto-metabolites of PGE2 and PGF2 alpha produced an antiarrhythmic effect on aconitine induced arrhythmias in rats. The ED50 values of these metabolites were approximately 2.0 micrograms/kg. The 13,14-dihydro-15-keto-metabolites of PGE2 and PGF2 alpha had no statistically significant antiarrhythmic effect. PGI2 (0.25-1.00 micrograms/kg) produced an antiarrhythmic effect between 15-54% (ED50 0.75 micrograms/kg), whereas 6-keto-PGF1 alpha, a metabolite of PGI2, showed no significant antiarrhythmic effect. The results suggest a participation of 15-keto-metabolites in the antiarrhythmic effects of PGE2 and PGF2 alpha.     

On the benefit of melatonin in protection against ouabain-induced arrhythmia through modulation of oxidative stress factors in isolated rat atria

Considering the cardioprotective and antioxidant properties of melatonin, in the present experiment, we investigated the possible involvement of oxidative stress factors in antiarrhythmic effects of melatonin in ouabain-induced arrhythmia in isolated rat atria. Male rats were divided into two groups, receiving either of melatonin (2 mg/kg) or vehicle, orally once daily for three weeks. Rats were anesthetized, and atria were isolated and incubated with ouabain in an organ bath. Time of onset of arrhythmia and asystole as well as atrial beating rate and contractile force were recorded. We also measured the activity of superoxide dismutase (SOD) and levels of thiobarbituric acid reactive substances (TBARS) in atria after injection of ouabain to animals. Pretreatment of animals with melatonin could significantly postpone the onset of arrhythmia and asystole compared with vehicle-treated group (P ≤ 0.001). Incubation of ouabain boosted the atrial beating rate in vehicle-treated group (P ≤ 0.01), while this response in melatonin-treated group was not significant (P > 0.05). Injection of ouabain decreased the activity of SOD and increased the levels of TBARS in atria (P ≤ 0.001, P ≤ 0.01, respectively), while pretreatment of animals with melatonin reversed these effects (P ≤ 0.05). It is concluded that melatonin possesses antiarrhythmic properties, and oxidative stress factors might mediate this response.     

Antiarrhythmic and electrophysiological properties of etmozin and its diethylamine analog]

Effects of antiarrhythmic drug etmosin and its diethylamine analogue (etmosin DAA) were compared in dogs with the ventricular rhythm disturbances induced by coronary artery ligation according to Harris' method. As demonstrated, both drugs stopped ventricular rhythm disturbances, but etmosin DAA had a more rapid and prolonged effect. Electrophysiological properties of etmosin and etmosin DAA were studied by the method of potential fixation on trabeculae of frog atria. Both drugs proved to reduce rapid sodium inflow, etmosin DAA acting more intensively and longer. Taking into account the high antiarrhythmic activity of etmosin DAA it is believed that this drug had good prospects for further investigation.     

Anti-arrhythmia activity of crown-lactone I and its effect on aconitine-modified sodium channels

Antiarrhythmic activity of macrocyclic crown-lactone I as well as its effect on biological and model membranes were studied. Crown-lactone displaces the potential dependence of stationary inactivation of TTX-sensible sodium neurons currents towards more negative potentials reducing the modification of those characteristics by aconitine. Proceeding from the comparison between crown-lactone and known antiarrhythmic agents effect on sodium currents a conclusion is made that crown-ethers antiarrhythmic activity cannot be explained by the rhythmoinotropic effect.     

菊米提取液抗实验性心律失常作用的研究

目的：观察菊米提取液对氯仿、乌头碱和缺血诱发的心律失常的作用：方法：采用氯仿诱导小鼠心律失常,静脉注射乌头碱和冠脉结扎法诱导大鼠心律失常,术前5d给予菊米提取液,记录心电图曲线、结果：菊米提取液能剂量依赖性地明显降低氯仿诱导的小鼠室颤发生率与对照组相比,奎尼丁可明显减少乌头碱（30μg／kg）诱导的大鼠室性早搏和室性心动过速的发生次数,缩短心律失常的持续时间=但菊米提取液组对乌头碱诱导的大鼠心律失常无明显作用：高浓度菊米提取液（2．0g／kg）可明显降低缺血复灌性心律失常评分。但低、中浓度菊米提取液（0．5g／kg和1．0g／kg）对缺血心脏心律失常评分无明显作用.结论：菊米提取液可对抗氯仿和缺血诱导的实验性心律失常,但对乌头碱引发的心律失常无影响.