Effect of ajmaline and its therapeutically used derivatives N-propylajmaline and di-monochloracetylajmaline on the functional refractory period and contractility of guinea pig atrium and aconitine arrhythmia in the rat]

1. In the isolated left atrium of the guinea pig ajmaline and di-monochloracetylajmaline (DCAA) show almost the same activity concerning prolongation of the functional refractory period. 2. In contrast to this N-propylajmaline (NPA) is much more effective than ajmaline. 3. NPA as compared to ajmaline and DCAA, however, shows a considerably smaller difference between the concentrations prolonging refractory period (I) and those decreasing contractility (II) in the guinea pig atrium (EC25). The quotient from I and II is 0.4 with NPA, 1.2 with ajmaline and 1.6 with DCAA. 4. Differences in efficacy similar to those observed in the guinea pig atrium are also found in experimental cardiac arrhythmias in the intact animal. NPA is much more effective than ajmaline regarding inhibition of extrasystoles, ventricular tachycardia and ventricular flutter due to aconitine infusion in the rat. In this experimental model DCAA shows slightly less activity than ajmaline; this difference is statistically significant.     

Mechanism of atrial flutter and fibrillation induced by aconitine in the dog, with observations on the role of cholinergic factors

The topical application of aconitine nitrate to the right atrial appendage in the “intact” anaesthetized dog produced atrial flutter. Premature systoles with fixed coupling preceded the development of flutter. In early stages of the arrhythmia, atrial rate was irregularly irregular. Also, the form of flutter beats was similar to that of preceding premature systoles. The fibrillatory activity of acetylcholine described by earlier workers has been confirmed. Transient atrial dissociation was seen after intravenous injection or topical application of acetylcholine. The occurrence of fibrillation in the left atrium after focal application of acetylcholine has been demonstrated, while the right atrial appendage containing the ectopic focus induced by aconitine continued to flutter. Aconitine produced slow-rate flutter in dogs treated with atropine or hemicholinium; this flutter was easily distinguishable from the sinus tachycardia produced by these drugs, by recording the electrocardiogram from a direct atrial lead from the area treated with aconitine, but not from limb lead II. The importance of these findings in the interpretation of the mechanism of atrial flutter and fibrillation is discussed.     

沙棘总黄酮对离体心脏的抗心律失常作用

沙棘总黄酮(TFH)对离体大鼠心脏可显著延长缺氧性心律失常出现时间,提高室颤阈值,延缓房室传导,减慢心率,减弱心肌收缩力和对抗由缺氧引起的心率减慢及心肌收缩力减弱的作用。TFH可轻度延长离体豚鼠左房功能不应期,明显对抗乌头碱诱发离体豚鼠右房节律失常的作用。     

Class III antiarrhythmic action in experimental atrial fibrillation and flutter in dogs

Progress in the pharmacological treatment of atrial fibrillation and flutter has been achieved by the introduction of the class III antiarrhythmic drug amiodarone. In the present study we tested amiodarone and a new class III antiarrhythmic drug, melperone, in experimentally induced atrial fibrillation and flutter in pentobarbital-anesthetized dogs. By high-rate stimulation in the right atrium, atrial fibrillation was induced in 4, and atrial flutter in 10 out of 22 dogs. Atrial flutter rate was 496 +/- 13 min-1 (median +/- 95% confidence interval). Both drugs converted the arrhythmias at doses from 2.5 to 10 mg . kg-1 and reduced that atrial flutter rate before conversion. Average ventricular rate during arrhythmias (261 +/- 16 min-1) decreased after amiodarone, and was unchanged or, in three out of nine dogs, increased after melperone. The doses of amiodarone converting the arrhythmias increased atrial refractoriness, whereas the effects on AV nodal conduction and refractoriness were variable. The results support the concept that atrial flutter is due to circus movement where the flutter rate is dependent upon atrial refractoriness. The class III antiarrhythmic drugs amiodarone and melperone seem to be equally potent in converting atrial arrhythmias.     

Monophasic action potentials during reentrant atrial flutter in the dog: effects of clofilium and acetylcholine

Monophasic action potentials (MAP) were recorded from canine atrium during reentrant flutter resulting from circus movement in atrial tissue above the tricuspid ring. A catheter and plaque contact electrodes were developed to record MAP from the epicardium or endocardium during sinus rhythm, paced rhythms, and flutter. The transmembrane action potential duration of tricuspid ring tissue also was studied in vitro. During flutter at cycle lengths of 140-160 ms, MAP showed incomplete repolarization. Pacing at comparable cycle lengths had a similar effect. Acetylcholine (10 micrograms/kg, i.v.) shortened MAP duration during pacing and, during flutter, decreased cycle length and increased MAP amplitude. Clofilium (500 micrograms/kg, i.v.) prolonged flutter cycle length by 18% and terminated the flutter within 30-120 s. During pacing at a cycle length of 300 ms, clofilium increased MAP duration and effective refractory period (ERP) by 30%. Transmembrane action potentials showed that clofilium (0.2 mg/L) modified only action potential duration. Conduction velocity was significantly decreased by clofilium during flutter but not during pacing at a cycle length of 300 ms. These data support the conclusion that in this model of flutter, the circus movement occurs in partially repolarized tissue. The circus movement can be accelerated by agents (acetylcholine) that reduce ADP, and slowed and terminated by agents (clofilium) that increase it.     

槐定碱和氧化槐定碱的抗心律失常作用

目的;研究氧化槐定碱和槐定碱对试验性心律失掌上作用以及对心肌生理我的影响。方法：应用各种心律失常模型观察药物对实验性心律失常的作用;离体心肌实验法观察药物对心房生理特性的影响。结果：Ｏｘｙ５００ｍｇ．ｋｇ＾－１ｉｖ对抗乌头碱,哇巴因和结扎冠状动脉左前降支诱发的室性心率失常,使室性异位搏动数减少,室速持续时间缩短,室颤的发生率由７５％减少到１２．５％。     

Hydrochlorides of N-hydroxyalkyl-alpha-piperidine carboxylic arylamides possessing antiarrhythmic activity

It has been demonstrated in experimental arrhythmias of animals (aconitine one in rats, strophanthine in guinea-pigs, creation of an "ectopic focus of excitation" in cats by electric stimulation) that new compounds, the derivatives of piperidine carboxylic acids, possess antiarrhythmic activity. In doses of 6-23 mg/kg, the compounds under study prevented the development of the mixed type arrhythmia induced by intravenous injection of aconitine, prolonged the time of survival and prevented the animals' death during intravenous injection of the arrhythmogenic doses of strophanthine, prolonged the refractory period, and increased the threshold of ventricular fibrillation in cats. As regards the power of the antiarrhythmic effect, the compounds under study--hydrochlorides of arylamides of N-hydroxyalkly-alpha-piperidine carboxylic acids--approach lidocaine, yield to marcaine, and exhibit a broader range of therapeutic action.     

Calcium antagonists. Clinical use in the treatment of arrhythmias

Calcium antagonists have recently emerged as a class of drugs for the treatment of angina, hypertension and certain cardiac arrhythmias. Verapamil is the prototype calcium antagonist and has the most clearly defined antiarrhythmic properties. Other agents in the class include D-600 (gallopamil), tiapamil, nifedipine, and diltiazem. The antiarrhythmic effects of these compounds can be correlated with their electrophysiological properties which may differ significantly among different compounds and also between isolated tissues in intact animals and man. As a class they do not increase the effective refractory period of the atria, ventricle, His-Purkinje fibres or the accessory pathways in the heart. The dominant effect is slowing of conduction in the AV node with the prolongation of the AV nodal refractory period. The most marked changes are produced by verapamil, the least with nifedipine which is devoid of antiarrhythmic actions. Verapamil and its congeners as well as diltiazem terminate paroxysmal supraventricular tachycardia and slow the ventricular response in atrial flutter and fibrillation. They are also of prophylactic value in preventing recurrences of paroxysmal supraventricular tachycardia and controlling the ventricular response in atrial flutter and fibrillation during long term oral therapy. Their value in ventricular arrhythmias is uncertain but they are unlikely to be effective except in those complicating coronary artery spasms. The relative merits and potencies of various calcium antagonists in different arrhythmias need further studies.     

左旋体盐酸非洛普的抗实验性心律失常作用

目的　研究左旋体盐酸非洛普 [levo 1 (2 ,6 二甲基苯氧基 ) 2 (3 ,4 二甲氧基苯乙氨基 )丙烷盐酸盐 ,l DDPH对实验性心律失常的抑制作用。方法　iv哇巴因、乌头碱或氯化钙制造大鼠、豚鼠室性心律失常模型 ;标准微电极技术记录动作电位 ;全细胞膜片钳技术记录L型钙电流 (ICa,L)。结果　l DDPH 5 0mg·kg-1抑制哇巴因诱发的豚鼠室性心律失常以及乌头碱和氯化钙诱发的大鼠室性心律失常 ;l DDPH 3 0 μmol·L-1缩短豚鼠右心室乳头肌细胞 5 0 %动作电位时程 (APD50 )并延长有效不应期 (ERP) (n =6,P <0 0 5 ) ;l DDPH抑制单个豚鼠心室肌细胞ICa,L,其IC50 值为 12 9(95 %可信限 :7 0～ 18 8) μmol·L-1(n =5 )。结论　l DDPH具有抗实验性心律失常作用 ;其机制与抑制ICa,L、缩短APD50 并延长ERP有关     

Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine.

1. It was investigated whether the calcium antagonistic coronary drugs verapamil and nifedipine have similar antiarrhythmic properties. Their effects on functional refractory period and contractile force in the isolated left guinea pig atrium were compared. To assess their influence on myocardial excitability the relation between threshold voltage and pulse duration was studied in the left guinea pig atrium. Furthermore, the influence on AV conduction was investigated in the conscous dog in haemodynamically equieffective dose ranges. 2. Verapamil as well as nifedipine cause a dose-dependent prolongation of the functional refractory period in the isolated left guinea pig atrium. The slope of the dose-response curve of nifedipine is, however, significantly less steep than that of verapamil. Maximum prolongation of refractory period which can be induced by nifedipine is significantly inferior to that occurring after verapamil; under nifedipine this prolongation is, however, accompanied by a significantly greater reduction in contractility. 3. In the isolated left guinea pig atrium the voltage-duration curve is shifted to the right and the chronaxia value is significantly increased by verapamil. Even in the highest dose possible nifedipine has no effect on atrial excitability. 4. In the conscious dog verapamil considerably prolongs AV conduction time whereas a moderate yet dose-dependent shortening of PQ duration is observed with equieffective nifedipine doses regarding the decrease in blood pressure and increase in heart rate. 5. The results indicate that nifedipine does not exert antiarrhythmic effects comparable to those of verapamil.     

Actions of a newly synthesized compound (711389-S) on various types of experimentally induced arrhythmias in mammalian species in situ

We examined effects of 711389-S, a new antiarrhythmic agent, on ouabain-induced arrhythmias in dogs and guinea-pigs, aconitine-induced arrhythmias in dogs and mice, adrenaline-induced arrhythmias in dogs under an anesthetized condition, and arrhythmias induced by coronary artery ligation and occlusion by a glass bead in dogs under conscious and un-restrained conditions. 711389-S (1-3 mg/kg, i.v.) decreased the number of ventricular extrasystoles induced by ouabain in dogs, and the doses of ouabain required to induce various types of arrhythmias were increased by pretreatment of guinea-pigs with intraduodenal application of 711389-S (5-10 mg/kg). In mice, 711389-S (3 mg/kg, i.v. or 10 mg/kg, p.o.) significantly prolonged the time to onset of arrhythmias induced by aconitine infusion. Atrial fibrillation induced by a topical application of aconitine on the atrium was blocked by 711389-S (1 mg/kg, i.v.) in dogs. 711389-S (1-3 mg/kg, i.v.) depressed arrhythmias induced by adrenaline and restored the sinus rhythm by significantly decreasing the number of ventricular ectopic beats induced by coronary ligation or occlusion in dogs. Oral administration of 711389-S (10-30 mg/kg) in dogs markedly depressed the ventricular ectopic beats induced by coronary ligation. The half decay time of 711389-S after a single bolus injection of 711389-S ranged from 60 to 80 min. Results indicate that 711389-S has similar antiarrhythmic effects to those of other Class I antiarrhythmic agents in situ, and they suggest that this compound might have potential usefulness as a new type of antiarrhythmic agent for clinical use.     

7-溴化乙氧苯四氢巴马汀的抗心律失常作用

7-溴化乙氧苯四氢巴马汀(EBP)10mg/kg对小鼠乌头碱、豚鼠哇巴因、兔肾上腺素诱发的心律失常有明显对抗作用;2mg/kg对大鼠冠脉结扎和再灌注引起的心律失常有保护作用;EBP能降低离体豚鼠乳头状肌及右房自律性,延长不应期,增加收缩性。EBP明显延长豚鼠乳头状肌APD_(20),APD(90),不影响APA,RP,OS,V_(max)。     

槐胺碱抗心律失常作用

槐胺碱(sophoramine)是从豆科槐属植物苦豆子Sophora alpicuroides Lin.中提取的一种淡黄色生物碱。本文主要研究其抗心律失常的作用。     

烟浪丁的抗心律失常作用

NICO 100 mg/kg iv,可明显对抗乌头碱和BaCl₂诱发大鼠及氯仿-肾上腺素引起兔的心律失常;降低CaCl₂所致的大鼠室颤率;提高豚鼠心脏哇巴因中毒时的耐量。50 mg/kg iv,也可预防结扎大鼠左冠状动脉引起的心律失常。50～100 mg/kg ip,能降低氯仿或ACh—CaCl₂引起的小鼠室颤率或房颤(扑)率。NICO可减慢豚鼠心率,且可拮抗异丙肾上腺素的正性变率作用。     

Suppression of ouabain-induced atrial arrhythmias by carotid sinus stimulation

In dogs anaesthetized with chloralose ectopic atrial arrhythmias were produced by subepicardial injection of ouabain. Stimulation of the right carotid sinus abruptly suppressed the ectopic arrhythmias. They returned on cessation of stimulation and sometimes already during the period of stimulation. It is suggested that in view of its response to carotid sinus stimulation the ouabain-induced arrhythmia resembles paroxysmal atrial tachycardia and that it is distinct from the aconitine-induced arrhythmia which on account of its response to vagal stimulation has been classified as atrial flutter.     

A multiple ion channel blocker, NIP-142, for the treatment of atrial fibrillation

Atrial fibrillation (AF) is one of the most frequent cardiac arrhythmia and is associated with increased cardiovascular morbidity and mortality, and the risk of stroke. Although currently available antiarrhythmic drugs are moderately effective in restoring normal sinus rhythm in patients with AF, excessive delay of ventricular repolarization by these agents may be associated with increased risk of proarrhythmia. Therefore, selective blockers of cardiac ion channel(s) that are exclusively present in the atria are highly desirable. NIP-142 is a novel benzopyrane derivative, which blocks potassium, calcium, and sodium channels and shows atrial specific action potential duration prolongation. NIP-142 preferentially blocks the ultrarapid delayed rectifier potassium current (I Kur) and the acetylcholine-activated potassium current (I KACh). Since I Kur and I KACh have been shown to be expressed more abundantly in the atrial than in the ventricular myocardium, the atrial-specific repolarization prolonging effect of NIP-142 is considered to be due to the blockade of these potassium currents. In canine models, NIP-142 was shown to terminate the microreentry type AF induced by vagal nerve stimulation and the macroreentry type atrial flutter induced by an intercaval crush. These effects of NIP-142 have been attributed to the prolongation of atrial effective refractory period (ERP), because this compound prolonged atrial ERP without affecting intraatrial and interatrial conduction times in these models. The ERP prolongation by NIP-142 was greater in the atrium than in the ventricle. NIP-142 also terminated the focal activity type AF induced by aconitine. In addition, NIP-142 reversed the atrial ERP shortening and the loss of rate adaptation induced by short-term rapid atrial pacing in anesthetized dogs. Thus, although clinical trials are required to provide evidence for its efficacy and safety, the novel multiple ion channel blocker, NIP-142, appears to be a useful agent for the treatment of several types of AF with a low risk of proarrhythmic activity.     

比较Lorcainide和几种抗心律失常药对实验性心律失常的作用

用麻醉大白鼠和豚鼠研究lorcainide抗心律失常作用,并与普鲁卡因胺、异搏定、苯妥英钠和阿托品进行比较。Iv lorcainide 3 mg/kg可对抗肾上腺素、乌头碱、氯化钡和哇巴因心律失常,但不能对抗氯化钙心律失常。Iv阿托品0.1 mg/kg对抗肾上腺素引起的大鼠心律失常作用强于lorcainide。苯妥英钠iv 20 mg/kg对抗乌头碱引起心律失常的作用比qorcainide显著;iv异搏定1.25 mg/kg对抗氯化钡心律失常的作用超过loreainide。Iv lorcainide 3 mg/kg提高哇巴因引起豚鼠心律失常所需剂量显著超过异搏定,普鲁卡因胺与苯妥英钠。     

THE EFFECTS OF DIAZEPAM ON RAT ISOLATED HEART MUSCLE

1. The effects of diazepam on spontaneously beating right atrium, left atrium and papillary muscle isolated from a rat heart were compared to those of chlorpro-mazine and phenytoin. 2. Arrhythmic contractions induced by threshold electrical stimulation in the rhythmic spontaneous contractions of the right atrium were prevented by diazepam (10 μg/ml). These arrhythmic contractions were not prevented by chlorpromazine (0.01–10 μg/ml), or by phenytoin (0.1–10μg/ml). 3. The refractory periods of the heart muscle, estimated by use of Govier's method, was increased by diazepam (10 μg/ml) by 90.5% in the left atrium and 54.4% in the papillary muscles. Chlorpromazine (1.0 μg/ml) and phenytoin (10 μg/ ml) increased the refractory period of papillary muscle by 42.8 and 54.1%, respectively, but had little effect on the refractory period of the left atrium. 4. The maximum driving frequency of the left atrium was decreased by diazepam (10 μg/ml) by 25.1% and by chlorpromazine (1.0 μg/ml) by 33.3%, while that of papillary muscle was little influenced by the drugs at these concentrations. Phenytoin (0.1–10 μg/ml) had little effect on the maximum driving frequency of the left atrium or of papillary muscle. 5. The rate and force of spontaneous contractions of the right atrium were decreased by phenytoin (10 μg/ml) by 36.7% and 97.0%, respectively. Diazepam (0.1–10 μg/ml) had little effect on rate and produced a concentration-dependent increase in force up to 151.5%. Chlorpromazine (0.01–1.0 μg/ml) had little effect on either the rate or force of spontaneous contraction of the right atrium. 6. The contractile force of the left atrium and of papillary muscle driven by electrical stimulation was depressed by diazepam (20 μg/ml), chlorpromazine (2.0 μg/ml) and phenytoin (20 μg/ml)- Diazepam (0.5–10 μg/ml) produced a concentration-dependent increase in force of up to 204.7% in the left atrium and 163.1% in papillary muscle. Chlorpromazine (0.01–1.0 μ/ml) had little effect on the force of the driven left atrium, but produced a concentration-dependent decrease in force of papillary muscle down to 40.1%. Phenytoin (10 μg/ml) reduced the force of contraction by 84.6 and 92.7%, respectively, in the left atrium and papillary muscle.