aconitine and Arrhythmias--Cardiac

Aconitum is one of the most widely used Chinese herbal medicines, and aconitine is the major toxic component in it. Aconitine can induce a variety of arrhythmias, resulting in death. Acute ethanol consumption causes arrhythmia as well. Poisoning cases caused by aconitum medicinal liquor are frequently encountered in the practice of forensic medicine. The molecular mechanisms of myocardial toxicity of these two drugs have much in common, and both of them affect the sodium channel, calcium channel and potassium channel of myocardial cell membrane and so on. This paper analyzes and discusses the possible co-effects of ethanol-aconitine on cardiomyocyte channel proteins, by reviewing researches on the mechanism of cardiotoxicity of ethanol and aconitine in recent years, in order to provide ideas and references for the research on the molecular mechanism of arrhythmia caused by combined poisoning.. 乙醇-乌头碱致心律失常的毒理分子机制研究进展.. 乌头属植物是广泛使用的中草药代表之一，乌头碱是其中最主要的毒性成分，主要引起多种心律失常而致死。急性乙醇摄入也可引起心律失常。法医学实践中常遇到乌头类药酒引起的中毒案例。这两者的心肌毒性分子机制有较多共通点，均对心肌细胞膜钠通道、钙通道及钾通道等产生影响。本文通过综述近年来乙醇、乌头碱心脏毒性机制的研究报道，分析讨论乙醇-乌头碱可能共同影响的心肌细胞通道蛋白，为联合中毒致心律失常的分子机制研究提供思路与参考。.. 法医毒理学；中毒；乙醇；乌头碱；心律失常；综述.

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Drugs, Chinese Herbal; Ethanol; Humans

We present detailed data on the role of central and peripheral opioid receptors in the regulation of heart resistance to arrhythmogenic factors. Stimulation of peripheral delta2- and kappa1-receptors increases heart resistance to the arrhythmogenic effect of acute ischemia and reperfusion. Activation of peripheral mu- and delta1-opioid receptors improves electrical stability of the heart in animals with postinfarction cardiosclerosis. Possible mechanisms for opioidergic regulation of heart resistance to arrhythmogenic factors are discussed.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium Chloride; Catecholamines; Heart; Myocardial Reperfusion Injury; Opioid Peptides; Rats; Receptors, Opioid

Antiarrhythmic drug allapinin has been used in clinical practice for a long time but data of investigation of its effects and mechanism of action are scanty. The aim of this review is to summarize results of clinical studies of allapinin supplementing them with personal unpublished data. The review embraces pharmacokinetics and pharmacodynamics of the drug, its efficacy in the treatment of various cardiac rhythm disturbances and side effects. The conclusion is made that clinical application of allapinin as class 1C antiarrhythmic drug according to Vaughan-Williams classification should be guided by general recommendations concerning indications and contraindications for this class of antiarrhythmic drugs. Special feature of allapinin is its high efficacy for prevention of attacks of paroxysmal atrial fibrillation.

Topics: Aconitine; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Humans; Treatment Outcome

The effects of antiarrhythmic agents, including Classes I and IV and 3-10 mM Mg2+ on aconitine-induced arrhythmias were examined using a conventional microelectrode and patch clamp method in Langendorff-perfused rabbit hearts and isolated guinea-pig ventricular myocytes. Intracoronary application of 0.1 microM aconitine induced polymorphic ventricular tachycardia (PVT) which continued for more than 60 minutes. Application of aconitine to ventricular myocytes caused a prolonged action potential duration (APD) and the appearance of early afterdepolarization (EAD) together with the occurrence of an inward hump of the I-V curve around -60 to -40 mV and increased outward current at positive voltages. Application of 10 microM TTX and 5 mM or higher Mg2+ restored aconitine-induced PVT to sinus rhythm in Langendorff-perfused preparations and also shortened the prolonged APD, demonstrating the abolishment of EAD by aconitine in ventricular myocytes. However, antiarrhythmic agents did not exert such effects. In conclusion, the antiarrhythmic actions of Mg2+ and TTX in aconitine-induced arrhythmia are to abolish EAD and shorten the prolonged APD by suppression of the inward Na+ current around -60 to -40 mV.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; In Vitro Techniques; Magnesium; Membrane Potentials; Myocardium; Patch-Clamp Techniques; Rabbits; Tachycardia, Ventricular; Tetrodotoxin

Both "chuanwu", the main root of Aconitum carmichaeli, and "caowu", the root of A kusnezoffii, are believed to possess anti-inflammatory, analgesic and cardiotonic effects and have been used in Chinese materia medica mainly for the treatment of musculoskeletal disorders. They contain the highly toxic C19 diterpenoid alkaloids of aconitine, mesaconitine and hypaconitine. After ingestion, patients may present with signs and symptoms that are typical of aconitine poisoning. Death may occur from ventricular arrhythmias, which are most likely to occur within the first 24 h. Management of aconitine poisoning is essentially supportive. There are no adequate studies in humans to indicate the most effective treatment of the ventricular arrhythmias. All clinicians should be alerted to the potential toxicity of "chuanwu" and "caowu".

Topics: Aconitine; Adult; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Drugs, Chinese Herbal; Female; Heart Ventricles; Hong Kong; Humans; Male; Middle Aged; Neuromuscular Blocking Agents; Poisoning; Retrospective Studies; Sodium Channels

Topics: Aconitine; Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disopyramide; Electrocardiography; Humans; Moricizine; Phenothiazines; Procainamide; Propranolol

Topics: Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Glycosides; Chloroform; Disease Models, Animal; Electric Stimulation; Electrophysiology; Heart; Heart Conduction System; Humans; Mice; Myocardial Contraction; Myocardial Infarction; Perfusion; Rats

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Dogs; Electric Stimulation; Hypoxia; Lactates; Muscles; Myocardium; Oscillometry; Purkinje Fibers; Time Factors; Ventricular Fibrillation

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Biological Availability; Clinical Trials as Topic; Humans; Tablets

Topics: Aconitine; Aconitum; Administration, Oral; Arrhythmias, Cardiac; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Injections, Intravenous; Placebos

The results of the trial point to a potent and protracted antiarrhythmic effect of allapinin equally pronounced with both intravenous and oral administration to patients with ventricular and supraventricular premature beats. The side effects of the drug in acute tests and during short-term course therapy are not significant.

Topics: Aconitine; Adolescent; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Electrocardiography; Female; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Monitoring, Physiologic; Tablets; Time Factors

Sophoridine (SR) has shown the potential to be an antiarrhythmic agent. However, SR's electrophysiological properties and druggability research are relatively inadequate, which limits the development of SR as an antiarrhythmic candidate.. To facilitate the development process of SR as an antiarrhythmic candidate, we performed integrated studies on the electrophysiological properties of SR in vitro and ex vivo to gain more comprehensive insights into the multi-ion channel blocking effects of SR, which provided the foundation for the further drugability studies in antiarrhythmic and safety studies. Firstly, SR's electrophysiological properties and antiarrhythmic potentials were recorded and assessed at the cell and tissue levels by comprehensively integrating the patch clamp with the Electrical and Optical Mapping systems. Subsequently, the antiarrhythmic effects of SR were validated by aconitine and ouabain-induced arrhythmia in vivo. Finally, the safety of SR as an antiarrhythmic candidate compound was evaluated based on the guidelines of the Comprehensive in Vitro Proarrhythmia Assay (CiPA).. The antiarrhythmic effect of SR was evaluated at the in vitro, ex vivo, and in vivo levels.. Isolated primary cardiomyocytes and stable cell lines were prepared to explore the electrophysiologic properties of being a multiple ion-channel blocker in vitro by whole-cell patch clamp. Using electrical and optical mapping, the negative chronotropic effect of SR was determined in langendorff-perfused rat or guinea-pig hearts.The antiarrhythmic activity of SR was assessed by the ex vivo tachyarrhythmia models induced by left coronary artery ligation (LCAL) and isoproterenol (ISO). Canonical models of aconitine and ouabain-induced arrhythmia were used to verify the antiarrhythmic effects in vivo. Finally, the pro-arrhythmic risk of SR was detected in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hSCCMs) using a Microelectrode array (MEA).. Single-cell patch assay validated the multiple ion-channel blockers of SR in transient outward current potassium currents (Ito), l-type calcium currents (ICa-l), and rapid activation delayed rectifier potassium currents (IKr). SR ex vivo depressed heart rates (HR) and ventricular conduction velocity (CV) and prolonged Q-T intervals in a concentration-dependent manner. Consistent with the changes in HRs, SR extended the active time of hearts and increased the action potential duration measured at 90% repolarization (APD90). SR could also significantly lengthen the onset time and curtail the duration of spontaneous ventricular tachycardia (VT) in the ex vivo arrhythmic model induced by LCAL. Meanwhile, SR could also significantly upregulate the programmed electrical stimulation (PES) frequency after the ISO challenge in forming electrical alternans and re-entrant excitation. Furthermore, SR exerted antiarrhythmic effects in the tachyarrhythmia models induced by aconitine and ouabain in vivo. Notably, the pro-arrhythmic risk of SR was shallow for a moderate inhibition of the human ether-à-go-go-related gene (hERG) channel. Moreover, SR prolonged field potential duration (FPDc) of hSCCMs in a concentration-dependent manner without early after depolarization (EAD) and arrhythmia occurrence.. Our results indicated that SR manifested as a multiple ion-channel blocker in the electrophysiological properties and exerts antiarrhythmic effects ex vivo and in vivo. Meanwhile, due to the low pro-arrhythmic risk in the hERG inhibition assay and the induction of EAD, SR has great potential as a leading candidate in the treatment of ventricular tachyarrhythmia.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; Humans; Ion Channels; Isoproterenol; Matrines; Myocytes, Cardiac; Ouabain; Potassium; Rats

Aconitine poisoning causes refractory ventricular arrhythmias (VAs). In a 20-year-old man, VAs of unknown etiology did not respond to drugs and electrical defibrillation. However, left stellate ganglion blockade (SGB) dramatically decreased arrhythmias without complications. At a later date, we found that refractory VAs were caused by aconitine poisoning. Left SGB is effective for treating refractory VAs with aconitine poisoning and can be easily performed with few complications for VAs of unknown etiology even if patients are receiving anticoagulant therapy. Also, left SGB can be performed to diagnose refractory VAs.

Topics: Aconitine; Adult; Arrhythmias, Cardiac; Autonomic Nerve Block; Electric Countershock; Humans; Male; Stellate Ganglion; Young Adult

The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products.. The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrolysis products were separated using column chromatography, and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. Further, in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared, and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products.. Two new diterpenoid alkaloids, pyroacetylaconitine and 16-epi-pyroacetylaconitine, a pair of epimers at C-16, were isolated. After comparing the structures of these compounds, possible transformation pathways were proposed. Compared with the prototype compound, 3-acetylaconitine, the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased. In the biological activity assay, the two pyrolysis products exhibited an effective increase in ventricular premature beat latency, a reduction in the occurrence of ventricular tachycardia, as well as an increase in the rate of arrhythmia inhibition, implying strong antiarrhythmic activity.. Compared with 3-acetylaconitine, its pyrolysis products displayed lower toxicity and good antiarrhythmic effects; thus, they have potential for being developed into antiarrhythmic medicines. Please cite this article as: Wang YJ, Wang Y, Tao P. Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine. J Integr Med. 2023; 21(3): 302-314.

Topics: Aconitine; Alkaloids; Arrhythmias, Cardiac; Cardiotoxicity; Diterpenes; Humans; Sand

Plant exposures leading to systemic or topical toxicity are common presentations seen in the emergency department. While often nonfatal, certain highly toxic plants result in cardiovascular or respiratory failure requiring invasive management. We describe a 65-y-old patient who presented with a refractory ventricular dysrhythmia secondary to an unintentional ingestion of an aconitine-containing plant after incorrect identification. Despite aggressive treatment with vasopressors, intravenous fluids, antiarrhythmics, as well as electrolyte correction and multiple attempted synchronized cardioversions, the patient remained in a refractory dysrhythmia with cardiogenic shock. Venoarterial extracorporeal membrane oxygen (ECMO) therapy was initiated successfully and resulted in rapid resolution of the unstable dysrhythmia. The patient was weaned from ECMO in under 48 h and was discharged without neurological or cardiovascular sequelae. This case highlights management options available to clinicians who encounter toxicity associated with aconitine ingestion. Fatal consequences were averted, and caution is required with the use of plant-identifying applications and resources.

Topics: Aconitine; Arrhythmias, Cardiac; Eating; Humans; Oxygen; Shock, Cardiogenic

Danhong injection (DHI) is widely used in the treatment of cardiovascular and cerebrovascular diseases, and its safety and effectiveness have been widely recognized and applied in China. However, the potential molecular mechanism of action for the treatment of arrhythmia is not fully understood.. In this study, through network pharmacology and. First, the potential therapeutic effect of DHI on arrhythmia was investigated in an. Early afterdepolarizations (EADs) were observed during aconitine treatment in hiPSC-CMs, and the proarrhythmic effect of aconitine was partially rescued by DHI, indicating that the antiarrhythmic role of DHI was verified in an. DHI can alleviate aconitine-induced arrhythmia in an

Topics: Aconitine; Arrhythmias, Cardiac; Drugs, Chinese Herbal; Humans; Induced Pluripotent Stem Cells; Molecular Docking Simulation; Network Pharmacology

Several previous studies have suggested that sublethal doses of Escherichia coli lipopolysaccharide (endotoxin) and monophosphoryl lipid A Re595, a nonpyrogenic derivative of Salmonella minnesota lipopolysaccharide, exhibit antiarrhythmic effects in the rat model of ischemia-reperfusion arrhythmias.. In this study, the protective effect of lipopolysaccharide derivatives was also further investigated in drug (aconitine or ouabain)-induced arrhythmia models, and conclusions were drawn with particular emphasis on the molecular characteristics of different types of lipopolysaccharide.. The importance of the molecular structure for the antiarrhythmic effect of monophosphoryl lipid A and E. coli lipopolysaccharide was tested in the ischemia-reperfusion arrhythmia model. In contrast to monophosphoryl lipid A from Salmonella typhimurium SL 684 which has only monophosphoryl residue in its structure, monophosphoryl lipid A Re595, obtained from S. minnesota, and E. coli lipopolysaccharide which have both mono and diphosphoryl residue reduced the duration of ventricular tachycardia (e.g., during reperfusion: vehicle: 176 ± 22.8; monophosphoryl lipid A Re595: 132.83 ± 12.1, as second, n=8-10, P < .05) and the incidence of ventricular fibrillation. The antiarrhythmic effects of E. coli lipopolysaccharide and monophosphoryl lipid A Re595 in ischemia-reperfusion arrhythmia model were absent in either aconitine- (e.g., onset time for ventricular ectopic beats: saline 25.3 5.0, E. coli lipopolysaccharide 24.3 ± 7.1; vehicle: 24.0 ± 4.5, monophosphoryl lipid A SL684 23.8 ± 4.3, as second, n=6, P > .05) or ouabain-induced arrhythmia models in mice.. Therefore, we conclude that lipopolysaccharide derivatives exhibit antiarrhythmic effect only in ischemia-reperfusion arrhythmias, and lipopolysaccharide should possess diphosphoryl groups in its subcomponent composition for this antiarrhythmic effect.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Escherichia coli; Lipopolysaccharides; Mice; Ouabain; Rats; Rodentia

Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α

Topics: Aconitine; Adrenergic Antagonists; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Calcium Chloride; Epinephrine; Methoxamine; Pyrrolidinones; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, beta-1

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α

Topics: Aconitine; Adrenergic Antagonists; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Calcium Chloride; Epinephrine; Rats; Rats, Wistar; Receptors, Adrenergic, alpha; Receptors, Adrenergic, alpha-1; Salicylamides

Due to a mix-up an older couple (69 years and 71 years) ate a meal with herbs from their garden that contained leaves of monkshood (Aconitum napellus). The monkshood plants grew close to the herbs in their garden. Both patients developed the typical symptoms of aconitine poisoning with paresthesia, hypotension and bradycardia. Over the course of time both developed cardiac arrhythmia with ventricular extrasystoles and required monitoring on the intensive care unit (ICU). The husband was more severely affected and needed catecholamines for successful treatment of hypotension (70/40 mmHg) and bradycardia (45 bpm). The toxicological analysis of the patients' serum taken 3.5 h after ingestion led to the detection of 1.8 ng/ml and 2.0 ng/ml aconitine, respectively. The patients were discharged in good general condition after 1 and 2 days, respectively. Monkshood (Aconitum napellus) is one of the most toxic native plants that can also be found in gardens due to its popularity as an ornamental plant. All parts of the plant contain toxic diterpenoid alkaloids, such as aconitine. Aconitine causes persistent activation of the fast voltage-gated sodium channels resulting in severe cardiac and neurological toxicity. Treatment of aconitine-induced ventricular arrhythmias is challenging as they are often refractory to electrical cardioversion and antiarrhythmic drugs.. Aufgrund einer Verwechslung aß ein älteres Ehepaar eine Mahlzeit mit Kräutern aus ihrem Garten, die Blätter des Blauen Eisenhuts (Aconitum napellus) enthielt. Die Eisenhutpflanzen wuchsen im Garten in der Nähe der Kräuter. Beide Patienten entwickelten die typische Symptomatik einer Aconitinvergiftung mit Parästhesien, Hypotonie und Bradykardie. Im Verlauf hatten beide Herzrhythmusstörungen mit ventrikulären Extrasystolen und mussten intensivmedizinisch behandelt werden. Katecholamine wurden bei dem stärker betroffenen Ehemann erfolgreich eingesetzt. Bei der toxikologischen Untersuchung des Serums, entnommen 3,5 h nach der Mahlzeit, wurden 1,8 ng/ml bzw. 2,0 ng/ml Aconitin nachgewiesen. Die Patienten konnten nach einem bzw. 2 Tagen in gutem Allgemeinzustand entlassen werden.

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Humans; Levisticum; Plant Leaves; Poisoning

Topics: Aconitine; Animals; Animals, Newborn; Arrhythmias, Cardiac; Cell Line; Cell Survival; Gene Expression Regulation; Heart Ventricles; Histones; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Mitochondria; Muscle Proteins; Myocytes, Cardiac; Potassium Channels; Rats; Receptor, Notch1; Superoxides

Taurine-magnesium coordination compound (TMCC) exhibits antiarrhythmic effects in cesium-chloride-and ouabain-induced arrhythmias; however, the mechanism underlying these effects on arrhythmia remains poorly understood. Here, we investigated the effects of TMCC on aconitine-induced arrhythmia in vivo and the electrophysiological effects of this compound in rat ventricular myocytes in vitro. Aconitine was used to induce arrhythmias in rats, and the dosages required to produce ventricular premature contraction (VPC), ventricular tachycardia (VT), ventricular fibrillation (VF), and cardiac arrest (CA) were recorded. Additionally, the sodium current (I

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels, L-Type; Electrophysiological Phenomena; Female; Heart Arrest; Heart Ventricles; Ion Channels; Magnesium Compounds; Male; Myocytes, Cardiac; Patch-Clamp Techniques; Rats; Rats, Wistar; Sodium Channels; Taurine

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Atropine; Humans; Male; Parasympatholytics; Tachycardia; Voltage-Gated Sodium Channel Agonists

Within urban air sheds, specific ambient air pollutants typically peak at predictable times throughout the day. For example, in environments dominated by mobile sources, peak nitrogen dioxide (NO2) levels coincide with morning and afternoon rush hours, while peak levels of ozone (O3), occur in the afternoon.. Given that exposure to a single pollutant might sensitize the cardiopulmonary system to the effects of a subsequent exposure to a second pollutant, we hypothesized that a morning exposure to NO2 will exaggerate the cardiovascular effects of an afternoon O3 exposure in rats.. Rats were divided into four groups that were each exposed for 3 h in the morning (m) and 3 h in the afternoon (a) on the same day: (1) m-Air/a-Air, (2) m-Air/a-O3 (0.3 ppm), (3) m-NO2 (0.5 ppm)/a-Air and (4) m-NO2/a-O3. Implanted telemetry devices recorded blood pressure and electrocardiographic data. Sensitivity to the arrhythmogenic agent aconitine was measured in a separate cohort.. Only m-NO2/a-O3-exposed rats had significant changes in electrophysiological, mechanical and autonomic parameters. These included decreased heart rate and increased PR and QTc intervals and increased heart rate variability, suggesting increased parasympathetic tone. In addition, only m-NO2/a-O3 exposure decreased systolic and diastolic blood pressures and increased pulse pressure and QA interval, suggesting decreased cardiac contractility.. The findings indicate that initial exposure to NO2 sensitized rats to the cardiovascular effects of O3 and may provide insight into the epidemiological data linking adverse cardiovascular outcomes with exposures to low concentrations of O3.

Topics: Aconitine; Administration, Inhalation; Air Pollutants; Animals; Arrhythmias, Cardiac; Blood Pressure; Electrocardiography; Heart Rate; Hypertension; Male; Nitrogen Dioxide; Ozone; Rats; Rats, Inbred SHR

It is well known that various traditional Chinese medicines produce antiarrhythmic actions. The aims of this study were to examine whether total flavones derived from Choerospondias axillaris folium (TFCF) also produced antiarrhythmic effects using a rat model of aconitine-induced arrhythmia and to compare these observations with the effects of total flavones of Choerospondias axillaris fructus (TFC). Wistar rats were orally administered TFC (0.2 g/kg) or TFCF (0.1, 0.2, or 0.4 g/kg) daily for 7 d. Subsequently, aconitine iv at 25 µg/kg was used to induce arrhythmia in these animals. Control (C) physiological saline and positive verapamil rats were also administered orally. The starting times of ventricular ectopic beats (VE), ventricular tachycardia (VT), ventricular fibrillation (VF), and heart arrest (HA) were recorded. In comparison to C, TFCF and TFC significantly prolonged the starting time of VE, VT, VF, and HA induced by aconitine. With respect to hemodynamics, TFC and high-dose TFCF were effective in reducing HR without associated changes in BP in all groups. TFC and TFCF decreased left ventricular systolic pressure (LVSP) and maximal velocity rate of ventricular pressure (+dp/dt max and -dp/dt min) with no marked effect on left ventricular end diastolic pressure (LVEDP) and -dp/dtmin. Data demonstrated that TFCF and TFC were equally effective in diminishing the aconitine-mediated arrhythmias. In addition, TFCF and TFC produced a similar reduction in HR with no accompanying change in BP. These findings indicate that the TFCF- and TFC-induced alterations may be attributed to inhibition of ventricular contraction without altering ventricular diastolic function.

Topics: Aconitine; Anacardiaceae; Animals; Arrhythmias, Cardiac; Female; Flavonoids; Hemodynamics; Male; Plant Extracts; Plant Leaves; Rats; Rats, Wistar

Seizures are associated with altered autonomic activity, which has been implicated in the development of cardiac dysfunction and structural damage. This study aimed to investigate the involvement of the autonomic nervous system in seizure-induced cardiomyopathy. Male Sprague-Dawley rats (320-350 g) were implanted with EEG/ECG electrodes to allow simultaneous telemetric recordings during seizures induced by intrahippocampal (2 nmol, 1 μl/min) kainic acid and monitored for 7 days. Seizure activity occurred in conjunction with increased heart rate (20%), blood pressure (25%), and QTc prolongation (15%). This increased sympathetic activity was confirmed by the presence of raised plasma noradrenaline levels at 3 h post-seizure induction. By 48 h post-seizure induction, sympathovagal balance was shifted in favor of sympathetic dominance, as indicated by both heart rate variability (LF/HF ratio of 3.5 ± 1.0) and pharmacological autonomic blockade. Functional cardiac deficits were evident at 7 and 28 days, as demonstrated by echocardiography showing a decreased ejection fraction (14% compared with control, P < 0.05) and dilated cardiomyopathy present at 28 days following seizure induction. Histological changes, including cardiomyocyte vacuolization, cardiac fibrosis, and inflammatory cell infiltration, were evident within 48 h of seizure induction and remained present for up to 28 days. These structural changes most probably contributed to an increased susceptibility to aconitine-induced arrhythmias. This study confirms that prolonged seizure activity results in acute and chronic alterations in cardiovascular control, leading to a deterioration in cardiac structure and function. This study further supports the need for modulation of sympathetic activity as a promising therapeutic approach in seizure-induced cardiomyopathy.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Blood Pressure; Cardiomyopathies; Cardiomyopathy, Dilated; Excitatory Amino Acid Agonists; Fibrosis; Heart Rate; Kainic Acid; Male; Myocardium; Myocytes, Cardiac; Norepinephrine; Rats; Rats, Sprague-Dawley; Status Epilepticus; Stroke Volume; Sympathetic Nervous System; Vacuoles; Voltage-Gated Sodium Channel Agonists

Diesel exhaust (DE) has been shown to increase the risk of cardiac arrhythmias. Although biodiesel has been proposed as a "safer" alternative to diesel, it is still uncertain whether it actually poses less threat.. We hypothesized that exposure to pure or 20% soy biodiesel exhaust (BDE) would cause less sensitivity to aconitine-induced arrhythmia than DE in rats.. Spontaneously hypertensive (SH) rats implanted with radiotelemeters were exposed once or for 5 d (4 h) to either 50 mg/m(3) (low), 150 mg/m(3) (medium), or 500 mg/m(3) (high) of DE (B0), 20% (B20) or 100% (B100) soy biodiesel exhaust. Arrhythmogenesis was assessed 24 h later by continuous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR), and electrocardiogram (ECG) were monitored.. Rats exposed once or for 5 d to low, medium, or high B0 developed arrhythmia at significantly lower doses of aconitine than controls, whereas rats exposed to B20 were only consistently sensitive after 5 d of the high concentration. B100 caused mild arrhythmia sensitivity at the low concentration, only after 5 d of exposure at the medium concentration and after either a single or 5 d at the high concentration.. These data demonstrate that exposure to B20 causes less sensitivity to arrhythmia than B0 and B100. This diminished effect may be due to lower irritant components such as acrolein and nitrogen oxides. Thus, in terms of cardiac health, B20 may be a safer option than both of the pure forms.

Topics: Aconitine; Air Pollutants; Animals; Arrhythmias, Cardiac; Biofuels; Dose-Response Relationship, Drug; Glycine max; Inhalation Exposure; Male; Rats; Rats, Inbred SHR; Vehicle Emissions

Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase.

Topics: Aconitine; Animals; Apoptosis; Arrhythmias, Cardiac; Blotting, Western; Calcium; Calcium Channel Blockers; Calcium Signaling; Cell Survival; Electrocardiography; Flow Cytometry; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Male; Microscopy, Electron, Transmission; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Primary Cell Culture; Rats; Rats, Wistar; Sarcomeres; Signal Transduction

A comparative study of the acute toxicity and antiarrhythmic activity of new domestic derivatives of dimethylacetamide showed that the introduction of amino and carboxylic acid residues into the structure of compounds is accompanied by reduction of the toxic properties of new substances on the average 2.73 times (p = 0.002) upon intraperitoneal introduction to animals. It has been established that the derivatives are able to prevent the formation of aconitine induced arrhythmias and eliminate the arrhythmia that occurs on the second day of myocardial infarction in dogs. Original derivatives of dimethylacetamide exhibit antiarrhythmic properties and their activity increases in proportion to the acute toxicity (r = 0.83, p = 0.0043).

Topics: Acetamides; Aconitine; Adjuvants, Immunologic; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cryoprotective Agents; Dogs; Dose-Response Relationship, Drug; Female; Male; Mice; Myocardial Infarction; Rats

Aconitine is a well-known arrhythmogenic toxin and induces triggered activities through cardiac voltage-gated Na(+) channels. However, the effects of aconitine on intracellular Ca(2+) signals were previously unknown. We investigated the effects of aconitine on intracellular Ca(2+) signals in rat ventricular myocytes and explored the possible mechanism of arrhythmogenic toxicity induced by aconitine. Ca(2+) signals were evaluated by measuring L-type Ca(2+) currents, caffeine-induced Ca(2+) release and the expression of NCX and SERCA2a. Action potential and triggered activities were recorded by whole-cell patch-clamp techniques. In rat ventricular myocytes, the action potential duration was significantly prolonged by 1 µM aconitine. At higher concentrations (5 µM and 10 µM), aconitine induced triggered activities and delayed after-depolarizations (6 of 8 cases), which were inhibited by verapamil. Aconitine (1 µM) significantly increased the ICa-L density from 12.77 ± 3.12 pA/pF to 18.98 ± 3.89 pA/pF (n=10, p<0.01). The activation curve was shifted towards more negative potential, while the inactivation curve was shifted towards more positive potential by 1 μM aconitine. The level of Ca(2+) release induced by 10 mM caffeine was markedly increased. Aconitine (1 µM) increased the expression of NCX, while SERCA2a expression was reduced. In conclusion, aconitine increased the cytosolic [Ca(2+)]i by accelerating ICa-L and changing the expression of NCX and SERCA2a. Then, the elevation of cytosolic [Ca(2+)]i induced triggered activities and delayed after-depolarizations. Arrhythmogenesis toxicity of aconitine is related to intracellular Ca(2+) signals.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Blotting, Western; Caffeine; Calcium; Cells, Cultured; Male; Myocytes, Cardiac; Patch-Clamp Techniques; Rats; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Aconitine, well-known for its high cardiotoxicity, causes severe arrhythmias, such as ventricular tachycardia and ventricular fibrillation, by opening membrane sodium channels. Tetrodotoxin, a membrane sodium-channel blocker, is thought to antagonize aconitine activity. Tetrodotoxin is a potent blocker of the skeletal muscle sodium-channel isoform Na(v)1.4 (IC50 10 nM), but micromolar concentrations of tetrodotoxin are required to inhibit the primary cardiac isoform Na(v)1.5. This suggests that substantial concentrations of tetrodotoxin are required to alleviate the cardiac toxicity caused by aconitine. To elucidate the interaction between aconitine and tetrodotoxin in the cardiovascular and respiratory systems, mixtures of aconitine and tetrodotoxin were simultaneously administered to mice, and the effects on electrocardiograms, breathing rates, and arterial oxygen saturation were examined. Compared with mice treated with aconitine alone, some mice treated with aconitine-tetrodotoxin mixtures showed lower mortality rates and delayed appearance of arrhythmia. The decreased breathing rates and arterial oxygen saturation observed in mice receiving aconitine alone were alleviated in mice that survived after receiving the aconitine-tetrodotoxin mixture; this result suggests that tetrodotoxin is antagonistic to aconitine. When the tetrodotoxin dose is greater than the dose that can block tetrodotoxin-sensitive sodium channels, which are excessively activated by aconitine, tetrodotoxin toxicity becomes prominent, and the mortality rate increases because of the respiratory effects of tetrodotoxin. In terms of cardiotoxicity, mice receiving the aconitine-tetrodotoxin mixture showed minor and shorter periods of change on electrocardiography. This finding can be explained by the recent discovery of tetrodotoxin-sensitive sodium-channel cardiac isoforms (Na(v)1.1, 1.2, 1.3, 1.4 and 1.6).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biomarkers; Disease Models, Animal; Electrocardiography; Heart Rate; Male; Mice; Mice, Inbred ICR; Myocardium; Oxygen; Respiratory Rate; Sodium Channel Blockers; Tetrodotoxin; Time Factors; Voltage-Gated Sodium Channels

The experiments on white outbred awaken male rats have shown that derivatives of adamant-2-ylamides of alkylamidocarbonic acids exhibit prominent antiarrhythmic (antifibrillatory) effect on the model of calcium chloride arrhythmia. The most pronounced effect was demonstrated by N-[2(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide. This compound was also active on the model of aconitine arrhythmia, which is characteristic of class-I antiarrhythmic agents. It is established that N-[2-(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide has prominent antiarrhythmic activity and is more safe than other antiarrhythmic drugs of class I (lidocaine, ethmosine, novocainamide), class IV (verapamil), and class III (cardiocyclide).

Topics: Aconitine; Adamantane; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzamides; Male; Rats; Voltage-Gated Sodium Channel Agonists

Arctigenin possesses biological activities, but its underlying mechanisms at the cellular and ion channel levels are not completely understood. Therefore, the present study was designed to identify the anti-arrhythmia effect of arctigenin in vivo, as well as its cellular targets and mechanisms.. A rat arrhythmia model was established via continuous aconitine infusion, and the onset times of ventricular premature contraction, ventricular tachycardia and death were recorded. The Action Potential Duration (APD), sodium current (I(Na)), L-type calcium current (I(Ca, L)) and transient outward potassium current (I(to)) were measured and analysed using a patch-clamp recording technique in normal rat cardiomyocytes and myocytes of arrhythmia aconitine-induced by.. Arctigenin significantly delayed the arrhythmia onset in the aconitine-induced rat model. The 50% and 90% repolarisations (APD50 and APD90) were shortened by 100 µM arctigenin; the arctigenin dose also inhibited the prolongation of APD50 and APD90 caused by 1 µM aconitine. Arctigenin inhibited I(Na) and I(Ca,L) and attenuated the aconitine-increased I(Na) and I(Ca,L) by accelerating the activation process and delaying the inactivation process. Arctigenin enhanced Ito by facilitating the activation process and delaying the inactivation process, and recoverd the decreased Ito induced by aconitine.. Arctigenin has displayed anti-arrhythmia effects, both in vivo and in vitro. In the context of electrophysiology, I(Na), I(Ca, L), and I(to) may be multiple targets of arctigenin, leading to its antiarrhythmic effect.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels, L-Type; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Furans; Ion Channels; Lignans; Male; Myocytes, Cardiac; Patch-Clamp Techniques; Potassium Channels; Rats; Rats, Wistar; Sodium Channels

Doxorubicin (Dox) is an anthracycline antibiotic used as anticancer agent. However, its use is limited due to its cardiotoxicity which is mainly attributed to accumulation of reactive oxygen species.. This study was conducted to assess whether the antioxidant, proanthocyanidins (Pro) can ameliorate Dox-induced cardiotoxicity in rats.. Male Sprague-Dawely rats were divided into four groups. Group I was control. Group II received Pro (70 mg/kg, orally) once daily for 10 days. Group III received doxorubicin 15 mg/kg i.p. as a single dose on the 7th day and Group IV animals were treated with Pro once daily for 10 days and Dox on the 7th day. The parameters of study were serum biomarkers, cardiac tissue antioxidant status, ECG, and effect on aconitine-induced cardiotoxicity.. Cardiac toxicity of doxorubicin was manifested as a significant increase in heart rate, elevation of the ST segment, prolongation of the QT interval and an increase in T wave amplitude. In addition, Dox enhanced aconitine-induced cardiotoxicity by a significant decrease in the aconitine dose producing ventricular tachycardia (VT). Administration of Pro significantly suppressed Dox-induced ECG changes and normalized the aconitine dose producing VT. The toxicity of Dox was also confirmed biochemically by significant elevation of serum CK-MB and LDH activities as well as myocardial MDA and GSH contents and decrease in serum catalase and myocardial SOD activities. Administration of Pro significantly suppressed these biochemical changes.. These results suggest that proanthocyanidins might be a potential cardioprotective agent against Dox-induced cardiotoxicity due to its antioxidant properties.

Topics: Aconitine; Animals; Antibiotics, Antineoplastic; Antioxidants; Arrhythmias, Cardiac; Biomarkers; Cardiomyopathy, Dilated; Cardiotonic Agents; Cardiotoxins; Doxorubicin; Drug Resistance; Grape Seed Extract; Heart; Male; Myocardium; Oxidative Stress; Phytotherapy; Proanthocyanidins; Rats; Rats, Sprague-Dawley; Tachycardia; Voltage-Gated Sodium Channel Agonists

To investigate the ability of the pericardium meridian (PM) to mitigate or enhance the cardiotoxic effects of aconitine injected at specific acupoint and non-acupoint sites in rabbits.. This study consisted of 3 experiments that were designed to test the effects of injection of 30 μg/kg of aconitine at acupoints on the PM (Test 1), at non-acupoint sites on the PM (Test 2), and at acupoints on other meridians and non-meridian sites (Test 3). In Test 1, 24 rabbits were randomly assigned to receive injections at Quze (PC3), Tianquan (PC2), or intramuscularly. In Test 2, 24 rabbits were randomly assigned to receive injections of aconitine at non-acupoint I, non-acupoint II, or intramuscularly. In Test 3, 48 rabbits were randomly assigned to receive injections at Neiguan (PC6), Sanyinjiao (SP6), Yangjiao (GB35), a non-meridian and non-acupoint site (NMNA), intravenously, and intramuscularly. Electrocardiographs of the rabbits were performed before, during and after injection to determine the incidence of arrhythmia, latency of ventricular rhythm, and recovery rate after aconitine injection. The recovery time index and extent of arrhythmia scores were calculated.. In all groups the incidence of arrhythmia was 100%, and the latency of ventricular rhythm was less than 30 min. In Tests 1 and 2, the recovery rates of the Quze and non-acupoint II groups were significantly higher than those of the muscular group (P < 0.05). In Test 3, the recovery time index and extent of arrhythmia scores of the Neiguan group were low. There were no significant differences between the other acupoint groups, or the NMNA group, when compared with the group receiving aconitine intramuscularly.. Acupoints or non-acupoints along the PM could reduce the severity of the arrhythmia induced by aconitine in healthy rabbits. Meridians play an important role in protecting body functions.

Topics: Aconitine; Acupuncture Points; Acupuncture Therapy; Analysis of Variance; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Electrocardiography; Male; Meridians; Pericardium; Rabbits; Random Allocation

Ozone (O₃) is a well-documented respiratory oxidant, but increasing epidemiological evidence points to extrapulmonary effects, including positive associations between ambient O₃ concentrations and cardiovascular morbidity and mortality.. With preliminary reports linking O₃ exposure with changes in heart rate (HR), we investigated the hypothesis that a single inhalation exposure to O₃ will cause concentration-dependent autonomic modulation of cardiac function in rats.. Rats implanted with telemeters to monitor HR and cardiac electrophysiology [electrocardiography (ECG)] were exposed once by whole-body inhalation for 4 hr to 0.2 or 0.8 ppm O₃ or filtered air. A separate cohort was tested for vulnerability to aconitine-induced arrhythmia 24 hr after exposure.. Exposure to 0.8 ppm O₃ caused bradycardia, PR prolongation, ST depression, and substantial increases in atrial premature beats, sinoatrial block, and atrioventricular block, accompanied by concurrent increases in several HR variability parameters that were suggestive of increased parasympathetic tone. Low-O₃ exposure failed to elicit any overt changes in autonomic tone, heart rhythm, or ECG. However, both 0.2 and 0.8 ppm O₃ increased sensitivity to aconitine-induced arrhythmia formation, suggesting a latent O₃-induced alteration in myocardial excitability.. O₃ exposure causes several alterations in cardiac electrophysiology that are likely mediated by modulation of autonomic input to the heart. Moreover, exposure to low O₃ concentrations may cause subclinical effects that manifest only when triggered by a stressor, suggesting that the adverse health effects of ambient levels of air pollutants may be insidious and potentially underestimated.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Autonomic Agents; Cohort Studies; Dose-Response Relationship, Drug; Electrocardiography; Heart; Heart Rate; Inhalation Exposure; Male; Oxidants, Photochemical; Ozone; Rats; Rats, Inbred SHR; Telemetry

The purpose of this study was to evaluate percutaneous penetration and arrhythmogenic effects of aconitine after transdermal administration, compared with the oral route. Skin penetration of aconitine was tested by a microdialysis technique in rats and in vivo recovery was determined by retrodialysis. After oral and transdermal administration of aconitine, dialysate was sampled at 20 min intervals until the end of the experiment for the determination of concentration of aconitine in skin. Blood samples were collected and analyzed using a validated HPLC-MS/MS method. In addition, we concurrently recorded the electrocardiogram (ECG). The in vivo recovery of aconitine in the skin was calculated to be 39.59%. The C(max) values for aconitine absorbed into the skin after oral and transdermal administration were 1.51 ± 0.53 and 2723.8 ± 848.8 ng/mL, respectively, and within the plasma, 215.86 ± 79.29 and 20.92 ± 3.15 ng/mL. The C(max) value for the plasma concentration of aconitine after oral administration was approximately 10 times higher than with the transdermal route. For oral administration, the ECG revealed various types of arrhythmias at a period of T(max) , which is normal in transdermal gel administration. These results indicate that transdermal aconitine gel is a safe formulation that can deliver the drug in sufficient amounts and safe concentrations to produce therapeutic action in rats.

Topics: Aconitine; Administration, Cutaneous; Administration, Oral; Animals; Arrhythmias, Cardiac; Chromatography, High Pressure Liquid; Electrocardiography; Male; Microdialysis; Rats; Rats, Sprague-Dawley; Skin; Skin Absorption; Tandem Mass Spectrometry

To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent.. The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes.. In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a-6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED₅₀ value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and V(max), prolonged APD(90) and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and V(max) in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in I(Na) (IC₅₀=26.9 μmol/L) and I(Ca,L)(IC₅₀=69.2 μmol/L), whereas the inward rectifier (I(K1)) and the delayed rectifier potassium currents (I(K)) were unaffected.. As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels, L-Type; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Male; Myocytes, Cardiac; Ouabain; Patch-Clamp Techniques; Potassium Channels; Rabbits; Rats; Rats, Sprague-Dawley; Sodium Channels; Sulfuric Acid Esters

Many studies have shown that the relationship between alcohol consumption and most cardiovascular diseases is U-shaped, with nondrinkers and heavier drinkers having higher risks than moderate drinkers. However, the association between cardiac arrhythmias and acute alcohol consumption is not well understood. We set up several experimental arrhythmia animal models to examine the effects of acute administration of ethanol on arrhythmia. The results showed 0.4, 0.8 and 1.6 g/kg ethanol consumption obviously delayed the onset time of atrial fibrillation (AF) (P < 0.05 or P < 0.01) and increased the survival rates on acetylcholine-CaCl₂-induced AF in mice. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption significantly delayed the onset time of ventricular tachycardia (VT), ventricular fibrillation (VF) and cardiac arrest (CA) (P < 0.01), and 0.4 and 0.8 g/kg ethanol consumption increased the survival rates on CaCl₂-induced arrhythmia in rats. Ethanol (0.4 g/kg) essentially increased the cumulative dosage of aconitine required to CA (P < 0.05), and 0.8 g/kg, 1.6 g/kg ethanol reduced the cumulative aconitine dosage to induce VT, VF and CA (P < 0.05 or P < 0.01) on aconitine-induced arrhythmia in rats. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption remarkably increased the cumulative dosage of deslanoside to induce ventricualr premature contraction (P < 0.01) on deslanoside-induced arrhythmia in guinea pigs. Collectively, our results indicate that low concentrations of ethanol had anti-arrhythmic effect on experimental arrhythmia, and high concentrations of ethanol may aggravated the occurrence of experimental arrhythmia.

Topics: Acetylcholine; Aconitine; Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Calcium Chloride; Cardiotonic Agents; Central Nervous System Depressants; Cholinergic Agonists; Deslanoside; Disease Models, Animal; Drug Interactions; Ethanol; Guinea Pigs; Heart Arrest; Male; Mice; Mice, Inbred ICR; Rats; Rats, Sprague-Dawley; Risk Factors; Tachycardia, Ventricular; Ventricular Fibrillation; Voltage-Gated Sodium Channel Agonists

Oxymatrine is one of the main alkaloid components extracted from SOPHORA roots and has been shown to play various protective roles in the cardiovascular system. The present study was designed to study the protective effect of oxymatrine on arrhythmias and their ionic channel mechanism. Rat arrhythmic models were established by aconitine injection and coronary artery ligation. Rat cardiomyocytes were acutely isolated, and the whole-cell patch clamp technique was employed to investigate the effects of oxymatrine on sodium channels. Pretreatment with oxymatrine markedly increased the dose of aconitine required to induce arrhythmias in rats. Additionally, oxymatrine significantly delayed the initial time and shortened the duration time of rat arrhythmias induced by coronary artery ligation. Cardiac mortality rate in coronary artery ligation-induced arrhythmias was also effectively decreased by oxymatrine in rats. The electrophysiological study showed that oxymatrine could significantly inhibit sodium and calcium currents in isolated rat cardiomyocytes in a concentration-dependent manner. In summary, oxymatrine plays a remarkably preventive role in rat arrhythmias through the inhibition of sodium and calcium currents.

Topics: Aconitine; Alkaloids; Animals; Arrhythmias, Cardiac; Calcium; Cardiovascular Agents; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Myocytes, Cardiac; Phytotherapy; Plant Extracts; Plant Roots; Quinolizines; Rats; Rats, Wistar; Sodium; Sodium Channels; Sophora

Diesel exhaust (DE), which is emitted from on- and off-road sources, is a complex mixture of toxic gaseous and particulate components that leads to triggered adverse cardiovascular effects such as arrhythmias.. We hypothesized that increased risk of triggered arrhythmias 1 day after DE exposure is mediated by airway sensory nerves bearing transient receptor potential (TRP) channels [e.g., transient receptor potential cation channel, member A1 (TRPA1)] that, when activated by noxious chemicals, can cause a centrally mediated autonomic imbalance and heightened risk of arrhythmia.. Spontaneously hypertensive rats implanted with radiotelemeters were whole-body exposed to either 500 μg/m³ (high) or 150 μg/m³ (low) whole DE (wDE) or filtered DE (fDE), or to filtered air (controls), for 4 hr. Arrhythmogenesis was assessed 24 hr later by continuous intravenous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR) and electrocardiogram (ECG) were monitored.. Rats exposed to wDE or fDE had slightly higher HRs and increased low-frequency:high-frequency ratios (sympathetic modulation) than did controls; ECG showed prolonged ventricular depolarization and shortened repolarization periods. Rats exposed to wDE developed arrhythmia at lower doses of aconitine than did controls; the dose was even lower in rats exposed to fDE. Pretreatment of low wDE-exposed rats with a TRPA1 antagonist or sympathetic blockade prevented the heightened sensitivity to arrhythmia.. These findings suggest that a single exposure to DE increases the sensitivity of the heart to triggered arrhythmias. The gaseous components appear to play an important role in the proarrhythmic response, which may be mediated by activation of TRPA1, and subsequent sympathetic modulation. As such, toxic inhalants may partly exhibit their toxicity by lowering the threshold for secondary triggers, complicating assessment of their risk.

Topics: Aconitine; Air Pollutants; Animals; Ankyrins; Arrhythmias, Cardiac; Calcium Channels; Electrocardiography; Heart; Heart Rate; Male; Rats; Rats, Inbred SHR; Sympathetic Nervous System; Telemetry; TRPA1 Cation Channel; TRPC Cation Channels; Vehicle Emissions

Lethal cardiac arrhythmias contribute to mortality in a number of pathological conditions. Several parameters obtained from a non-invasive, easily obtained electrocardiogram (ECG) are established, well-validated prognostic indicators of cardiac risk in patients suffering from a number of cardiomyopathies. Increased heart rate, decreased heart rate variability (HRV), and increased duration and variability of cardiac ventricular electrical activity (QT interval) are all indicative of enhanced cardiac risk. In animal models, it is valuable to compare these ECG-derived variables and susceptibility to experimentally induced arrhythmias. Intravenous infusion of the arrhythmogenic agent aconitine has been widely used to evaluate susceptibility to arrhythmias in a range of experimental conditions, including animal models of depression and hypertension, following exercise and exposure to air pollutants, as well as determination of the antiarrhythmic efficacy of pharmacological agents. It should be noted that QT dispersion in humans is a measure of QT interval variation across the full set of leads from a standard 12-lead ECG. Consequently, the measure of QT dispersion from the 2-lead ECG in the rat described in this protocol is different than that calculated from human ECG records. This represents a limitation in the translation of the data obtained from rodents to human clinical medicine. Status epilepticus (SE) is a single seizure or series of continuously recurring seizures lasting more than 30 min, and results in mortality in 20% of cases. Many individuals survive the SE, but die within 30 days. The mechanism(s) of this delayed mortality is not fully understood. It has been suggested that lethal ventricular arrhythmias contribute to many of these deaths. In addition to SE, patients experiencing spontaneously recurring seizures, i.e. epilepsy, are at risk of premature sudden and unexpected death associated with epilepsy (SUDEP). As with SE, the precise mechanisms mediating SUDEP are not known. It has been proposed that ventricular abnormalities and resulting arrhythmias make a significant contribution. To investigate the mechanisms of seizure-related cardiac death, and the efficacy of cardioprotective therapies, it is necessary to obtain both ECG-derived indicators of risk and evaluate susceptibility to cardiac arrhythmias in animal models of seizure disorders. Here we describe methods for implanting ECG electrodes in the Sprague-Dawley laboratory rat (Rattus n

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Electrocardiography; Electrodes, Implanted; Rats; Rats, Sprague-Dawley; Risk Factors; Status Epilepticus

Under conditions of Na(+) channel hyperactivation with aconitine, the changes in action potential duration (APD) and the restitution characteristics have not been well defined in the context of aconitine-induced arrhythmogenesis. Optical mapping of voltage using RH237 was performed with eight extracted rabbit hearts that were perfused using the Langendorff system. The characteristics of APD restitution were assessed using the steady-state pacing protocol at baseline and 0.1 µM aconitine concentration. In addition, pseudo-ECG was analyzed at baseline, and with 0.1 and 1.0 µM of aconitine infusion respectively. Triggered activity was not shown in dose of 0.1 µM aconitine but overtly presented in 1.0 µM of aconitine. The slopes of the dynamic APD restitution curves were significantly steeper with 0.1 µM of aconitine than at baseline. With aconitine administration, the cycle length of initiation of APD alternans was significantly longer than at baseline (287.5 ± 9.6 vs 247.5 ± 15.0 msec, P = 0.016). The functional reentry following regional conduction block appears with the progression of APD alternans. Ventricular fibrillation is induced reproducibly at pacing cycle length showing a 2:1 conduction block. Low-dose aconitine produces arrhythmogenesis at an increasing restitution slope with APD alternans as well as regional conduction block that proceeds to functional reentry.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Electrocardiography; Heart; Heart Conduction System; Myocardium; Rabbits; Sodium Channels; Ventricular Fibrillation

The antiarrhythmic effects of 100; 150; and 300microg/kg i.p. oxygen/ozone mixture were tested on arrhythmias induced by i) ischemia; ii) ischemia/reperfusion; iii) aconitine (15microg/kg/i.v.); potassium chloride (1.5% i.v.) in rats. 25min of cardiac left descending coronary artery ischemia caused severe incidence of ventricular tachycardia, ventricular fibrillation and mortality. These were significantly reduced by pre-treatment of rats with oxygen/ozone mixture at doses of 150 and 300microg/kg. In separate experiments using a protocol of 5min ischemia followed by 8min reperfusion this caused arrhythmias starting within 6+/-1s. The incidence of ventricular tachycardia was 100%, while ventricular fibrillation occurred in 75% of the animals and lasted 85+/-14s. The mortality was 62.5%. These figures were significantly (P<0.01) reduced in animals treated with 150microg/kg oxygen/ozone and a substantial increase observed with 300microg/kg, whilst not affected by the lower dose of 100microg/kg. 150 and 300microg/kg oxygen/ozone prolonged the onset time for the appearance of arrhythmias induced by aconitine (300microg/kg oxygen/ozone, approximately 81% longer). Oxygen/ozone also reduced the ventricular tachycardia duration, ventricular fibrillation incidence, arrhythmia score, and increased the rat's survival rate. As for example, this latter was increased from 25% (aconitine) to 50% (aconitine+oxygen/ozone 150microg/kg). 100microg/kg oxygen/ozone was without effect. None of the oxygen/ozone doses affected the arrhythmias caused by potassium chloride 1.5% i.v. All the oxygen/ozone antiarrhythmic effects were similar to those observed with lidocaine (1.5mg/kg i.v.). In conclusion, oxygen/ozone has antiarrhythmic effects against arrhythmias caused by aconitine, myocardial ischemia and ischemia/reperfusion.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Male; Myocardial Ischemia; Oxygen; Ozone; Potassium Chloride; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The effect of histone deacetylase inhibitors on dystrophic heart function is not established. To investigate this aspect, dystrophic mdx mice and wild-type (WT) animals were treated 90 days either with suberoylanilide hydroxamic acid (SAHA, 5 mg/kg/day) or with an equivalent amount of vehicle.. The following parameters were evaluated: (i) number of ventricular arrhythmias in resting and stress conditions (restraint test) or after aconitine administration; (ii) cardiac excitability, conduction velocity, and refractoriness; (iii) expression and distribution of connexins (Cxs) and Na(v)1.5 sodium channel. Ventricular arrhythmias were negligible in all resting animals. During restraint, however, an increase in the number of arrhythmias was detected in vehicle-treated mdx mice (mdx-V) when compared with SAHA-treated mdx (mdx-SAHA) mice or normal control (WT-V). Interestingly, aconitine, a sodium channel pharmacologic opener, induced ventricular arrhythmias in 83% of WT-V mice, 11% of mdx-V, and in 57% of mdx-SAHA. Epicardial multiple lead recording revealed a prolongation of the QRS complex in mdx-V mice in comparison to WT-V and WT-SAHA mice, paralleled by a significant reduction in impulse propagation velocity. These alterations were efficiently counteracted by SAHA. Molecular analyses revealed that in mdx mice, SAHA determined Cx remodelling of Cx40, Cx37 and Cx32, whereas expression levels of Cx43 and Cx45 were unaltered. Remarkably, Cx43 lateralization observed in mdx control animals was reversed by SAHA treatment which also re-induced Na(v)1.5 expression.. SAHA attenuates arrhythmias in mdx mice by a mechanism in which Cx remodelling and sodium channel re-expression could play an important role.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Connexins; Disease Models, Animal; Electrocardiography, Ambulatory; Heart Conduction System; Heart Rate; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Mice, Inbred mdx; Muscular Dystrophy, Duchenne; NAV1.5 Voltage-Gated Sodium Channel; Restraint, Physical; Sodium Channels; Telemetry; Time Factors; Vorinostat

Experiments on conscious male rats have shown that, under conditions of the aconitine-induced arrhythmia model, afobazole and other 2-mercaptobensimidazole derivatives exhibit antiarrhythmic effect, i.e. possess properties of rapid Na+ channel antagonists. The effect of afobazole under these conditions was significantly more pronounced than that of the reference drugs lidocaine and procainamide. The antiarrhythmic (antifibrillatory) effect of afobazole was also detected under the conditions of arrhythmia caused by high doses of calcium chloride. This drug was 1.5 times more effective in its antifibrillatory action than lidocaine, but it was less effective than verapamil. It has been also found that afobazole possesses a wider therapeutic spectrum than the well-known antiarrhythmic drugs of class I and IV (lidocaine, procainamide, ethmosine and verapamil).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzimidazoles; Calcium Chloride; Male; Morpholines; Rats; Sodium Channel Blockers; Structure-Activity Relationship

Myocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (I(Nap)) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on I(Nap) and in integrative models of I(Nap)-induced arrhythmias.. Sodium current was investigated using patch clamp technique on wild-type and DeltaKPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia- and aconitine-induced arrhythmias in the rat.. We demonstrated that F 15845 is a potent blocker of I(Nap) acting from the extracellular side of the channel. Blockade of I(Nap) was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the I(Nap) activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where I(Nap) is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias.. F 15845, a novel anti-anginal drug targeting I(Nap), demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Benzothiepins; Cell Line; Heart Atria; Humans; Male; Myocardial Ischemia; Patch-Clamp Techniques; Purkinje Fibers; Rabbits; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Swine; Veratridine

We demonstrated here that an initial treatment with aconitine- or barium-chloride-induced arrhythmias and resulted in reduced susceptibility of the heart to the induction of arrhythmias by a repeated drug treatment 24 h after the initial one, a delayed preconditioning cardioprotection. This delayed preconditioning was accompanied by enhanced expression of cardiac muscarinic M(3) receptor and abolished by M(3)-selective antagonist. We conclude that muscarinic M(3) receptors might play an important role in conferring the pharmacological preconditioning against arrhythmias. This study thus expands our understanding of the cellular function and pathophysiological roles of muscarinic M(3) receptor and reconsolidates our view of cardioprotective effects of muscarinic M(3) receptor on myocardium.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Barium Compounds; Chlorides; Female; Ischemic Preconditioning, Myocardial; Male; Muscarinic Antagonists; Rats; Rats, Wistar; Receptor, Muscarinic M3; Time Factors

Piceatannol is more potent than resveratrol in free radical scavenging in association with antiarrhythmic and cardioprotective activities in ischaemic-reperfused rat hearts. The present study aimed to investigate the antiarrhythmic efficacy and the underlying ionic mechanisms of piceatannol in rat hearts.. Action potentials and membrane currents were recorded by the whole-cell patch clamp techniques. Fluo-3 fluorimetry was used to measure cellular Ca2+ transients. Antiarrhythmic activity was examined from isolated Langendorff-perfused rat hearts.. In rat ventricular cells, piceatannol (3-30 micromol.L(-1)) prolonged the action potential durations (APDs) and decreased the maximal rate of upstroke (V(max)) without altering Ca2+ transients. Piceatannol decreased peak I(Na) and slowed I(Na) inactivation, rather than induced a persistent non-inactivating current, which could be reverted by lidocaine. Resveratrol (100 micromol.L(-1)) decreased peak I(Na) without slowing I(Na) inactivation. The inhibition of peak I(Na) or V(max) was associated with a negative shift of the voltage-dependent steady-state I(Na) inactivation curve without altering the activation threshold. At the concentrations more than 30 micromol.L(-1), piceatannol could inhibit I(Ca,L), I(to), I(Kr), Ca2+ transients and Na+-Ca2+ exchange except I(K1). Piceatannol (1-10 micromol.L(-1)) exerted antiarrhythmic activity in isolated rat hearts subjected to ischaemia-reperfusion injury.. The additional hydroxyl group on resveratrol makes piceatannol possessing more potent in I(Na) inhibition and uniquely slowing I(Na) inactivation, which may contribute to its antiarrhythmic actions at low concentrations less than 10 micromol.L(-1).

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Caffeine; Calcium Channel Blockers; Calcium Channels, L-Type; Cell Line; Electric Stimulation; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Free Radical Scavengers; Humans; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Myocytes, Cardiac; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Resveratrol; Sodium Channel Agonists; Sodium Channel Blockers; Sodium Channels; Stilbenes

Chinese medicine plays an important role in providing medical care for people in countries with large Chinese communities, including Hong Kong. The aconite herb is one of the commonly-prescribed ingredients for various clinical problems. However, due to its narrow therapeutic index, toxicities are not uncommonly encountered, including life-threatening cardiac arrhythmias like ventricular arrhythmias. We report a 57-year-old woman with reversible intraventricular conduction defect attributed to the use of processed Fuzi.

Topics: Aconitine; Arrhythmias, Cardiac; Bundle-Branch Block; Drugs, Chinese Herbal; Electrocardiography; Female; Hong Kong; Humans; Medicine, East Asian Traditional; Middle Aged; Treatment Outcome

This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca(2+)](i)) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca(2+)](i) overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M(3)-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M(3)-mAChR. The mechanism may be related to the improvement of Ca(2+) handling.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Disease Models, Animal; Female; Guinea Pigs; Male; Microscopy, Confocal; Muscarinic Agonists; Muscarinic Antagonists; Myocytes, Cardiac; Ouabain; Pilocarpine; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3; Time Factors

Epidemiological studies demonstrate an association between arrhythmias and air pollution. Aconitine-induced cardiac arrhythmia is widely used experimentally to examine factors that alter the risk of arrhythmogenesis. In this study, Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats acutely exposed to synthetic residual oil fly ash (s-ROFA) particles (450 mug/m(3)) were "challenged" with aconitine to examine whether a single exposure could predispose to arrhythmogenesis. Separately, SH rats were exposed to varied particulate matter (PM) concentrations (0.45, 1.0, or 3.5 mg/m(3) s-ROFA), or the irritant gas acrolein (3 ppm), to better assess the generalization of this challenge response. Rather than directly cause arrhythmias, we hypothesized that inhaled air pollutants sensitize the heart to subsequent dysrhythmic stimuli. Twenty-four hour postexposure, urethane-anesthetized rats were monitored for heart rate (HR), electrocardiogram, and blood pressure (BP). SH rats had higher baseline HR and BP and significantly longer PR intervals, QRS duration, QTc, and JTc than WKY rats. PM exposure caused a significant increase in the PR interval, QRS duration, and QTc in WKY rats but not in SH rats. Heart rate variability was significantly decreased in WKY rats after PM exposure but increased in SH rats. Cumulative dose of aconitine that triggered arrhythmias in air-exposed SH rats was lower than WKY rats and even lower for each strain postexposure. SH rats exposed to varied concentrations of PM or acrolein developed arrhythmia at significantly lower doses of aconitine than controls; however, there was no PM concentration-dependent response. In conclusion, a single exposure to air pollution may increase the sensitivity of cardiac electrical conduction to disruption. Moreover, there seem to be host factors (e.g., cardiovascular disease) that increase vulnerability to triggered arrhythmias regardless of the pollutant or its concentration.

Topics: Aconitine; Air Pollution; Animals; Arrhythmias, Cardiac; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Particle Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Risk Factors

Status epilepticus (SE) is a seizure or series of seizures that persist for >30 min and often results in mortality. Death rarely occurs during or immediately following seizure activity, but usually within 30 days. Although ventricular arrhythmias have been implicated in SE-related mortality, the effects of this prolonged seizure activity on the cardiac function and susceptibility to arrhythmias have not been directly investigated. We evaluated myocardial damage, alterations in cardiac electrical activity, and susceptibility to experimentally induced arrhythmias produced by SE in rats. SE resulted in seizure-related increases in blood pressure, heart rate, and the first derivative of pressure, as well as modest, diffuse myocyte damage assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. Ten to twelve days following seizures, electrocardiographic recordings showed arrhythmogenic alterations in cardiac electrical activity, denoted by prolonged QT interval corrected for heart rate and QT dispersion. Finally, SE increased susceptibility to experimentally induced (intravenous aconitine) cardiac arrhythmias. These data suggest that SE produces tachycardic ischemia following the activation of the sympathetic nervous system, resulting in cardiac myofilament damage, arrhythmogenic alterations in cardiac electrical activity, and increased susceptibility to ventricular arrhythmias.

Topics: Aconitine; Actin Cytoskeleton; Action Potentials; Animals; Arrhythmias, Cardiac; Biomarkers; Blood Pressure; Disease Models, Animal; Disease Susceptibility; Electrocardiography; Heart Rate; In Situ Nick-End Labeling; Lithium Chloride; Male; Myocardium; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus; Sympathetic Nervous System; Time Factors; Troponin I

It is well known that choline has protective effects on ischemic arrhythmias. We designed the present study to evaluate the antiarrhythmic effects of choline and to detect its related mechanisms in aconitine-induced rat and ouabain-induced guinea pig models of arrhythmia. Laser scanning confocal microscopy and patch-clamp technique were utilized to study the action of choline on intracellular calcium concentration and L-type calcium current (ICa-L) of cardiac myocytes. M3 receptor antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) was applied preliminarily to evaluate the role of the M3 receptor. Choline significantly increased the survival time of arrhythmic rats and guinea pigs, delayed the onset of arrhythmias and ventricular tachycardia, and decreased the arrhythmia score. The overload of intracellular Ca2+ induced by aconitine or ouabain was reduced in isolated myocytes pretreated with choline. Choline reduced the increased density of ICa-L induced by aconitine or ouabain. Moreover, the beneficial effects of choline were reversed by 4-DAMP. Choline produced antiarrhythmic actions on arrhythmia models by stimulating the cardiac M3 receptor. The mechanism may be related to the improvement of Ca2+ handling.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium; Choline; Disease Models, Animal; Female; Guinea Pigs; Male; Myocytes, Cardiac; Ouabain; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3

The present study established a model of RyR(2) knockdown cardiomyocytes and elucidated the role of RyR(2) in aconitine-induced arrhythmia. Cardiomyocytes were obtained from hearts of neonatal Sprague-Dawley rats. siRNAs were used to down-regulate RyR(2) expression. Reduction of RyR(2) expression was documented by RT-PCR, western blot, and immunofluorescence. Ca(2+) signals were investigated by measuring the relative intracellular Ca(2+) concentration, spontaneous Ca(2+) oscillations, caffeine-induced Ca(2+) release, and L-type Ca(2+) currents. In normal cardiomyocytes, steady and periodic spontaneous Ca(2+) oscillations were observed, and the baseline [Ca(2+)](i) remained at the low level. Exposure to 3 microM aconitine increased the frequency and decreased the amplitude of Ca(2+) oscillations; the baseline [Ca(2+)](i) and the level of caffeine-induced Ca(2+) release were increased but the L-type Ca(2+) currents were inhibited after application of 3 microM aconitine for 5 min. In RyR(2) knockdown cardiomyocytes, the steady and periodic spontaneous Ca(2+) oscillations almost disappeared, but were re-induced by aconitine without affecting the baseline [Ca(2+)](i) level; the level of caffeine-induced Ca(2+) release was increased but L-type Ca(2+) currents were inhibited. Alterations of RyR(2) are important consequences of aconitine-stimulation and activation of RyR(2) appear to have a direct relationship with aconitine-induced arrhythmias. The present study demonstrates a potential method for preventing aconitine-induced arrhythmias by inhibiting Ca(2+) leakage through the sarcoplasmic reticulum RyR(2) channel.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Caffeine; Calcium Channels, L-Type; Calcium Signaling; Cells, Cultured; Gene Expression; Gene Silencing; Membrane Potentials; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Small Interfering; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Transfection

The present work was designed to investigate the relationship between hemodynamic parameters and the susceptibility of ventricular arrhythmia to aconitine in conscious Lyon hypertensive rats (LH).. Male LH and Lyon low blood pressure rats (LL) were used. After the determination of baroreflex sensitivity (BRS), ventricular arrhythmia was induced by aconitine infusion in conscious rats. Blood pressure (BP) was recorded during the period of infusion.. Compared with the LL rats, the LH rats possessed significantly higher BP, blood pressure variability and lower BRS. The threshold of aconitine required for ventricular fibrillation and cardiac arrest in the LH rats were significantly lower than those in the LL rats. It was found that all the hemodynamic parameters studied were not correlated with the threshold of aconitine required for arrhythmia, with the exception of BRS, which was positively related to the threshold of aconitine required for ventricular premature beat.. The LH rats possessed greater susceptibility to aconitine-induced ventricular arrhythmias when compared to the LL rats. This greater susceptibility could not be attributed to any one of the hemodynamic parameters alone studied in the LH rats. It is proposed that various hypertension-associated abnormalities, including the abnormal hemodynamics, may co-contribute to this vulnerability to ventricular arrhythmias.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Baroreflex; Blood Pressure; Disease Susceptibility; Hypertension; Male; Rats

Aconitine is an effective ingredient in Aconite tuber, an important traditional Chinese medicine. Aconitine is also known to be a highly toxic diterpenoid alkaloid with arrhythmogenic effects. In the present study, we have characterized the properties of arrhythmic cytotoxicity and explored the possible mechanisms of aconitine-induced cardiomyocytes. Results show that aconitine induces significant abnormity in the spontaneous beating rate, amplitude of spontaneous oscillations and the relative intracellular Ca(2+) concentration. Also, mRNA transcription levels and protein expressions of SR Ca(2+) release channel RyR(2) and sarcolemmal NCX were elevated in aconitine-induced cardiomyocytes. However, co-treatment with ruthenium red (RR), a RyR channel inhibitor, could reverse the aconitine-induced abnormity in intracellular Ca(2+) signals. These results demonstrate that disruption of intracellular Ca(2+) homeostasis in the cardiac excitation-contraction coupling (EC coupling) is a crucial mechanism of arrhythmic cytotoxicity in aconitine-induced cardiomyocytes. Moreover, certain inhibitors appear to play an important role in the detoxification of aconitine-induced Ca(2+)-dependent arrhythmias.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium; Calcium Signaling; Calcium-Binding Proteins; Cells, Cultured; Heart Rate; Homeostasis; Myocardial Contraction; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Ruthenium Red; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Calcium Exchanger; Thapsigargin

Aconite poisoning was examined in five patients (four males and one female) aged 49 to 78 years old. The electrocardiogram findings were as follows: ventricular tachycardia and ventricular fibrillation in case 1, premature ventricular contraction and accelerated idioventricular rhythm in case 2, AIVR in case 3, and nonsustained ventricular tachycardia in cases 4 and 5. The patient in case 1 was given percutaneous cardiopulmonary support because of unstable hemodynamics, whereas the other patients were treated with fluid replacement and antiarrhythmic agents. The main aconitine alkaloid in each patient had a half-life that ranged from 5.8 to 15.4 h over the five cases, and other detected alkaloids had half-lives similar to the half-life of the main alkaloid in each case. The half-life of the main alkaloid in case 1 was about twice as long as the half-lives in the other cases, and high values for the area under the blood concentration-time curve and the mean residence time were only observed in case 1. These results suggest that alkaloid toxicokinetics parameters may reflect the severity of toxic symptoms in aconite poisoning.

Topics: Accelerated Idioventricular Rhythm; Aconitine; Aconitum; Aged; Area Under Curve; Arrhythmias, Cardiac; Biotransformation; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Electrocardiography; Female; Half-Life; Humans; Male; Middle Aged; Severity of Illness Index; Tachycardia, Ventricular; Tandem Mass Spectrometry; Toxicology; Ventricular Fibrillation; Ventricular Premature Complexes

The antiarrhythmic action of the newly developed compound 44Bu (an original compound that was synthesized at our Faculty of Pharmacy) was tested on a model of aconitine-induced arrhythmia and compared with the effect of lidocaine. Both tested substances were administered either as therapeutic or prophylactic agents. 44Bu was highly effective in reducing the occurrence of ventricular fibrillation from 94% to 8% by therapeutic administration, and to 0% by prophylactic administration. The overall mortality rate was significantly reduced by 44Bu from 100% to 25% in the case of therapeutic administration, and to 0% in the case of prophylactic administration. In contrast, there was not any significant difference between therapeutic and prophylactic administration of lidocaine. The occurrence of ventricular fibrillation dropped from 94% to 50% with therapeutic administration, and to 67% with prophylactic administration of lidocaine. The overall mortality rate was significantly reduced from 100% to 63% and to 67%, respectively. We conclude that the 44Bu compound is a highly effective agent in suppressing aconitine-induced arrhythmias. The antiarrhythmic effect of 44Bu was significantly more evident in comparison with lidocaine, particularly in the case of its prophylactic administration.

Topics: Aconitine; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzoates; Lidocaine; Male; Models, Biological; Rats; Rats, Wistar; Ventricular Fibrillation

Intravenous glialin in a dose of 7 mg/kg suppressed the number of ectopic contractions caused by double ligature of the left coronary artery by the method of Harris and almost 2-fold prolonged animal life-span in comparison with the control. The maximum antiarrhythmic effect of glialin developed after 180 min and persisted for 5 h. Glialin injected intravenously (10 mg/kg) after myocardial infarction under conditions of programmed electrical stimulation inhibited conduction of evoked impulse in the atria, Purkinje fibers, and ventricular myocardium and did not modify the effective refractory periods of the atria and ventricles.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Electrophysiology; Glycyrrhizic Acid; Heart Conduction System; Myocardial Infarction

Viscum coloratum flavonoids (VCF) have been demonstrated to produce a variety of biological actions. An accumulating line of evidence supported the view that VCF may exert protective effects on the cardiovascular system. The aim of the study was to assess the antiarrhythmic activity as well as the electrophysiological properties of VCF. The antiarrhythmic effects of VCF were observed in a rat model of arrhythmia induced by aconitine. VCF significantly and dose-dependently increased the dosage of aconitine required to induce the arrhythmia indexes. Electrophysiological experiment revealed that VCF shortened APD through inhibition of ICa-L.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels; Drugs, Chinese Herbal; Flavonoids; Myocytes, Cardiac; Random Allocation; Rats; Rats, Wistar; Viscum

Topics: Aconitine; Alkanesulfonic Acids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Chloride; Cardiotonic Agents; Male; Myocardial Ischemia; Rats; Rats, Wistar

Antiarrhythmic activity of a membrane-protecting agent Sal'magin was studied in rats with aconitine-induced cardiac arrhythmias. The test preparation was more potent than amiodaron in producing the antiarrhythmic effect in rats with Na(+)-induced cardiac arrhythmias. The absence of side effects, low toxicity, and high animal survival rate under experimental conditions suggest that Sal'magin holds much promise as an antiarrhythmic drug in clinical practice.

Topics: Aconitine; Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Female; Male; Rats; Salicylates; Sodium Channels

Aconitum alkaloids are well known for their acute and high toxicity, for example, in the causation of severe arrhythmias leading to death. Aconitine, one of the major Aconitum alkaloids, is a highly toxic compound from the Aconitum species. However, there has been no studies reported on the influence of the chronic administration of aconitine. Thus, this study was conducted to investigate the influence of chronic administration of aconitine in experimental animal models. A dose of 1mg/kg per day was administered to the experimental animal models. We determined the concentration of aconitine and its metabolites (benzoylaconine and aconine) in organs and blood with gas chromatography/selected ion monitoring (GC/SIM). In addition, we concurrently recorded the electrocardiogram (ECG). Fifteen minutes after administration on day 0, the early aconitine administered group (acute group) revealed peak organ and blood concentration levels of aconitine with a gradual decrease, thereafter. The concentration of aconitine in organs and blood (from days 0 to 22; 90 min after the last administration of aconitine) gradually decreased according to repeated administration, whereas benzoylaconine and aconine increased. ECG revealed various types of arrhythmias. However, the frequency of arrhythmias remarkably decreased with time and repeated administration of aconitine. These results indicate two possibilities. First, the increase in the activity of aconitine metabolism. Secondly, the decrease of effectiveness to the heart due to long-term (chronic) administration of aconitine.

Topics: Aconitine; Alkaloids; Animals; Arrhythmias, Cardiac; Drug Administration Schedule; Electrocardiography; Gagging; Gas Chromatography-Mass Spectrometry; Male; Mice; Mice, Inbred ICR; Models, Animal; Plant Extracts; Tissue Distribution

The effects of Cl- channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and niflumic acid (NFA) on aconitine-induced arrhythmias were investigated. Left ventricular pressure and electrocardiogram were monitored in Langendorff-perfused rat hearts. Whole-cell patch-clamp and current-clamp techniques were used to measure sodium current (I(Na)) and action potential (AP), respectively, in single rat cardiac ventricular myocytes. Addition of the Na+ channel agonist aconitine (0.1 microM) to the perfusion solution produced polymorphic ventricular arrhythmias with a latent period of 25.5 +/- 6.3 s. NPPB could reverse aconitine-induced arrhythmias. A similar effect was observed by using NFA. NPPB and NFA reversibly depressed the upstroke of the AP in a dose-dependent manner with IC50 values of approximately 12.3 and approximately 73.1 microM, respectively, without significantly affecting the resting potential of rat ventricular myocytes. Both Cl- channel blockers inhibited I(Na) and induced a leftward shift of the steady-state inactivation of I(Na). In conclusion, the results of this study demonstrate that NPPB as well as NFA can suppress aconitine-induced arrhythmias in rat hearts mainly by inhibiting cardiac I(Na).

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Chloride Channels; Electrocardiography; Female; Heart Ventricles; In Vitro Techniques; Male; Myocytes, Cardiac; Niflumic Acid; Nitrobenzoates; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Sodium Channels

To compare the actions of the three flavone ingredients in choerospondias axillaris on arrhythmias Induced by aconitine.. Langendorff perfuse was applied in the experiment, the antiarrhythmic action was to study by using aconitine on the the isolated heart; The antiarrhythmic action of the three flavone ingredients in choerospondias axillaris was to study by using i.v. aconitine in rat to induce arrhythmias.. Compared with the NS group, sample 1 and sample 2 both significantly prolonged the beginning time of VF of isolated heart and increased the dosage of aconitine, sample 3 reduced the beginning time of VF of isolated heart and decreased the dosage of aconitine, sample 1 and sample 2 both greatly prolonged the beginning time of VE, VT, VF, HA; sample 3 greatly reduced the beginning time of VT,VF. The actions of the three samples were in a concentration-dependent way.. Sample 1 and sample 2 both resisted the occurrence of arrhythmias induced by aconitine, sample 3 markedly promoted the occurrence of arrhythmias induced by aconitine.

Topics: Aconitine; Anacardiaceae; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Female; Flavones; In Vitro Techniques; Male; Phytotherapy; Plants, Medicinal; Random Allocation; Rats; Rats, Wistar

To search for compounds for the treatment of cardiovascular diseases through prodrug structural modifications of cyclovirobuxine D, a single efficient composition distilled from Box plant in China, which was used to treat angina and myocardial infarction.. According to prodrug design principle, a series of cyclovirobuxine D analogues were prepared, suc as succinate, phosphate and amino acid ester, and their biological activities were tested.. Seven new compounds were obtained and confirmed with 1H NMR, MS, and element analysis.. In pharmacology experiment, for treating arrhythmia induced by aconitine, succinate and amino acid ester of cyclovirobuxine D (I and VII) showed better activities than that of cyclovirobuxine D. The normal rhythm of the heart duration of I and VII were ( 11.53 +/- 7.62) min and (12.68 +/- 9.25) min, compared with 0.9% NaCl solution and cyclovirobuxine D, (2.36 +/- 1.68) min and (10.25 +/- 6.59) min (P < 0.01), respectively. Another pharmacology experiment, for treating arrhythmia induced by chloroform, the negative ratio of I and VII were 80% and 82%, compared with 0.9% NaCl solution and cyclovirobuxine D, 43% and 52% (P < 0.05), respectively. The difference between new compounds and cyclovirobuxine D was distinct.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Buxus; Chloroform; Drugs, Chinese Herbal; Female; Heart Rate; Male; Mice; Plants, Medicinal; Prodrugs; Random Allocation; Rats; Rats, Sprague-Dawley

The anti-arrhythmic effect was tested on the model of aconitine-induced arrhythmia. The experiment was performed in vivo with 31 male Wistar laboratory rats. Group A was first administered aconitine and, after the onset of the first sinus rhythm disorders, the 44Bu compound was administered. Group B was first administered the 44Bu compound and only after that the aconitine. The control group was administered aconitine and saline as a replacement of the tested compound. In group A, there was a decrease in the ventricular fibrillation occurrence from 100 % to 8 % (p < 0.001) after the administration of the 44Bu compound. In the B group, the onsets of all monitored arrhythmia types were delayed by an average of 15.6 min. Ventricular rhythm occurrence was decreased from 100 to 20 %, as well as ventricular fibrillations, from 100 to 0 % (p < 0.001).

Topics: Aconitine; Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzoates; Drug Evaluation, Preclinical; Male; Rats; Rats, Wistar

Antiarrhythmic properties of taurhythman were demonstrated on experimental models of ventricular (early occlusion and calcium chloride-induced) and atrioventricular (aconitine-induced) arrhythmias. The preparation reduced or prevented episodes of paroxysmal tachycardia and ventricular fibrillation, decreased the incidence of arrhythmias, and increased the lethal dose (LD) of arrhythmogenic agents. By its efficiency, taurhythman was superior to procainamide and comparable to lidocaine.

Topics: Aconitine; Alkanesulfonic Acids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiotonic Agents; Disease Models, Animal; Heart Arrest; Lidocaine; Male; Procainamide; Rats; Tachycardia, Paroxysmal; Ventricular Fibrillation

Previously, we identified a novel neuron-specific protein (PAHX-AP1) that binds to Refsum disease gene product (PAHX), and we developed transgenic (TG) mice that overexpress heart-targeted PAHX-AP1. These mice have atrial tachycardia and increased susceptibility to aconitine-induced arrhythmia. This study was undertaken to elucidate the possible changes in ion channels underlying the susceptibility to arrhythmia in these mice. RT-PCR analyses revealed that the cardiac expression of adrenergic beta(1)-receptor (ADRB1) was markedly lower, whereas voltage-gated potassium channel expression (Kv2.1) was higher in PAHX-AP1 TG mice compared with non-TG mice. However, the expression of voltage-sensitive sodium and calcium channels, and muscarinic receptor was not significantly different. Propranolol pretreatment, a non-specific beta-adrenoceptor antagonist, blocked aconitine-induced arrhythmia in non-TG mice, but not in PAHX-AP1 TG mice. Our results indicate that, in the PAHX-AP1 TG heart, the modulation of voltage-gated potassium channel and ADRB1 expression seem to be important in the electrophysiological changes associated with altered ion channel functions, but ADRB1 is not involved in the greater susceptibility to aconitine-induced arrhythmia.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Carrier Proteins; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Heart Rate; Intracellular Signaling Peptides and Proteins; Ion Channels; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Potassium Channels, Voltage-Gated; Propranolol; Receptors, Adrenergic, beta-1; Receptors, Muscarinic; Refsum Disease

The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 microM) suppressed abnormal electrical activity induced by aconitine, but SEA (100 microM) did not show such effects. KBR (10 microM) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1-100 microM) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na+ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.

Topics: Aconitine; Action Potentials; Aniline Compounds; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Computer Simulation; Disease Models, Animal; Electrophysiology; Guinea Pigs; Heart Ventricles; Kinetics; Muscle Cells; Phenyl Ethers; Sodium Channels; Sodium-Calcium Exchanger; Thiourea

To observe the effects of ouabain and aconitine on APD and ion channels in isolated guinea pig and rat ventricular myocytes; to elucidate the action mechanisms of these two drugs and set up new arrhythmic models on cellular level.. In isolated ventricular myocytes of guinea pig and rat, the effects of ouabain and aconitine on APD, ICa-L, Ik, Ito and Ik1 were observed using the whole cell patch clamp technique.. Ouabain (5 micromol x L(-1)) obviously prolonged the APD90, increased ICa-L, decreased Ik and Ik1 in guinea pig ventricular myocytes. Aconitine (1 micromol x L(-1)) lengthened the APD90, increased ICa-L, decreased Ito and increased Ik1 in rat ventricular myocytes.. The targets on ouabain- and aconitine-induced arrhythmias included APD, ICa-L, Ik, Ito, and Ik1. APD, ICaL, Ik and Ito must be the powerful ones, both in arrhythmic and antiarrhythmic courses. The ouabain- and aconitine- induced arrhythmic models on cellular level were built to study the antiarrhythmic mechanisms of chemicals and evaluate new drugs. These two new-type models in vitro were stable, liable, repeatable and economic, which were superior to those typical models in vivo.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Channels, L-Type; Cell Separation; Female; Guinea Pigs; Heart Ventricles; Male; Myocytes, Cardiac; Ouabain; Potassium Channels, Inwardly Rectifying; Rats; Rats, Wistar

To study the effect of modified starfish sterol [C03, succinic acid (5-epiandroene-17-one-3beta-ol) diester] on experimental arrhythmias.. Arrhythmias were induced by drugs (Aco, Oua, BaCl2 and adrenalin) i.v., ligating the left anterior descending coronary artery and electricity.. C03 71.4 mg x kg(-1) (ig) was shown to increase the dose of Oua inducing VP, VT, VF and CA in guinea pigs (P < 0.01); C03 (26.8, 80.4 mg x kg(-1)) was found to increase the dose of Aco inducing VF and CA in rats (P < 0.01); C03 (8.9, 26.8, 80.4 mg x kg(-1)) increase the dose of barium chloride and delay the onset time of ventricular arrhythmias (P < 0.01); C03 (14.1, 42.3 mg x kg(-10) shorten time of recovering induced by adrenalin in rabbits (P < 0.01); C03 (80.4 mg x kg(-1)) was shown to reduce the number of ventricular arrhythmias induced by coronary artery ligation in rats (P < 0.05), C03 increase VFT induced by electricity in rabbits, VFT of C03 14.1 mg x kg(-1) increased from (5.1 +/- 2.5) V to (11.0 +/- 2.7) V (P < 0.01), 42.3 mg x kg(-1) increased from (6.1 +/- 1.7) V to (15 +/- 5) V (P < 0.01).. Starfish sterol has anti-arrhythmic effect.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium Compounds; Cats; Chlorides; Epinephrine; Guinea Pigs; Materia Medica; Mice; Ouabain; Rabbits; Rats; Starfish; Sterols; Ventricular Fibrillation

To clarify mechanisms that the antiarrhythmic effects of matrine and berbamine are weaker than those of amiodarone and RP58866.. Experimental arrhythmic models were induced by aconitine, coronary artery ligation and electric stimulation in rats and rabbits. Whole-cell patch-clamp techniques were used to record IK1, IKr, IKs and Ito.. Matrine and berbamine significantly increased the dose of aconitine for induction of ventricular premature and ventricular tachycardia in rats, decreased the number of arrhythmias induced by coronary artery ligation in rats and increased ventricular fibrillation threshold (VFT) induced by electric stimulation in rabbits, but the anti-arrhythmic potency of matrine and berbamine was lower than that of amiodarone and RP58866. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866. The IC50 of matrine for IK1, IKr, IKs, Ito were (46 +/- 3), (32.9 +/- 1.2), (37 +/- 8) and (7.6 +/- 0.5) mol x L(-1), respectively. The IC50 of amiodarone for IK1, IKr, IKs, Ito were (21 +/- 5) , (3.7 +/- 0.7), (5.9 +/- 0.9) and (5.9 +/- 0.6) mol x L(-1), respectively.. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866, which might be the reason that the antiarrhythmic effects of matrine and berbamine were weaker than those of amiodarone and RP58866.

Topics: Aconitine; Alkaloids; Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzylisoquinolines; Chromans; Dogs; Female; Guinea Pigs; Male; Matrines; Piperidines; Potassium Channels; Quinolizines; Rabbits; Rats

During aconitine-induced arrhythmias the antiarrhythmic effect of DALDA (Tyr-D-Arg-Phe-Lys-NH2) and nociceptin (orphanin FQ) administered intravenously depended on activation of nitric oxide synthase. K(ATP) channels were not involved in the realization of this effect. Endogenous prostanoids played a minor role in the antiarrhythmic effect of nociceptin and did not contribute to the protective influence of DALDA. The antiarrhythmic effect of orphanin FQ administered intravenously did not depend on functional activity of the autonomic nervous system. However, the effect of orphanin FQ after intracerebroventricular infusion was determined by changes in the state of this system.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Glyburide; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nociceptin; Oligopeptides; Opioid Peptides; Potassium Channels; Rats; Rats, Wistar

It has been found that intravenous administration of nociceptin (0.4 mg/kg) prevents development of aconitine-induced arrhythmias but has no effect on the incidence of occlusion, reperfusion, CaCl2-induced arrhythmias, and exacerbates epinephrine-evoked dysrhythmias. Pretreatment with hexamethonium, atropine, guanethidine and naloxone did not abolish the arrhythmic effect of nociceptin. Intracerebroventricular infusion of orphanin FQ was shown to increase cardiac tolerance of arrhythmogenic influence of aconitine, but this effect is completely abolished by hexamethonium administration. It has been suggested that stimulation of both central and peripheral ORL1 receptors increases cardiac resistance against arrhythmogenic effect of aconitine via different mechanisms.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Electrocardiography; Epinephrine; Heart; Heart Rate; Injections, Intravenous; Injections, Intraventricular; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Rats; Rats, Wistar; Receptors, Opioid

Antiarrhythmic activity of oral allapinin was studied in 64 patients with ischemic heart disease. 27 of the patients had undergone coronary artery bypass grafting 2 to 12 months before, 19 patients had postinfarction cardiosclerosis, 38--arterial hypertension, 30--circulation insufficiency stage I. Arrhythmia presented as ventricular extrasystole (n = 28), paroxysmal atrial fibrillation (n = 18), paroxysmal atrial tachycardia (n = 11), frequent supraventricular extrasystole (n = 7). Arrhythmia continued from 6 months to 8 years. An effective single dose was defined with acute pharmacological test. The treatment course lasted for 21 days. Allapinin proved to be highly effective: ventricular ectopic activity was suppressed in 71.4% patients, atrial tachycardia paroxysms were prevented in 72.7%, paroxysms of atrial fibrillation--in 77.8%. Allapinin tolerance was good. Extracardiac side effects occurred most frequently, but dose lowering was necessary only in 6.2%. The drug was discontinued because of cardiac side effects in 4.7% cases. ECG monitoring is a highly informative method of the treatment efficacy control.

Topics: Aconitine; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Artery Bypass; Drug Tolerance; Electrocardiography; Humans; Hypertension; Male; Middle Aged; Monitoring, Physiologic; Myocardial Ischemia; Time Factors

To study the effect of Daidzein on Antiarrhythmia.. The conventional antiarrhythmia methods were used.. Daidzein was remarkedly effective in preventing ventricular fibrillation induced by chloroform in mice and arrhythmia induced by aconitine in rats. The arrhythmia induced by adrenalin in rabbits was antagonized by Daidzein and it could obviously inhibit the action potential amplitude of isolated sciatic nerves in toads. And it could also prevent ventricular fibrillation induced by calcium chloride in rats, and obviously reduce the death rate of rats. Its anti-arrhythmic effect was dose-dependent.. Daidzein has obvious protective effect on drug-induced arrhythmia, which may be related to its inhibition of Na+ or Ca2+ influx and its blocking beta-adrenergic receptor.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bufo bufo; Calcium Chloride; Chloroform; Epinephrine; Female; In Vitro Techniques; Isoflavones; Male; Mice; Phytotherapy; Plants, Medicinal; Pueraria; Rabbits; Rats; Rats, Wistar; Ventricular Fibrillation

We have found that intravenous administration of cannabinoid receptor (CB) agonist HU-210 (0.05 mg/kg), increases cardiac resistance against arrhythmogenic effect of epinephrine, aconitine, coronary artery occlusion and reperfusion in rats. Pretreatment with CB2-receptor antagonist, SR144528 (1 mg/kg), completely abolished the antiarrhythmic effect of HU-210. However this effect of HU-210 was not attenuated by pretreatment with CB1-receptor antagonist, SR141716A (3 mg/kg). We also found that HU-210 (0.05 mg/kg) decreased the relationship between infarction size and area of ischemia. It is concluded that CB2 receptor stimulation promotes an increase in the cardiac resistance against arrhythmogenic influences and probably increases myocardial tolerance of both ischemic and reperfusion damages in rats.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Camphanes; Cannabinoids; Coronary Artery Disease; Dronabinol; Epinephrine; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

From a cDNA library of Chinese scorpion Buthus martensii Karsch, full-length cDNAs of 351 nucleotides encoding precursors (named BmKIM) that contain signal peptides of 21 amino acid residues, a mature toxin of 61 residues with four disulfide bridges, and an extra Gly-Lys-Lys tail, were isolated. The genomic sequence of BmKIM was cloned and sequenced; it consisted of two exons disrupted by an intron of 1622 bp, the largest known in scorpion toxin genomes, inserted in the region encoding the signal peptide. The cDNA was expressed in Escherichia coli. The recombinant BmKIM was toxic to both mammal and insects. This is the first report that a toxin with such high sequence homology with an insect-specific depressant toxin group exhibits toxicity to mammals. Using whole cell patch-clamp recording, it was discovered that the recombinant BmKIM inhibited the sodium current in rat dorsal root ganglion neurons and ventricular myocytes and protected against aconitine- induced cardiac arrhythmia.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Circular Dichroism; Cloning, Molecular; DNA, Complementary; Escherichia coli; Gene Library; Heart; Heart Ventricles; Molecular Sequence Data; Myocardium; Neurons; Peptides; Rabbits; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Scorpion Venoms; Scorpions; Sodium; Sodium Channels

The aim of study was to modify the structure of indoline-2,3-diones and 1,2-benzenedicarboximides using the pharmacophores of new generation antiarrhythmics and to assess the impact of their structure upon the acute toxicity and antiarrhythmic action. The quaternary derivatives of N-aminoalkylindoline-2,3-diones and N-aminoalkyl-1,2-benzenedicarboximides were synthesized. The acute toxicity of compounds for white mice was tested. Using the calcium chloride- and aconitine-induced arrhythmia models in rats the antiarrhythmic action of derivatives was assessed. It was shown, that the antiarrhythmic action of N-aminoalkyl-1,2-benzenedicarboximides increases by lengthening of alkylene chain from one methylene group to two or by the presence of methanesulfonamide group in benzene ring. These structural changes, especially the presence of methanesulfonamido group, cause the decrease of acute toxicity. Among the N-aminoalkylindoline-2,3-diones the most antiarrhythmic action and minimal toxicity demonstrates the compound containing the bromo-substituted benzene ring.

Topics: Aconitine; Alkenes; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Chloride; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Indoles; Lethal Dose 50; Male; Mice; Quaternary Ammonium Compounds; Rats

To evaluate the therapeutic effect of Yangxin Fumai Oral Liquid (YFOL), a Chinese herbal medicine for nourishing heart and restoring pulse, in treating patients with extrasystole.. The effect of YFOL was observed in treating 30 patients with different kinds of extrasystole and compared with that in 30 patients treated by propafenone. The effect of YFOL on experimental arrhythmia was studied in animals as well.. Clinical observation showed that the effect of YFOL against extrasystole in the two groups was similar, but the YFOL group showed better effect in symptom improvement (P < 0.01) with no marked side-effects. Experimental study showed that YFOL could reduce the chloroform induced ventricular fibrillation occurrence in mice, delay the initiating time of ventricular extrasystole, tachycardia and fibrillation induced by aconitine, BaCl2 and coronary artery ligation in rats, or shorten the lasting time of arrhythmia, reduce the attacking rate of ventricular extrasystole. There was significant difference in comparing with the control group (P < 0.05, P < 0.01).. YFOL is a good and convenient Chinese herbal preparation for different kinds of extrasystole with low toxic and side-effects in clinical practice.

Topics: Aconitine; Adult; Aged; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium Compounds; Cardiac Complexes, Premature; Chlorides; Drugs, Chinese Herbal; Female; Humans; Male; Mice; Middle Aged; Rats; Rats, Sprague-Dawley

Topics: Aconitine; Arrhythmias, Cardiac; Drug Overdose; Drugs, Chinese Herbal; Female; Humans; Middle Aged; Quadriplegia; Sodium Channels

The effects of 6,7,8, 9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury were evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chloro derivative of TY-12533) and cariporide on the platelet Na(+)/H(+) exchanger in vitro were almost equal at pH 6.2 and decreased at pH 6.7; but TY-12533 was four times more potent than TY-50893 and cariporide at pH 6.7. TY-12533, TY-50893 and cariporide administered before ischemia (0.01-1 mg/kg, i.v.) suppressed the ischemia/reperfusion-induced arrhythmias to the same extent in vivo; but TY-12533 was more effective than cariporide and TY-50893 when they were administered during ischemia (0.1-1 mg/kg). Similar results were obtained for the inhibitory effects of these drugs administered before ischemia (0.03-0.1 mg/kg, i.v.) and during ischemia (0.1-1 mg/kg) on the ischemia/reperfusion-induced myocardial infarction. These differences between TY-12533 and the other drugs in vitro and in vivo may be ascribed to the pK(a) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiotonic Agents; Disease Models, Animal; Guanidines; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Pyridines; Rats; Rats, Wistar; Sodium-Hydrogen Exchangers; Sulfones

The synthesis of analogues of N,2-diphenyl-N-(4-piperidyl)acetamide endowed with antiarrhythmic activity is reported. Benzoyl, cinnamoyl, acetyl and propionyl groups replace the phenacyl group as N-acyl substituent, while pyridine replaces benzene as aromatic ring bound to the amide nitrogen. The title compounds were evaluated for antiarrhythmic activity on experimental arrhythmias induced by aconitine in rats. The presence of a n-propyl chain and an unsubstituted cinnamoyl moiety (1j) gives the highest protection against aconitine induced extrasystoles while the best efficacy against lethal effects is due to the presence of a n-propyl chain and an acetyl moiety (1m).

Topics: Aconitine; Aminopyridines; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chromatography, Thin Layer; Female; Gas Chromatography-Mass Spectrometry; Magnetic Resonance Spectroscopy; Male; Piperidines; Rats; Spectrophotometry, Infrared

AH-1058 is a newly synthesized antiarrhythmic agent. We investigated the antiarrhythmic and electrophysiological effects of AH-1058 in experimental arrhythmia models and isolated cardiomyocytes. In the ouabain-induced arrhythmia model of the guinea pig, pretreatment with AH-1058 (0.1-0.3 mg/kg, i.v.) delayed the appearance of premature ventricular complex (PVC) and ventricular fibrillation (VF) induced by intravenous infusion of ouabain. However, disopyramide (10 mg/kg, i.v.) delayed only that of PVC, and verapamil (1 mg/kg, i.v.) failed to affect the ouabain-induced ventricular arrhythmias. In the reperfusion-induced arrhythmia model of the rat, in which 5-min coronary occlusion and 10-min reperfusion were produced, AH-1058 (0.1-0.3 mg/kg, i.v.) inhibited the incidence of both ventricular tachycardia (VT) and VF, whereas disopyramide (5 mg/kg, i.v.) inhibited only reperfusion-induced VF. On the other hand, a higher dose of AH-1058 (1 mg/kg, i.v.) did not affect the aconitine-induced arrhythmias in rats, which were inhibited by disopyramide (5 mg/kg, i.v.). We also confirmed oral activity of AH-1058 in the reperfusion-induced arrhythmia model of the rat. AH-1058, at doses of 2-4 mg/kg, dose-dependently inhibited VT and VF. Electrophysiological experiments with patch-clamp techniques revealed that AH-1058 potently suppressed the L-type Ca2+ currents in isolated cardiomyocytes of the guinea pig. These results suggest that AH-1058 is a potent antiarrhythmic drug having a Ca2+ channel-blocking action. The antiarrhythmic profile of AH-1058 is different from that of disopyramide and verapamil.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bridged Bicyclo Compounds; Electrophysiology; Female; Guinea Pigs; Male; Membrane Potentials; Ouabain; Perfusion; Piperidines; Rats; Rats, Sprague-Dawley

Topics: Aconitine; Amphetamine; Animals; Anti-Arrhythmia Agents; Arginine Vasopressin; Arrhythmias, Cardiac; Atropine; Ketamine; Mice; Potassium Chloride; Rats; Tropanes

To compare the effects of oxysophoridine (Oxy) and sophoridine (Sop) on experimental arrhythmias and myocardial physiologic properties.. Arrhythmias were induced by drugs and myocardial ischemia. Physiologic properties were determined on isolated heart atria.. Oxy 500 mg.kg-1 (1/6 LD50) decreased the incidence of ventricular arrhythmias induced by aconitine (P < 0.01), increased the threshold dose of ouabain-induced ventricular premature (VP, P < 0.05), ventricular tachycardia (VT, P < 0.05), ventricular fibrillation (VF, P < 0.01), and cardiac arrest, (P < 0.01). After i.v. Oxy 500 mg.kg-1 into the rats with ligation of left anterior descending coronary artery, the total numbers of ectopic beats were decreased (P < 0.05), the incidence of VF was lowered, and the duration of VT was shortened (P < 0.01). Oxy 250 mg.kg-1 (1/13 LD50) i.v. shortened the duration of arrhythmias induced by BaCl2 (P < 0.01) and delayed the onset of arrhythmias induced by chloroform-epinephrine (P < 0.05). Oxy produced dose-dependent positive inotropic effects in the isolated left atrial of guinea pigs, increased the concentration of epinephrine to elicit automaticity in left atria, decreased slightly the excitability, and prolonged the functional refractory period. Sop produced the similar effects on arrhythmias as Oxy.. Oxy produced the similar anti-arrhythmic effects as Sop did at the equivalent effective dose.

Topics: Aconitine; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium Compounds; Chlorides; Female; Guinea Pigs; Heart Arrest; Male; Matrines; Mice; Myocardial Contraction; Myocardial Ischemia; Ouabain; Quinolizines; Rabbits; Rats; Rats, Wistar; Refractory Period, Electrophysiological

Extracts of the plant Aconitum spec. are used in traditional Chinese medicine predominantly as anti-inflammatory and analgesic agents, the latter allegedly equally potent as morphine but without any habit-forming potential. As the only pharmacologically active compounds, the C19 diterpenoid alkaloid aconitine, and some of its derivatives, have been proven to be antinociceptive in different analgesic assays, but the mode of action is unknown. To elucidate the mode of action, ten aconitine-like derivatives were investigated with respect to their affinity for voltage-dependent Na+ channels, the action on synaptosomal Na+ and Ca2+ homoeostasis and their antinociceptive, arrhythmogenic and acute toxic properties. Since aconitine is known to bind to site II of Na+ channels, we determined the affinity of the aconitine-like derivatives in vitro to synaptosomal membranes by the [3H]-batrachotoxinin-binding assay and their properties on intrasynaptosomal concentrations of free Na+ and Ca2+ ([Na+]i and [Ca2+]i), both the latter determined fluorometrically with SBFI and Fura-2 respectively. Furthermore, the alkaloids' arrhythmogenic potential was investigated in guinea-pig isolated atria and the antinociceptive action on formalin-induced hyperalgesia and the acute toxic action estimated in mice. The results show that the alkaloids could be divided into at least three groups. The first is characterized by a high affinity to the site II of Na+ channels (Ki about 1.2 microM), the ability to enhance [Na+]i and [Ca2+]i (EC50 about 3 microM), a strong arrhythmogenic action that starts at about 30 nM, an antinociceptive effect (ED50 about 0.06 mg/kg) and high acute toxicity (LD50 values about 0.15 mg/kg). To this group belong aconitine, 3-acetylaconitine and hypaconitine. The second group, with lappaconitine as the only member, has an affinity to Na+ channels an order of magnitude lower (Ki = 11.5 microM), less acute toxicity (LD50 about 5 mg/kg), and a two orders of magnitude lower antinociceptive action (ED50 about 2.8 mg/kg) and lower cardiotoxicity (bradycardia observed at 3 microM). Additionally, lappaconitine suppresses the increase in [Ca2+]i of aconitine-stimulated synaptosomes and increases the excitation threshold of left atria, indicating an inhibition of Na+ channels. The other derivatives, i.e. delcorine, desoxydelcorine, karakoline, lappaconidine, lappaconine and lycoctonine, belong to the third group, which has hardly any effects. They have a low affinity to

Topics: Aconitine; Analgesics; Animals; Arrhythmias, Cardiac; Batrachotoxins; Calcium; Diterpenes; Drugs, Chinese Herbal; Formaldehyde; Guinea Pigs; Heart Atria; Hyperalgesia; Male; Mice; Plants, Medicinal; Sodium; Sodium Channels; Structure-Activity Relationship; Synaptosomes

Aconitum and Delphinium alkaloids are currently under investigation in search for new analgesic and anti-inflammatory drugs. It has been reported that the analgesic compound lappaconitine (LA), a C19 diterpenoid alkaloid from Aconitum sinomontanum nakai is an inhibitor of tetrodotoxin-sensitive, voltage-dependent sodium channels. In the present study we investigated the cardiac effects of LA and its metabolite N-deacetyllappaconitine (DLA) in electrically stimulated left and spontaneously beating right atria isolated from guinea-pig hearts. In all experiments, equieffective concentrations were larger with DLA than with LA. At a stimulation frequency of 2.5 Hz the time constant for the onset of LA effects (tau = 56 +/- 29 min) was markedly larger than the one for DLA effects (tau = 14 +/- 8 min). The compounds exerted a significant negative inotropic action at 0.06 microM (LA) and 0.2 microM (DLA). Asystolia of right atria occurred at 4.5 microM (LA) and 10 microM (DLA). Therefore, cardiotoxicity of LA and DLA was much lower compared to aconitine, which caused arrhythmia at 10 nM in our model. For both alkaloids a use-dependent mode of action could be demonstrated. In addition, preincubation with 0.3 microM LA prevented arrhythmia induced by aconitine or ouabain. We conclude that lappaconitine is a naturally occurring compound with class-I antiarrhythmic action.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; Heart Atria; Male; Ouabain; Plants, Medicinal

It is known that the antineoplastic drug adriamycin (ADR) can cause cardiotoxic effects. Some data imply that pretreatment with selenium (Se) and the radio- and chemoprotector, amifostine (WR-2721), may confer a protective effect. The aim of this study was to evaluate the efficacy of single doses of Se and WR-2721, alone or in combination, in the prevention of acute ADR-induced cardiotoxicity in male Wistar rats. Se, in the form of sodium selenite (1.6 mg/kg i.p.), and WR-2721 (300 mg/kg i.p.) were given 24 hours and 20 minutes, respectively, before ADR (6 mg/kg i.v.). The cardiotoxicity of ADR was recorded 48 hours after its administration because earlier studies revealed that structural damage of the myocardium occurs within this period. Evaluation of these toxic effects, as well as of the cardioprotective efficacy of the administered drugs, was performed using (1) ECG-records before and during the infusion of the proarrhythmogenic compound, aconitine (8 microg/kg/min i.v.) and (2) the serum activity of creatine kinase (CK), aspartate aminotransferase-(AST), lactate dehydrogenase (LDH), and its isoenzyme alpha-hydroxybutyrate dehydrogenase (alpha-HBDH). The results showed that the arrhythmogenic dose of aconitine was significantly reduced in ADR-treated rats (57.22 vs. 99.65 microg/kg in control; p < 0.05) and that this proarrhythmogenic compound caused a significant increase in heart rate in such animals compared to controls. Pretreatment with Se, WR-2721, and their combination partly reversed the arrhythmogenic dose of aconitine to control (72.09, 82.1, and 88.99 microg/kg, respectively). Se failed to prevent an aconitine-induced increase in heart rate, whereas WR-2721 and their combination successfully counteracted this effect. In addition, ADR produced a significant increase in the serum activity of all monitored enzymes. Pretreatment with Se failed to prevent this increase, whereas pretreatment with WR-2721 did. The best result was obtained with their combination. We conclude that the radio- and chemoprotector, WR-2721, particularly in combination with Se, may provide a significant protective effect against acute ADR-induced cardiotoxicity in rats.

Topics: Aconitine; Amifostine; Animals; Antibiotics, Antineoplastic; Arrhythmias, Cardiac; Aspartate Aminotransferases; Creatine Kinase; Doxorubicin; Drug Therapy, Combination; Electrocardiography; Heart Diseases; Hydroxybutyrate Dehydrogenase; L-Lactate Dehydrogenase; Male; Radiation-Protective Agents; Rats; Rats, Wistar; Selenium

Alkaloids from Aconitum sp., used as analgesics in traditional Chinese medicine, were investigated to elucidate their antinociceptive and toxic properties considering: (1) binding to Na+ channel epitope site 2, (2) alterations in synaptosomal Na+ and Ca2+ concentration ([Na+]i, [Ca2+]i), (3) arrhythmogenic action of isolated atria, (4) antinociceptive and (5) acute toxic action in mice. The study revealed a high affinity group (Ki 1 microM) and a low affinity group (Ki 10 microM) of alkaloids binding to site 2. The compounds of the high affinity group induce an increase in synaptosomal [Na+]i and [Ca2+]i (EC50 3 microM), are antinociceptive (ED50, 25 microg/kg), provoke tachyarrhythmia and are highly toxic (LD50 70 microg/kg), whereas low affinity alkaloids reduce [Ca2+]i, induce bradycardia and are less antinociceptive (ED50 20 mg/kg) and less toxic (LD50 30 mg/kg). These results suggest that the alkaloids can be grouped in Na+ channel activating and blocking compounds, but none of the alkaloids seem to be suitable as analgesics because of the low LD50/ED50 values.

Topics: Aconitine; Alkaloids; Animals; Arrhythmias, Cardiac; Calcium; Cerebral Cortex; Drugs, Chinese Herbal; Guinea Pigs; Heart Atria; Humans; Ion Channel Gating; Lethal Dose 50; Male; Mice; Pain Measurement; Rats; Rats, Wistar; Sodium; Sodium Channels; Synaptosomes

Blockade of the mu and delta receptors exerted no effect upon the heart resistance against arrhythmogenic influences. Stimulation of the delta receptors increased the myocardial resistance against arrhythmogenic influences. Autonomic nervous system seems to take no part in this effect.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium Chloride; Disease Models, Animal; Disease Susceptibility; Epinephrine; Heart Rate; Male; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Vasoconstrictor Agents

For the purpose of searching for new drug with high potency and simple chemical structure, the dominant conformation and structural parameters of Guan-Fu base (GFA) molecule were modelled and calculated with a SGI-4D 25G computer. The propanediolamine chain in GFA might be considered to be a pharmacophore responsible for the bioactivity and the configuration of the chain seemed important. Thus, thirteen compounds of (erythro)-p-x-PhCHOHCHOHCH2NHR(x = H, I1-7; X = NO2, II1-6) were prepared. Among them, 10 compounds showed antiarrhythmic effect on aconitine-induced arrhythmia in rats. The ED50(to stop VT) of I2 and ED50(to stop VP) of I3 were shown to be comparable with those of GFA. In the synthesis, no stereoselectivity was found in the Prevost reaction with allylamine analogues (a1-7). After a1-7 were acetylated, the erythro type products(I1-7) were obtained.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Molecular Conformation; Molecular Structure; Phenylpropionates; Rats; Rats, Sprague-Dawley

LR-A/113 is a benzothiazepine drug similar to diltiazem with Ca(2+)-antagonist properties. Our previous studies showed that LR-A/113 determines anthypertensive effects comparable to diltiazem in normotensive and hypertensive rats. The aim of this study is to determine LR-A/113 effects respect to verapamil and diltiazem on CaCl2, aconitine and ouabain arrhythmias. Experiments were carried out on normotensive anesthetized rats and guinea pigs treated with CaCl2, aconitine and ouabaine and pretreated or not with verapamil, diltiazem or LR-A/113. Verapamil, diltiazem and LR-A/113, significantly delayed onset of arrhythmias and cardiac standstill induced by CaCl2 and aconitine. Moreover, pretreatments with verapamil, diltiazem or LR-A/113 reduced occurrence of arrhythmias in animals. In our models of arrhythmias LR-A/113 showed a significant antiarrhythmic effect of a magnitude almost similar to diltiazem but lower than for verapamil.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Calcium Chloride; Diltiazem; Male; Ouabain; Rats; Rats, Sprague-Dawley

We examined the effects of an aconitine-like compound, TJN-505 (1alpha-16beta-dimethoxy-20-ethyl-14alpha-(4-methox ybenzoyloxy)-aconitan-8,13-diol hydrochloride), on canine arrhythmias provoked by digitalis, two-stage coronary ligation, adrenaline, programmed electrical stimulation, or aconitine. TJN-505 (2-2.5 mg/kg i.v.) suppressed digitalis-, two-stage coronary ligation- and adrenaline-induced ventricular arrhythmias. The antiarrhythmic plasma concentrations (IC50) of TJN-505 for these arrhythmia models were 1.26, 0.94 and 1.31 microg/ml, respectively. TJN-505 (2 mg/kg i.v. followed by the infusion of 0.1 mg/kg per min) prolonged PR, QRS, QTc and JTc intervals and the ventricular effective refractory period and reduced the incidence of programmed electrical stimulation-induced arrhythmias in dogs with 7-day-old myocardial infarction (P < 0.05). TJN-505 (2 mg/kg i.v.) also suppressed the aconitine-induced atrial arrhythmias. In conclusion, TJN-505 suppressed various canine ventricular and atrial arrhythmias and seems to act as a blocker of multiple channels.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels; Digitalis; Dogs; Electrocardiography; Epinephrine; Female; Male; Plants, Medicinal; Plants, Toxic; Potassium Channels; Sodium Channels

The past experiment showed that there was a specific change of H+ concentration in Neiguan (PC 6) of the rabbit suffering from arrhythmia induced by aconitine. When arrhythmia appeared, th ecocentration of H+ in Neiguan (PC 6) increased obviously. The authors found that it happened not only in the regular points but also along the course of the Heart Meridian and Pericardium Meridian in the furthe study and research. This may mean that on the course of the corresponding meridian there is a specific change of H+ concentration when the Zang-fu organs are in dysfunctional. But the mechanism and biological significance of the change of H+ concentration should remain to be further studied.

Topics: Aconitine; Acupuncture Points; Animals; Arrhythmias, Cardiac; Female; Hydrogen-Ion Concentration; Male; Meridians; Rabbits

Topics: Aconitine; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Carbamates; Chemical Phenomena; Chemistry, Physical; Cornea; Guinea Pigs; Heart Rate; Lethal Dose 50; Mice; Pyrrolidines; Rabbits

Moxonidine is a centrally acting antihypertensive agent with potent action on I1-imidazoline receptors. Moxonidine as an SIR modulator elicits a persistent reduction in circulating levels of epinephrine, demonstrating a reduction in sympathetic tone. In the first experiment the threshold dose of ouabain needed to induce ventricular arrhythmia and asystole was determined in guinea pigs, and the influence of moxonidine was tested. In a dose range of 0.1-0.4 mg/kg body weight i.v., moxonidine increased the threshold dose needed to induce ventricular tachycardia, premature ventricular beats, ventricular flutter, ventricular fibrillation, and asystole. The effect was dose-dependent and statistically significant. Clonidine, in a dose range of 0.2-0.8 mg/kg body weight i.v., also increased the threshold dose of ouabain necessary to induce different cardiac rhythm disturbances. Moxonidine was more effective than clonidine. Pretreatment with the alpha 2-receptor and I1-receptor-influencing substances efaroxan, idazoxan, and SKF 86466 attenuated the effect of moxonidine and clonidine. Efaroxan, idazoxan, or SKF 86466 alone reduced the threshold dose of ouabain necessary to induce cardiac arrhythmia as a sign for arrhythmogenic effects. The alpha 1-receptor antagonist prazosin had no influence on ouabain-induced arrhythmia. Pretreatment with prazosin reduced the moxonidine but not the clonidine effect. In the second experiment the influence of moxonidine on aconitine-induced extrasystoles (ES) in the spontaneously beating guinea pig auricle was investigated. Moxonidine in a dose of 10(-7)-10(-8) M reduced the number of ES. A 10-fold higher dose had no influence on ES number. The beta-blocking agent propranolol showed antiarrhythmic effects in both methods. The ouabain-induced cardiac arrhythmia is associated with increased sympathetic tone on central stimulation. The reduced sympathetic tone by centrally acting moxonidine via imidazoline receptors seems responsible for the antiarrhythmic effect of this drug. Clonidine also reduced the sympathetic tone via imidazoline receptor. The selectivity of clonidine to imidazoline receptors is less pronounced than is that of moxonidine. The interaction of moxonidine with imidazoline receptors is not clear. The possible interaction between imidazoline and alpha-adrenoceptors in relation to the antiarrhythmic effect of moxonidine or clonidine is also unknown. Modulation of imidazoline receptors by moxonidine could be an agonisti

Topics: Aconitine; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Ouabain; Receptors, Drug

To study the effects of acute restraint stress on ventricular electric stability (VES) and its mechanisms of action.. VES was evaluated both in vivo and in vitro by the changes of arrhythmogenic responses to icv or ip aconitine in rats and iv BaCl2 or adrenaline in rabbits following restraint stress for different durations. Pretreatments and the assay of heart-specific enzymes were made.. The heart sensitivity to these drugs was promoted after stress for 2 h, but obtunded after stress for 8 h (the latency of ventricular arrhythmia to icv aconitine was shortened from 4.1 +/- 0.9 min in control rats to 2.9 +/- 0.9 min after stress for 2 h, P < 0.05; but prolonged to 9.3 +/- 3.8 min after stress for 8 h, P < 0.05). In Langendorff heart, the changes of VES induced by stress were similar to those in vivo, but to lesser degree. Pretreatment with adrenalectomy inhibited the descending phase of VES, while pretreatment with both aminophylline and vagotomy remarkably depressed the ascending phase at 8 h. In addition, the serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), and aspartate aminotransferase and their isozymes, LDH1 and CK-MB, were elevated at 2 h, and rose continuously at 8 h.. Acute restraint stress causes biphasic changes of VES. The initial decrease of VES was related to adrenal catecholamine release, whereas the following increase of VES was ascribed to adaptive decrease of cAMP and vagal activation. The changes of VES did not always parallel the injury of heart.

Topics: Aconitine; Adaptation, Physiological; Animals; Arrhythmias, Cardiac; Barium Compounds; Chlorides; Creatine Kinase; Disease Susceptibility; Electrophysiology; Heart Ventricles; L-Lactate Dehydrogenase; Male; Rabbits; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stress, Physiological

We have made two kinds of experimental arrhythmia of rabbits by injecting aconitine and stimulating hypothalamus. Acupuncture could improve arrhythmia, after Ca++ in Neiguan (PC6) was chelated with EDTA solution the effect of acupuncturing Neiguan (PC6) was abolished. It indicates that Ca++ may be the key factor of acupuncture effect and one of the important material bases of the functional activity of meridians and collaterals.

Topics: Aconitine; Acupuncture Points; Acupuncture Therapy; Animals; Arrhythmias, Cardiac; Biological Transport, Active; Calcium; Female; Hypothalamus; Male; Meridians; Rabbits

A series of the new aminoalkyl esters of chlor-, methyl- and alkoxy carbanilates was synthesized. All the compounds prepared were found to exhibit antiarrhythmic activities comparable with those of mexiletine.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Carbamates; Cardiac Complexes, Premature; Epinephrine; Guinea Pigs; Mexiletine; Ouabain; Rats; Tocainide

The effects of garlic (Allium sativum L., Liliaceae) dialysate were studied on arrhythmias induced in anaesthetized dogs and on isolated left rat atria. Garlic dialysate suppressed premature ventricular contractions (PVC) and ventricular tachycardia (VT) in ouabain-intoxicated dogs as well as the ectopic rhythms induced by isoprenaline (10(-6) M) and aconitine (10(-8) M) on electrically driven left rat atria. The effective refractory period (ERP) and the sinus node recovery time (SNRT) of isolated rat atria were prolonged in a dose-dependent manner by the administration of this extract. Garlic dialysate decreased the positive inotropic and chronotropic effects of isoprenaline in a concentration-dependent manner. These last effects were increased by propranolol. The results suggest that garlic dialysate has a significant antiarrhythmic effect in both ventricular and supraventricular arrhythmias.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Dialysis; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Electrocardiography; Female; Garlic; Heart Atria; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Ouabain; Plant Extracts; Plants, Medicinal; Propranolol; Rats; Refractory Period, Electrophysiological; Tachycardia

3, 15-Diacetylbenzoylaconine (Dia) is a new aconite alkaloid derivative. The analgesic ED50 (95% confidence limit) of sc Dia measured with the HAc-induced writhing method, hot-plate method and electric stimulation method in mice were 2.76 (2.34-3.26), 3.50 (2.69-4.54), and 4.20 (3.72-4.73) mg.kg-1, respectively. With the hot-plate method and tail flick method in rats, the analgesic ED50 of ip Dia were 2.75 (2.28-3.31) and 5.24 (4.35-6.31) mg.kg-1, respectively. The LD50 of sc Dia in mice and ip Dia in rats were 21.68 (17.25-27.25) and 10.96 (8.24-14.56) mg.kg-1, respectively. The magnitude of the analgesic therapeutic indices of Dia, 3-acetylaconitine (Ace) and aconitine (Aco) in all the above-mentioned algo-model were in the order of Dia > Ace > Aco. When they were injected iv at 0.1 ml.min-1 in rats, the doses of Dia, Ace, and Aco producing arrythmia were 3.3, 0.8, and 0.5 times as large as those producing analgesia while those of Dia, Ace, and Aco inducing respiratory inhibition were 3.9, 0.5 and 0.3 times, respectively. The magnitudes of the oil/water distribution coefficients with two method and the quotient ED50 icv/ED50 sc of Dia and Ace were > Aco.

Topics: Aconitine; Alkaloids; Analgesics; Animals; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Female; Lethal Dose 50; Male; Mice; Pain; Pain Threshold; Rats; Rats, Wistar; Respiration

To investigate whether the high mortality rate that occurs in streptozotocin (STZ)-diabetic spontaneously hypertensive rats (SHR) is related to abnormalities in glycemic control, in hemodynamics and cardiac function, or in susceptibility to the occurrence of ventricular arrhythmias.. Diabetes was induced in SHR and Wistar-Kyoto (WKY) rats by the intravenous injection of STZ 55 mg/kg. Intraperitoneal glucose tolerance tests were performed after six and 11 weeks. Blood pressure was measured in conscious rats at weeks 0 and 11 with a tail-cuff method and in anesthetized animals at week 12 through a cannulated artery. Response of myocardial function to rapid intravenous infusion of saline 10 mL/kg/min and the times of onset of ventricular arrhythmias during intravenous infusion of aconitine 20 micrograms/kg/min were determined in anesthetized rats at week 12. Plasma samples from the rats were assayed for glucose, insulin, triglycerides and carnitine.. STZ injection caused hyperglycemia, hypoinsulinemia and glucose intolerance equally in SHR and WKY. Diabetic SHR exhibited significant hypertriglyceridemia, depletion in plasma carnitine, impaired responses of blood pressure and myocardial function to rapid intravenous infusion of saline and a 37.5% mortality rate, whereas diabetic WKY did not exhibit these changes. SHR and WKY, diabetic or nondiabetic, were equally sensitive to the induction of ventricular arrhythmias by aconitine infusion.. Mortality of the STZ-diabetic SHR is not due to an exaggeration of the impaired glycemic control, but may be attributed to the occurrence of cardiac dysfunction. The development of life-threatening cardiac arrhythmias, while unlikely, cannot be completely excluded.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Blood Glucose; Blood Pressure; Carnitine; Diabetes Mellitus, Experimental; Drug Evaluation, Preclinical; Hypertension; Insulin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Saline Solution, Hypertonic; Streptozocin; Triglycerides

The experimental arrhythmic model was made with Aconitin in rabbits. The Neiguan (PC6) point was punctured to observe the influence on recovering time of arrhythmia. After the curative effect of puncturing Neiguan(P6) was confirmed, Ca2+ in the Quze (PC3) point of the Pericardium is chelated by EDTA solution to observe the influence on curative effect of arrhythmia by puncturing Neiguan. The result shows that the curative effect doesn't exist after the Ca2+ in Quze is chelated. It is probable that Ca2+ is one of the most important factors producing acupuncture effect. As a result, Ca2+ probably involves in the activities of channels and collaterals.

Topics: Aconitine; Acupuncture Points; Acupuncture Therapy; Animals; Arrhythmias, Cardiac; Calcium; Female; Male; Rabbits

By using the arrhythmic animal models, the effect of 6,7-dimethoxycoumarin (DMOC) on arrhythmia was investigated. The arrhythmia in anaesthetized rat were induced by iv aconitine 20 micrograms.kg-1 or CaCl2 5 mg.kg-1. The arrhythmia in anesthetized guinea pigs was induced by iv ouabain 3.6 micrograms.kg-1.min-1. Procainamide (PA) was used as a positive control. DMOC (33-500 mg.kg-1, ig) and PA (100-800 mg.kg-1, ig) in anaesthetized rats could delay the time of onset of arrhythmia induced by aconitine. The ED50 of DMOC and PA for postponing the occurrence of ventricular extrasystole (VE) were 88 mg.kg-1 (95% confidence interval was 43-165 mg.kg-1) and 183 mg.kg-1 (95% confidence interval was 109-304 mg.kg-1), respectively. The results suggested that the anti-arrhythmia potency of DMOC was higher than that of PA (P < 0.01).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coumarins; Electrocardiography; Female; Male; Mice; Ouabain; Procainamide; Rats; Rats, Wistar

Antiarrhythmic activity of Mexicord-Poland and Mexitil-Böehringer Ingelheim (D) was compared. In three models of experimentally evoked arrhythmia in animals, in used doses, both of examined preparations in the same degree prevented the occurrence of arrhythmia.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Barium Compounds; Chlorides; Digoxin; Electrocardiography; Female; Guinea Pigs; Male; Mexiletine; Rats

The pharmacological effects of the toad venom-containing drug "kyushin" on aconitine- and thyroxine-induced arrhythmia in guinea pigs, on the conduction system in Langendorff preparations of rabbit hearts and on the autonomic nervous system in cats were studied. "kyushin" significantly inhibited the aconitine-induced arrhythmia after intraduodenal administration (i.d.) with 80 mg/kg, and the thyroxine-induced arrhythmia with 40 mg/kg i.d. Although "kyushin" itself did not affect the conduction system with 30 mg/ml of the maximal concentration being able to be prepared, bufalin and cinobufagin as constituents of toad venom produced inhibition with 0.3 mg/ml and 1 mg/ml, respectively. The decrease in heart rate induced by electrical stimulation to the parasympathetic nerve (vagus nerve) was potentiated by "kyushin" at 30 mg/kg i.d. The anti-arrhythmic effects of "kyushin" may be attributable to both possible inhibitory effect on the conduction system and potentiating effect on the parasympathetic nervous system.

Topics: Aconitine; Amphibian Venoms; Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Cats; Digoxin; Electric Stimulation; Female; Guinea Pigs; Heart Conduction System; Heart Rate; In Vitro Techniques; Male; Materia Medica; Propranolol; Rabbits; Thyroxine

Electric stimulation and drug-induced ventricular fibrillation (VF), monophasic action potentials (MAP), and triggered activity were studied before and after administration of tetrahydroberberine (THB) in rabbits, rats or guinea pigs. At doses of 5, 10, and 20 mg.kg-1, i.v. THB increased the ventricular fibrillation threshold, and the BaCl2-induced VF was also prevented or terminated by THB in rabbits. Centrogenic VF induced by icv aconitine in rats was inhibited by pretreatment with THB in a dose-dependent manner, whereas VF induced by iv ouabain in guinea pig was inhibited to a lesser degree. For MAP, the duration at 90% repolarization (MAPD90) was prolonged remarkably, whereas the MAPD20, the MAP amplitude, and the maximal velocity of phase 0 were shortened or decreased slightly. The amplitudes of early afterdepolarization produced by cesium chloride (CsCl) were attenuated, while the cumulative threshold doses of CsCl for sustained ventricular tachycardia were elevated by THB. These results indicated that THB had an potent antifibrillatory effect, which might be attributed to its blockade of potassium, calcium, and sodium currents.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium Compounds; Berberine; Cesium; Chlorides; Female; Guinea Pigs; Male; Ouabain; Rabbits; Rats; Rats, Sprague-Dawley; Ventricular Fibrillation

The antiarrhythmic effect of Jiawei Zhigancao Tang injection (JZTI) was studied in experimental arrhythmia induced by aconitine or by CaCl2 in anesthetized rats. The prophylactic dose of JZTI (5g/kg, i.v.) reduced the incidence rate of premature ventricular complexes, ventricular tachycardia (P < 0.01), delayed the onset time of arrhythmia induced by CaCl2 (P < 0.01), and the recovery time of sinus rhythm occurred earlier than that of control group (P < 0.01). The therapeutic dose of JZTI (10g/kg, i.v.) raised the rate of aconitine-induced arrhythmia to sinus rhythm conversion (P < 0.05). The results showed that JZTI could significantly antagonize arrhythmia induced by aconitine or by Cacl2 in rats.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium Chloride; Drugs, Chinese Herbal; Rats; Tachycardia, Ventricular

Our previous experiments have suggested that besides the receptor cont and/or sensitivity a decrease of intracellular calcium level significantly participates in the mechanism of beta-blocker withdrawal 'rebound' phenomenon. This suggestion initiated studies in which possible changes in myocardial responsibility to cardioactive drugs were investigated in the condition of withdrawal of treatment with calcium entry blockers. The results showed increased cardiotoxicity of ouabain, aconitine and CaCl2, as well as an increased response of the heart to isoprenaline 24 hours after sudden cessation of treatment with verapamil (2 mg.kg-1 x 12 hours-1), diltiazem (3 mg.kg-1 x 12 hours-1) and nifedipine (0.5 mg.kg-1 x 12 hours-1). These results support the hypothesis of a common mechanism of the withdrawal syndrome of beta-lytics and calcium antagonists involving changes in intra-cellular calcium level. (Tab. 2, Fig. 4, Ref. 33.).

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Calcium Chloride; Female; Guinea Pigs; Heart; Isoproterenol; Male; Ouabain; Substance Withdrawal Syndrome

The effects of exogenous gamma-aminobutyric acid (GABA) 10 mg.kg-1 iv in preventing arrhythmias induced by drugs and ischemia were studied in mice, rats, and guinea pigs. It was found that the threshold dose of aconitine inducing arrhythmia in mice and the recovery rate to normal sinus rhythm increased significantly, ED50 of GABA was 5.4-5.8 mg.kg-1. The duration of ventricular tachycardia (VT) induced by aconitine in rats was shortened (P < 0.01). The incidence and the mortality of ventricular fibrillation (VF) in GABA group were decreased to 0/10 vs 6/10 and 5/10 in control, respectively (P < 0.05). The doses of ouabain to induce ectopic beats (EB), VT, VF, and cardiac arrest (CA) in guinea pigs were increased (P < 0.01). The incidence of VF induced by coronary artery ligation in rats was decreased to 0/5 in GABA group vs 4/5 in control group (P < 0.01). The total amount of EB, total time of VT, and VF were 66%, 41%, and 0% of the control group, respectively. The anti-arrhythmic effects of GABA were dose-dependent and as potent as procainamide (10 or 5 mg.kg-1, iv). The results suggest GABA (10 mg.kg-1, iv) may be useful for the prevention of VT and VF.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Female; gamma-Aminobutyric Acid; Guinea Pigs; Male; Mice; Ouabain; Procainamide; Rats; Rats, Wistar

Crebanine (Cre) iv 5 mg/kg could convert BaCl2-induced arrhythmia into sinus rhythm in rats, and could significantly increase the tolerant dose of aconitine to produce ventricular fibrillation (VF) and cardiac arrest (CA) in rats. The drug could also decrease the incidence of VF and CA by CaCl2 in rats and by chloroform in mice, but had no protective effects on ouabain-induced arrhythmias in guinea pigs.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Aporphines; Arrhythmias, Cardiac; Barium; Barium Compounds; Chlorides; Female; Guinea Pigs; Heart Arrest; Male; Mice; Ouabain; Rats; Rats, Wistar; Ventricular Fibrillation

The effect of Kappa-seleno-carrageenan, an organic compound containing selenium, on aconitine, BaCl2 and ouabain-induced arrhythmias were studied. When rats were given ip 9 mg.kg-1.d-1 x 5 d or ig single dose of 35, 70, 140 mg.kg-1, the threshold dose of aconitine was elevated significantly to induce HA. The effect seems to resemble that of ip Na2SeO3 1 mg.kg-1 x d-1 x 5 d. With increasing ig dose, the threshold dose of aconitine was elevated for inducing VE, VT, VF. When ip 9 mg.kg-1 x d-1 x 5 d or ig 70 mg.kg-1 was given, the threshold doses of BaCl2 in inducing VF (in rats) and ouabain in inducing VE (in guinea-pig) were elevated. However, no influence was observed for ip Na2SeO3 1 mg.kg-1 x d-1 x 5 d.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Carrageenan; Chlorides; Dose-Response Relationship, Drug; Female; Guinea Pigs; Male; Mice; Organoselenium Compounds; Ouabain; Rats; Selenium; Sodium Selenite

The antiarrhythmic effects of allapinine were studied in 57 patients with chronic circulatory failure (CCF) and cardiac arrhythmias by employing 48-hour Holter monitoring. Allapinine was found to suppress premature ventricular contraction, group premature ventricular contraction and 'runs' of ventricular tachycardia by 82.5, 88.6, and 93.1%, respectively. The antiarrhythmic activity of the agent was more pronounced in patients with coronary heart disease, Stages I-IIA CCF and left ventricular ejection fraction greater than 40%. In addition, in Stages I-IIA CCF allapinine increased myocardial contractility and left ventricular ejection fraction, whereas in Stages IIB-III CCF it showed a slight cardiodepressive effect. Thus, when given in the course therapy in patients with CCF, allapinine has a high antiarrhythmic activity and, to a lesser extent, affects central hemodynamics.

Topics: Aconitine; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Coronary Disease; Electrocardiography, Ambulatory; Female; Heart Diseases; Heart Valve Diseases; Hemodynamics; Humans; Male; Middle Aged

The antiarrhythmic actions of 3,6-dimethylamino-dibenzopyridonium edetate (IHC-72), lidocaine (Lid) and verapamil (Ver) on several models Were compared at equitoxic doses (equal fraction of LD50). The action of IHC-72 against aconitine induced arrhythmia was similar to that of Lid but stronger than that of Ver in anesthetized rats. The effect of IHC-72 on ouabain induced arrhythmia was also similar to that of Lid, but weaker than that of Ver in anesthetized guinea pigs. The activity of IHC-72 to raise electrical ventricular fibrillation thresholds (VFT) was weaker than that of Lid and Ver. The effects of IHC-72 in decreasing the incidence of ventricular premature beat(VP B), ventricular tachycardia (VT), ventricular fibrillation (VF) and shortening the duration of VT yielded by reperfusion were similar to those of Lid anf Ver in vivo.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Edetic Acid; Female; Guinea Pigs; Lidocaine; Male; Mice; Myocardial Reperfusion Injury; Onium Compounds; Ouabain; Rats; Rats, Inbred Strains; Ventricular Fibrillation; Verapamil

Out of 85 patients with cardiac arrhythmias in the presence of chronic coronary heart disease, 28 who were resistant to ethacisine and allapinine were included into the study. They had frequent and persistent arrhythmias. The patients were divided into 2 groups: (1) the patients receiving intravenous He-Ne laser therapy in combination with one of the above drugs; (n = 17) and (2) those taking He-Ne laser therapy alone (n = 11). The efficacy of the therapies were controlled by 24-hour monitoring. An antiarrhythmic effect was more frequently observed when He-Ne laser was combined with one of the above drugs than when it was given alone (67.4 and 36.3%, respectively).

Topics: Aconitine; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Drug Resistance; Helium; Humans; Laser Therapy; Middle Aged; Neon; Phenothiazines

In anesthetized rats, GABA 10 mg.kg-1 iv delayed the onset of ventricular premature (VP) (P less than 0.01) and ventricular tachycardia (VT) (P less than 0.01) and reduced the incidence of ventricular fibrillation (VF) (P less than 0.05). The anti-arrhythmic effects of GABA remained after cervical vagotomy, iv hexamethonium 10 mg.kg-1 or destruction of CNS. It was also seen on pithed rats. In Langendorff heart, GABA 100 mg.L-1 elevated the threshold doses of aconitine required to induce VT (P less than 0.01), VF (P less than 0.01), and heart stop (HS) (P less than 0.01). These results suggest that iv GABA counteracts aconitine-induced arrhythmia directly on the heart, not related to the neural regulation.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; gamma-Aminobutyric Acid; Hexamethonium Compounds; Male; Rats; Vagotomy

LG 6-101 (1-[3-(2-methoxy-3-(2-methylpropylamino)-propoxy)-4-methyl- 2-thienyl]-3-phenyl-1-propanon hydrochloride; MW: 426.02) and LG 6-102 (2-(2-methoxy-3-propylamino-propoxy)-3-phenyl-propiophenon hydrochloride; MW: 391.92) are two new antiarrhythmic substances. They are structurally related to propafenone which is a widely used class Ic-antiarrhythmic drug. In man the oral bioavailability of propafenone is only about 5-40%. Therefore the development of compounds with similar mode of action but higher oral bioavailability seems to be meaningful. Both, LG 6-101 and LG 6-102 proved to be effective in isolated auricles and in experimental animals after intravenous administration. In the present study we tested the antiarrhythmic effects of LG 6-101 and LG 6-102 in rats after oral administration. Animals were treated with LG 6-101 (16, 32, 64, 128, 256 mg kg-1 bodyweight), LG 6-102 (4, 8, 16, 32, 64 mg kg-1 bodyweight) and propafenone (32, 64, 128, 256 mg kg-1 bodyweight) by gavage twice daily during 4 days. Both, LG 6-101 and LG 6-102 showed strong antiarrhythmic effects against arrhythmias induced on the fifth day by infusion of aconitine (10 micrograms kg-1 min-1). LG 6-102 was significantly more effective against cardiac arrest caused by infusion of aconitine (P less than or equal to 0.05) than LG 6-101. Both substances had good effects on the delay of ventricular premature beats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aconitine; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biological Availability; Heart Arrest; Male; Propafenone; Rats; Rats, Inbred Strains

Anisodamine (Ani) is an alkaloid first isolated in China from the root of Anisodus tanguticus. Ani 10, 15 mg.kg-1 i.v. markedly shortened the duration of arrhythmias induced by aconitine (10 micrograms.kg-1 i.v.) or by BaCl2 (2 mg.kg-1 i.v.) in anesthetized rats. Ani significantly effected on arrhythmias induced by early coronary artery ligation in rats by reducing total numbers of ectopic beats and shortening the duration of ventricular tachycardia and ventricular fibrillation 30 min after coronary ligation. The incidence of ventricular fibrillation of mice induced by chloroform were reduced from 100% to 20% and 10% by i.v. Ani 1 and 10 mg.kg-1 respectively. Ani 0.05, 0.25 mumol.L-1 prolonged the duration of neurologic refractory period of isolated guinea pig left atria and 10 mg.kg-1 i.v. had no effect on tachycardia induced by i.v. isoproterenol (0.01 mg.kg-1) but blocked the stimulation of nervi vagus. After i.v. Ani 15 mg.kg-1 P-P, P-R and QT-c intervals on the ECG were prolonged. Mean arterial pressure and diastolic pressure were reduced but systolic pressure was not effected.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Barium; Barium Compounds; Chlorides; Female; Guinea Pigs; In Vitro Techniques; Male; Mice; Rats; Refractory Period, Electrophysiological; Solanaceous Alkaloids

Data are reported of a study of the efficacy of membrane-stabilizing antiarrhythmic agents--ethmosin, ethacisin, allapinin. The latter was used in the treatment of 85 patients with arrhythmias of different etiology and proved more effective as compared with ethmosin and ethacisin. In ventricular extrasystole the effect was favourable in 86%, in supraventricular--in 70% of patients.

Topics: Aconitine; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Drug Evaluation; Electrocardiography; Humans; Middle Aged; Moricizine; Phenothiazines; Remission Induction

The synthesis of esters derived from 7-(diphenylmethylene)bicyclo[2.2.1]heptan-2-endo-ol, obtained by LiAlH4 reduction of 7-(diphenylmethylene)bicyclo[2.2.1]heptan-2-one, is described. Some of these esters showed an appreciable antiarrhythmic activity in rats, as well as moderate hypotensive and local anesthetic activities in rats and mice, respectively.

Topics: Aconitine; Anesthesia; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Esters; Heart Rate; Humans; Magnetic Resonance Spectroscopy; Mice; Norbornanes; Rats; Reaction Time; Spectrophotometry, Infrared

The aim was to investigate the antiarrhythmic effects of (+)- and (-)-naloxone in various arrhythmia models in vivo.. Naloxone (1-40 mg.kg-1), naltrexone (20-40 mg.kg-1), or standard antiarrhythmic drugs (quinidine, lignocaine, phenytoin, (+)-sotalol) were injected intravenously. Ventricular extrasystoles were then elicited by infusion of either ouabain (guinea pigs) or aconitine (rats), or by electrical stimulation (guinea pigs).. Male Wistar rats and guinea pigs (n = 6-10) were used. Arterial blood pressure and ECG were recorded continuously.. Naloxone and naltrexone decreased the heart rate. The effect of naloxone was not stereospecific and is apparently not mediated by opioid receptors. Naloxone had no influence on ouabain induced arrhythmias or fibrillation threshold in guinea pigs. The appearance of aconitine induced extrasystoles was accelerated by 20 mg.kg-1 (-)-naloxone but delayed by 40 mg.kg-1. No effects were seen with (+)-naloxone or (-)-naltrexone.. The results show that naloxone does not possess prominent antiarrhythmic properties.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Depression, Chemical; Guinea Pigs; Heart Rate; Male; Naloxone; Naltrexone; Ouabain; Rats; Stereoisomerism

LG 6-101 (1-[3-(2-methoxy-3-(2-methylpropylamino)-propoxy)-4-methyl- 2-thienyl]-3-phenyl-1-propanone, hydrochloride) and LG 6-102 (2-(2-methoxy-3-propylamino-propoxy)-3-phenyl-propiophenone, hydrochloride) are two new antiarrhythmic drugs. They are structurally related to propafenone which is a widely used class 1 antiarrhythmic drug with relatively low bioavailability. Both substances were characterized in four animal models of arrhythmia and compared to propafenone. In isolated guinea pigs left auricles LG 6-101 and LG6-102 were about twice as effective as propafenone regarding the prolongation of the functional refractory period but did not decrease contractility more than propafenone. LG 6-101 was significantly more effective (p less than or equal to 0.002) than propafenone or LG 6-102 in delaying the onset of ventricular premature beats in ouabain induced arrhythmias in guinea pigs. In aconitine induced arrhythmias in rats, LG 6-101 and LG 6-102 did not differ in their antiarrhythmic effects from propafenone, whereas the protection against cardiac arrest was significantly (p less than or equal to 0.003) better for LG 6-101 than for propafenone or LG 6-102. In arrhythmias induced by occlusion of the left descending coronary artery in rats the drugs tested showed as good antiarrhythmic effects as propafenone. In this model the size of the ischemic area was also measured and LG 6-101 was the most effective drug in that respect. These results suggest that both LG 6-101 and LG 6-102 are potent antiarrhythmic substances which in some models were more effective than propafenone.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Female; Guinea Pigs; Heart; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Ouabain; Propafenone; Rats; Rats, Inbred Strains; Refractory Period, Electrophysiological

The authors summed up the practical experience gained in long-term maintenance treatment with allapinine, a new Soviet antiarrhythmic agent, given to 65 patients with various cardiac arrhythmias in the outpatient setting. The long-term allapinine use yielded good results: its efficacy was proved to be approximately equal (63% and 60%) in patients with ventricular or supraventricular extrasystoles, respectively, but it was 77% in those with paroxysmal atrial fibrillation. There were no decreases in antiarrhythmic activity of allapinine during its long-term therapy. The agent produced no significant effects on heart rate, blood pressure, and myocardial contractility. Its side effects were recorded in 17 (26.2%) patients, however, withdrawal of the agent was required only in 6 cases.

Topics: Aconitine; Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Female; Humans; Male; Middle Aged; Time Factors

Matrine (MT) is an alkaloid isolated from Sophra alopecuroids L. The LD50 of MT iv to mice was 72.1 mg/kg (95% CL 68.2-76.5 mg/kg). MT had significant effects on different experimental models of arrhythmias induced by aconitine, barium chloride or coronary ligation. The ECG of anesthetized rats was significantly changed after iv of MT. The HR was retarded and the PR and QTc intervals were prolonged.

Topics: Aconitine; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Chlorides; Female; Heart Rate; In Vitro Techniques; Male; Matrines; Muscle Contraction; Quinolizines; Rats

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Cats; Chlorides; Coronary Circulation; Drugs, Chinese Herbal; Female; Guinea Pigs; In Vitro Techniques; Male; Rats

Experiments were conducted to compare the anti-arrhythmic effects of the four kinds of Qianghuo(Notopterygium incisum; N. forbesii; Pleurospermum rivulorum; Angelica silvestris). It has been found that all the four kinds of Qianghuo can antagonize arrhythmia induced by aconitine. Notopterygium incisum can prolong the ventricular vibration induced by CaCl2 and Pleurospermum rivulorum can prolong the ventricle stop induced by BaCl2. Thus Qianghuo can be used as a sedative and anti-arrhythmic drug.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Calcium Chloride; Chlorides; Drugs, Chinese Herbal; Male; Rats

The antiarrhythmic effect of Shuiqin (Oenanthe javanica) injection was studied in rats. An injection of 3 ml/kg iv could significantly antagonize the arrhythmias induced by aconitine and BaCl2, and decrease the rates of ventricular fibrillation and death induced by CaCl2. The results suggest that Shuqin injection has a significant antiarrhythmic effect on experimental rats.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Calcium Chloride; Chlorides; Drugs, Chinese Herbal; Female; Injections, Intravenous; Male; Rats; Ventricular Fibrillation

Topics: Aconitine; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Exercise; Heart; Humans; Male; Middle Aged

The arrhythmias induced by chloroform-epinephine, BaCl2, and aconitine were prevented and antagonized by Ophiopogon total saponins (OTS) which were extracted from the root of Ophiopogon japonicus (Thunb) Ker-Gawl. The incidence of ventricular arrhythmia produced by ligation of the left anterior descending coronary artery was effectively decreased without any changes in the hemodynamic indices of dogs. The electrophysiological effects of OTS in vivo and in vitro were studied by means of contact electrode and intracellular microelectrode techniques. The results showed that OTS shortened APD10, APD50, APD90; decreased APA and Vmax of both monophasic and transmembrane action potentials. OTS also increased the ERP/APD ratio and prevented or abolished the arrhythmikinesis provoked by ouabain and aconitine. The anti-arrhythmic properties of OTS lead us to draw an inference that the anti-arrhythmic mechanism may be related to the blocking of sodium and calcium channels.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Barium; Barium Compounds; Chlorides; Chloroform; Drugs, Chinese Herbal; Female; In Vitro Techniques; Male; Rabbits; Rats; Saponins

The antiarrhythmic activity of IST was studied on some experimental models of cardiac arrhythmia--caused by adrenaline in rats, caused by barium in non-narcotized rabbits, caused by strophanthin in guinea pigs, caused by aconitine and calcium in rats. Rhythmic disturbances were recorded by a 12-channel polyphysiograph "Galileo" or a single-channel electrocardiograph "Cardiomat". The obtained results showed that IST manifested antiarrhythmic activity in respect to adrenaline, barium and strophanthin arrhythmias without affecting substantially aconitine and calcium arrhythmias. It is thought that antiarrhythmic activity of IST, found in the indicated experimental models of cardiac arrhythmias, is most probably connected with a lowering of the peripheral sympathetic activity, realized by a central way.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Aporphines; Arrhythmias, Cardiac; Barium; Barium Compounds; Calcium; Chlorides; Disease Models, Animal; Drug Evaluation, Preclinical; Epinephrine; Guinea Pigs; Male; Mice; Rabbits; Rats; Strophanthins

Putrescine, (150-300 mg kg-1 i.v.) injected into anaesthetized rats reversed aconitine-induced arrhythmia and restored sinus rhythm. In the same experimental model, quinidine and lignocaine had a transient therapeutic effect, procainamide was practically ineffective and verapamil worsened the aconitine arrhythmia, causing the death of all treated animals. These data demonstrate that putrescine has an antiarrhythmic effect in an experimental model particularly resistant to usual antiarrhythmic treatments.

Topics: Aconitine; Aconitum; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Injections, Intravenous; Putrescine; Rats; Rats, Inbred Strains

The administration of 65% alcohol extracts of Cordyceps sinensis can counteract the arrhythmias induced by aconitine or BaCl2 in rats, and increase the tolerant dose of ouabain to produce the arrhythmias in guinea pigs. The drug can reduce the heart rate of anesthetic rats, decreasing the contractility of isolated papillary muscle or atria in guinea pigs, but showing no effect on the automatic rhythmicity and the functional refractory period of the atria.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Chlorides; Drugs, Chinese Herbal; Female; Guinea Pigs; Hypocreales; In Vitro Techniques; Lepidoptera; Male; Myocardial Contraction; Ouabain; Rats; Rats, Inbred Strains

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Exploratory Behavior; Learning; Male; Rats; Time Factors

Topics: Aconitine; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Mexiletine; Middle Aged; Moricizine; Phenothiazines; Propranolol

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drugs, Chinese Herbal; Female; Guinea Pigs; Male; Mice; Rats; Solubility; Ventricular Fibrillation

The effect of allapinin on atrioventricular conductivity was assessed at intracardiac electrophysiologic investigation in 11 patients with various heart rhythm disorders. The effect of a 30 mg intravenous dose of the drug was evaluated 60 min after the injection. Allapinin significantly lengthened the P-Q interval and expanded the QRS complex. The effect was associated with a 24% increment in the P-A interval, a 7% increment in the A-H interval and a 31% increment in the H-V interval, suggesting that allapinin can be regarded as belonging to the first class of antiarrhythmic agents by Vaughan Williams' classification. Allapinin also shortened effective refractory time of the atrium and the atrioventricular node, as well as the total refractory period of the His-Purkinje system. Ventricular refractory periods were also shortened insignificantly. The drug is therefore assumed to have a vagolytic or, perhaps, sympathomimetic action.

Topics: Aconitine; Aconitum; Adolescent; Adult; Arrhythmias, Cardiac; Atrioventricular Node; Drug Evaluation; Electric Stimulation; Female; Heart Conduction System; Humans; Male; Middle Aged

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Chloride; Cats; Chick Embryo; Culture Techniques; Cymarine; Guinea Pigs; Indomethacin; Myocardial Contraction; Rats

Antiarrhythmic effects of AHR 10718 were examined using two-stage coronary ligation, digitalis and adrenaline-induced canine ventricular arrhythmias and aconitine-induced canine atrial arrhythmia. The minimum effective plasma concentration for each arrhythmia model was determined for quantitative analysis of the antiarrhythmic effects. AHR 10718 suppressed the above arrhythmias except for adrenaline-induced arrhythmia. The minimum effective plasma concentrations for arrhythmias induced by 24 hr coronary ligation, 48 hr coronary ligation and digitalis were 8.1 +/- 0.7 (by 10 mg/kg, i.v.), 2.9 +/- 0.9 (by 5 mg/kg, i.v.) and 2.8 +/- 0.6 (by 5 mg/kg, i.v.) microgram/ml, respectively (mean +/- S.D., n = 6). The correlation coefficients between the antiarrhythmic effects of AHR 10718 and its plasma concentrations were not high. This pharmacological profile is characteristic of class 1 Na channel blockers, and in particular, it is similar to those of disopyramide, procainamide and SUN 1165 from our previous studies. AHR 10718 is expected to become a clinically useful antiarrhythmic drug.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Digitalis Glycosides; Dogs; Epinephrine; Female; Heart Atria; Heart Rate; Heart Ventricles; Male; Phenylurea Compounds

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.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disopyramide; Dogs; Epinephrine; Female; Guinea Pigs; Male; Mice; Ouabain; Propanolamines; Species Specificity

The effect of antiarrhythmic drugs, ritmilen and allapinin, on endogenic prostanoid and cyclic nucleotide levels was examined in patients with heart rhythm disorders. Intravenous administration of antiarrhythmic agents is shown to be accompanied with increased release of prostacyclin that has antiarrhythmic properties into myocardial outflow. Both ritmilen and allapinin promoted the predominance of prostacyclin over thromboxane, with its intrinsic arrhythmogenic properties. Ritmilen- or allapinin-induced changes in prostaglandins E and F2 alpha consisted in that PGE prevailed, as compared to PGF2 alpha. There were no significant changes in cyclic nucleotide ratios (cAMP/cGMP) in response to treatment.

Topics: Aconitine; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cyclic AMP; Cyclic GMP; Dinoprost; Disopyramide; Female; Humans; Male; Middle Aged; Nucleotides, Cyclic; Prostaglandins; Prostaglandins E; Prostaglandins F; Stimulation, Chemical

The effect of Ritmilen and allapinin, a new Soviet antiarrhythmic drug, on hemodynamics and myocardial contractility were evaluated in 36 patients with various heart rhythm disorders during diagnostic coronary angiography. Ritmilen has been shown to have an essential cardiodepressive effect. An intravenous 150 mg dose of Ritmilen results in a depression of dp/dtmax, Veragut's index, ejection fraction, mean standard circular fibre shortening rate, and increase in left ventricular systolic and end diastolic pressure, total peripheral resistance and mean arterial blood pressure. Allapinin (30 mg) has no marked cardiodepressive effect, as compared to Ritmilen.

Topics: Aconitine; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Depression, Chemical; Disopyramide; Drug Evaluation; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction

The present study suggests that a diminished level of HDL is connected with an enhanced susceptibility to arrhythmogenic stimuli only in rats pretreated with a diet deficient in polyunsaturated fatty acids (PUFA), but not after a PUFA-rich or pellet diet. The endogenous level of total cholesterol did not influence the thresholds for ventricular flutter or ventricular fibrillation in aconitine-induced arrhythmia in rats or in ouabain-induced arrhythmia in guinea pigs.

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Cholesterol; Cholesterol, HDL; Fatty Acids, Unsaturated; Guinea Pigs; Ouabain; Rats; Rats, Inbred Strains

Aconitine will induce arrhythmias after the fiber has been completely repolarized. This arrhythmia is generally facilitated in the presence of high Ca2+ solution, yet the aconitine-induced arrhythmia occurs even in the presence of low Ca2+ solutions. We studied aconitine-induced arrhythmia (particularly the amplitude of delayed afterdepolarization) in the frog atrium or guinea-pig papillary muscles in Ca2+-free solution, in the presence or absence of Ca2+ channel blocking agents. In Ca2+-free solution, aconitine (10(-5) g/ml) decreased the resting potential, overshoot, Vmax, and shortened the duration of the 90% action potential, before the onset of delayed afterdepolarization in frog atrial preparations. Tetrodotoxin (TTX) (2 X 10(-7) g/ml) blocked these aconitine-induced electrical changes. Verapamil (10(-6) g/ml) in nominally Ca2+-free solution blocked neither the generation of delayed afterdepolarization nor the triggered activity, while LaCl3 (0.5 mM) or TTX halted it. Delayed afterdepolarization appeared following the aconitine-induced transient increase in twitch tension. This transient increase in twitch tension was blocked by LaCl3 and TTX but not by verapamil. Delayed afterdepolarization in Ca2+-free solution demonstrated the voltage dependence of a U shape between -40 and -80 mV and was inhibited by low Na+ and high K+. Under the influence of aconitine in the guinea pig papillary muscle exposed to the Ca2+-free solution, depolarizing clamp pulses produced a transient inward current, and here the sigmoid time- and voltage-dependent characteristics were similar to those seen in the case of digitalis intoxication. These results suggest that intracellular Na+ loading plays an important role in the aconitine-induced delayed afterdepolarization and transient inward currents in low Ca2+ solution.

Topics: Aconitine; Aconitum; Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Guinea Pigs; Heart; Heart Atria; Membrane Potentials; Myocardium; Rana catesbeiana; Tetrodotoxin

The antiarrhythmic activities of AN-132, 3-(diisopropylaminoethylamino)-2',6'-dimethylpropionanilide X 2H3PO4, compared with three reference drugs, were examined in several arrhythmic models of rats, guinea-pigs and dogs. When compared on a weight basis, AN-132 given in oral or i.v. route proved to be more potent and longer-acting than disopyramide, propaphenone and mexiletine against supraventricular and ventricular arrhythmias induced by chloroform, aconitine, ouabain and halothane-adrenaline.

Topics: Aconitine; Anilides; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chloroform; Disopyramide; Dogs; Epinephrine; Ethylenediamines; Female; Guinea Pigs; Halothane; Male; Mexiletine; Ouabain; Propafenone; Rats; Rats, Inbred Strains

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; Heart; Male; Ouabain; Rats; Rats, Inbred Strains

Trapidil and some selected derivatives of trapidil were investigated in ouabain induced arrhythmia in guinea-pigs and in aconitine induced arrhythmia in rats. In both models trapidil exerted a marked antiarrhythmic effect. Investigations on ouabain induced arrhythmia showed that three derivatives were more effective than trapidil concerning the threshold for premature ventricular beats and flutter. One derivative only was able to decrease the sensitivity for fibrillation in the same order of magnitude as trapidil. On aconitine induced arrhythmia all derivatives of trapidil were less effective in elevating the threshold of arrhythmia than trapidil itself, but three derivatives showed antiarrhythmic properties.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; Male; Propranolol; Pyrimidines; Rats; Strophanthins; Trapidil

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cimetidine; Diphenhydramine; Female; Guinea Pigs; Histamine H2 Antagonists; Male

The effects of two histamine H2-receptor antagonists, ranitidine and cimetidine, on ventricular arrhythmias induced by acute coronary artery ligation and by aconitine infusion were studied in pentobarbitone-anaesthetized rats. The changes in arterial blood pressure and heart rate were also observed. It was found that both drugs significantly reduced the incidence, and prolonged the time of onset, of ventricular tachycardia and ventricular fibrillation following acute coronary artery ligation; however, they did not significantly alter the incidence or time of onset of ventricular dysrhythmias caused by aconitine infusion. These findings further support the hypothesis that histamine release may contribute to the genesis of early ventricular arrhythmias resulting from acute myocardial ischaemia. Since the decreased blood pressure induced by coronary artery ligation was not significantly prevented by pretreatment with either histamine H2-receptor blocker, this suggests that histamine may not be responsible for the blood pressure changes during acute myocardial ischaemia.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Blood Pressure; Cimetidine; Coronary Vessels; Heart Rate; Heart Ventricles; Male; Ranitidine; Rats; Rats, Inbred Strains

BW A256C (5(3)-amino-6-(2,3-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2 -isopropyl-1,2,4-triazine) is a novel class 1 antiarrhythmic agent designed to combine the features of potency with reduced central nervous system penetration. BW A256C reduced the maximum rate of depolarization of guinea-pig ventricle and dog Purkinje fibres in vitro (EC50, 2.2 X 10(-6) M and 1.8 X 10(-6) M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine-induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses. In anaesthetized dogs, intravenous administration of BW A256C (0.25-1 mg kg-1) caused a dose-dependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery. In conscious dogs, intravenous infusion (total dose, 1.5 mg kg-1) or oral administration of BW A256C (1.25-5 mg kg-1) caused dose-dependent suppression of the ventricular ectopic activity that occurred following 20-24 h of permanent coronary artery ligation. In the conscious dog, BW A256C was approximately 7 times more potent and was also longer acting than flecainide. Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3-4 times greater than the antiarrhythmic levels were associated with a proarrhythmic activity.

Topics: Aconitine; Action Potentials; Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Electrocardiography; Female; Guinea Pigs; In Vitro Techniques; Male; Membrane Potentials; Rats; Rats, Inbred Strains; Time Factors; Triazines

AD6 is a coumarinic derivative which increases both coronary blood flow and prostacyclin production, while it decreases platelet responsiveness. We tested its action on experimental cardiac arrhythmias. AD6 (2.5-10 mg/kg) was able to antagonize the arrhythmogenic action of aconitine in rats and of adrenaline in cats. AD6 action was also tested in vitro. The drug (20-50 microM) prolonged the functional refractory period of guinea-pig atrial and ventricular muscle and lengthened the refractory period shortened by hypoxia. Intracellular electrophysiological experiments showed that AD6 prolongs action potential duration (APD) of guinea-pig atrial myocardium, sino-atrial node and cat Purkinje fibers. The results obtained in vitro may explain the effect on experimental arrhythmias, therefore suggesting a protective action on cardiac rhythm disturbances.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Cats; Chromonar; Coumarins; Epinephrine; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Myocardial Contraction; Rats; Rats, Inbred Strains; Sinoatrial Node

The antiarrhythmic activity of iprindole was compared to that of imipramine in a variety of experimental arrhythmia models. Iprindole at 20 mg/kg i.v. showed efficacy in reverting ouabain- and aconitine-induced arrhythmias in pentobarbital anesthetized dogs, and at 15-30 mg/kg i.v. reduced the severity of the ventricular arrhythmias following acute coronary artery occlusion in anesthetized pigs. Imipramine (5-10 mg/kg i.v.) was also effective in reverting ouabain- and aconitine-induced arrhythmias, but appeared to exacerbate arrhythmias during coronary occlusion. In microelectrode experiments on isolated dog Purkinje fibers, iprindole reduced maximal upstroke velocity (Vmax) and action potential duration (characteristics of Class Ib antiarrhythmic agents) at concentrations greater than 1 microgram/ml. Significant decreases in Vmax occurred at lower iprindole concentrations when membrane potential was reduced by increasing external potassium from 4 to 10 mM, suggesting that electrical activity in depolarized cells may be selectively suppressed by iprindole. The present data indicate that iprindole may exert beneficial therapeutic effects in the treatment of cardiac arrhythmias, mediated, at least in part, through a Class I mechanism of action.

Topics: Aconitine; Action Potentials; Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Female; Indoles; Iprindole; Kinetics; Male; Ouabain; Purkinje Fibers; Swine

Antiarrhythmic and antifibrillation properties of bonnecor, a derivative of dibenzepin, were studied in comparison with ethmozine, quinidine and novocainamide, using various experimental arrhythmia models. Bonnecor activity was somewhat smaller than that of ethmozine, and much greater than that of quinidine and novocainamide in the mixed atrioventricular arrhythmia model simulated in aconitin-treated rats and the ventricular arrhythmia model simulated by two-degree coronary occlusion in dogs. Intravenous 1 mg/kg and oral 6 mg/kg bonnecor doses prevented ventricular fibrillation caused by acute coronary occlusion in rats, while ethmozine showed no such effect.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dibenzazepines; Dogs; Drug Evaluation, Preclinical; Guinea Pigs; Heart Rate; In Vitro Techniques; Rabbits; Rats; Strophanthins; Structure-Activity Relationship

Topics: Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Barium; Barium Compounds; Chlorides; Female; Guinea Pigs; Heterocyclic Compounds; Iodine; Male; Mice; Ouabain; Rabbits; Rats

The effects of an ethanol extract of the plant Sophora flavescens Ait. on cardiac arrhythmias induced by coronary artery ligation in rats, and by aconitine infusion in mice, were studied. Pretreatment with intravenous injection of the extract, 120 mg/kg, significantly reduced the incidence and delayed the onset of ventricular tachycardia in rats subjected to ligation of the left coronary artery. The time of onset of both initial cardiac arrhythmias and persistent ventricular tachycardia induced by aconitine infusion in mice was also significantly prolonged. These preliminary findings suggest that the ethanol extract of Sophora flavescens Ait. possesses antiarrhythmic activity.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Ligation; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Mice; Mice, Inbred ICR; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred Strains

The change in endogenous antiarrhythmic peptide (AAP) levels in serum, heart and kidney from rats under several drug-induced arrhythmias was investigated using a sensitive and specific radioimmunoassay. The extracts from serum, heart and kidney were fractionated by Sephadex G-25 chromatography to obtain a fraction which was found at the same position as that of synthetic AAP. In serum, the immunoreactive (IR)-AAP level increased about threefold under CaCl2-, aconitine- and epinephrine-induced arrhythmias. In heart, the IR-AAP level was doubled by CaCl2, increased 1.4 times by aconitine and decreased by one third by epinephrine. The levels in serum and heart were slightly increased by ADP. The kidney IR-AAP level was not changed under these drug-induced arrhythmias. Considering the previous result that AAP could protect against CaCl2- and aconitine-induced arrhythmias but not against epinephrine-induced arrhythmia, the change in the IR-AAP level in heart coincided with the effect of AAP given to animals under arrhythmia. Quinidine, propranolol and verapamil had no effect on serum IR-AAP level. These results suggested that endogenous AAP in heart worked to suppress certain arrhythmia.

Topics: Aconitine; Adenosine Diphosphate; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Chloride; Epinephrine; Oligopeptides; Radioimmunoassay; Rats

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; Dogs; Guinea Pigs; Humans; Ion Channels

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Myocardium; Propranolol; Rats; Swine

In comparison with detajmium, prajmalium, ajmaline, quinidine, lidocaine, disopyramide, propranolol, and Ethmozin the substance GS 015 is tested on the aconitin-induced arrhythmia of the rat, the auricular fibrillation by aconitin of the dog, the ventricular arrhythmia induced by ouabaine of the dog, the arrhythmia caused by calcium chloride of the rat, and the arrhythmia induced by barium chloride of the rabbit. The particular qualities of effect in the special forms of arrhythmia are discussed in connection with the study of the antiarrhythmic action in case of coronary occlusion, with the increase of the electric fibrillatory threshold, and with the electrophysiologic tests.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Calcium Chloride; Chlorides; Dibenzazepines; Dogs; Heart Rate; Ouabain; Rabbits; Rats; Strophanthidin

The method for inducing arrhythmias or asystole by the application of a 50 Hz alternating current (ac) has been applied to isolated guinea-pig left atria and papillary muscles in order to characterize arrhythmogenic and antiarrhythmic substances. Aconitine, BaCl2 (less than 2 mmol/l) and hypoxia decrease threshold of ac-arrhythmia and ac-asystole, in both tissues to a similar extent, whereas carbachol and BaCl2 (greater than 2 mmol/l) increase threshold. The calcium antagonists nifedipine and diltiazem lower threshold of ac-asystole but differ with respect to threshold of ac-arrhythmia, which is increased by 10(-6) mol/l diltiazem in left atria and papillary muscles by about 30% and remains nearly unaffected with nifedipine. The Na+-inhibitory substance flecainide reverses the decrease in threshold of ac-arrhythmia and ac-asystole brought about by aconitine. Threshold of ac-arrhythmia lowered by hypoxia is increased by diltiazem in a concentration-dependent manner, whereas decrease of threshold of ac-asystole is even augmented. Therefore, the method offers an opportunity of quantifying the action of arrhythmogenic agents at concentrations which are too low to induce arrhythmia, as well as to characterize the activity of antiarrhythmic drugs in the presence of arrhythmogenic substances.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Calcium Channel Blockers; Carbachol; Chlorides; Electric Stimulation; Guinea Pigs; Heart Atria; Hypoxia; In Vitro Techniques; Isoproterenol; Male; Papillary Muscles; Receptors, Cholinergic

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Chlordiazepoxide; Dogs; Injections, Intravenous; Injections, Intraventricular; Lanatosides

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Blood Pressure; Cats; Female; Heart Rate; Lethal Dose 50; Male; Mice; Myocardial Contraction; Rats; Structure-Activity Relationship

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cimetidine; Female; Guanidines; Guinea Pigs; Heart; In Vitro Techniques; Male; Ouabain; Rabbits; Rats; Refractory Period, Electrophysiological

Topics: Aconitine; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chloroform; Female; Guinea Pigs; Isoquinolines; Male; Mice; Ouabain; Rats; Selenious Acid; Selenium

Comparative study of antiarrhythmic properties of marcaine and lidocaine was made on aconitine- and strophanthine-induced experimental arrhythmias and in rhythm disorders induced by electrical stimulation of the ventricles. Marcaine (5 mg/kg) prevented the development of rhythm disorders induced in rats by intravenous injection of aconitine (40 micrograms/kg) and also raised the arrhythmogenic dose of strophanthine (ouabain) in guinea-pigs. Administration of marcaine to anesthetized cats in a dose of 2 mg/kg reduced the assimilation of the rhythm imposed on the heart ventricles at the expense of an increase in the effective refractory period and increased the threshold of electrical fibrillation of the ventricles more noticeably and for a longer time as compared with lidocaine administered in a dose of 5 mg/kg. Marcaine compares very favourably with lidocaine as regards the potency and duration of the antiarrhythmic effect. However, it is inferior to lidocaine from the standpoint of the therapeutic action range. Toxic effects of marcaine do not make clear the prospects of its clinical use as an antiarrhythmic drug. Nevertheless the search of new effective antiarrhythmic drugs among marcaine analogs holds promise.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bupivacaine; Cats; Electric Stimulation; Guinea Pigs; Lethal Dose 50; Lidocaine; Male; Mice; Ouabain; Rats

Possible antiarrhythmic activities of 5-methyl-7-diethylamino-s-triazolo(1,5-a)pyrimidine (trapidil, Rocornal) were investigated in vitro and in vivo. Trapidil significantly increased the amount of aconitine or ouabain needed for production of ventricular arrhythmias in rats and guinea pigs. Trapidil also produced a significant increase in threshold current of electrical stimuli which induced ventricular tachycardia in dogs under acute myocardial ischemia. Electrophysiological examinations on effects of trapidil on isolated rabbit ventricular muscle cells showed shortening of the action potential duration (APD) and prolongation of the effective refractory period (ERP), resulting in an increase in the ratio of ERP/APD. The results indicate that trapidil will have a possible effectiveness in inhibiting ventricular arrhythmias.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Dogs; Electric Stimulation; Electrophysiology; Female; Male; Ouabain; Pyrimidines; Rats; Rats, Inbred Strains; Trapidil

Antiarrhythmic actions of lorcainide were compared with those of disopyramide on different types of arrhythmias in animal models. It was shown in dogs that lorcainide and disopyramide were approximately equipotent against the arrhythmias following coronary occlusion. In guinea pigs, lorcainide was less effective than disopyramide against the ouabain-induced arrhythmia. Both drugs showed a weak protective action against the aconitine-induced ventricular arrhythmias, but had no effect on the cardiac arrest. In the arrhythmias induced by the application of acetylcholine on the right auricle of guinea pigs, the disappearance of P-waves and the disturbance of R-R intervals were inhibited by disopyramide, but lorcainide had no influence on these events; both prevented the atrial fibrillation induced by acetylcholine application. Both drugs by themselves induced ventricular arrhythmias in guinea pigs.

Topics: Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Coronary Vessels; Disopyramide; Dogs; Female; Guinea Pigs; Ligation; Male; Ouabain; Piperidines

With the aim of finding an antidysrhythmic agent suitable for intravenous or oral administration we have examined a range of steroids carrying basic substituents. The primary screen involved control of cardiac dysrhythmias induced by intravenous infusion of aconitine into pentobarbitone-anaesthetised artificially-respired rats. The best activity was found among a series of 11 alpha-alkylamino steroids and structure-activity studies included modification of the alkylamino group and variation of substituents in ring A and at the 17-position. Good oral and intravenous activity was found among 17 beta-methoxycarbonyl-5 alpha-androstanes and methyl 2 beta-ethoxy-3 alpha-hydroxy-11 alpha-(3-methylbutylamino)-5 alpha-androstane-17 beta-carboxylate hydrochloride (CCI 22277) was selected for more detailed pharmacological study.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Heart; Male; Rats; Steroids; Structure-Activity Relationship

Topics: Aconitine; Aconitum; Action Potentials; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Heart; In Vitro Techniques

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Chlorides; Dogs; Female; Guinea Pigs; Heart; In Vitro Techniques; Ion Channels; Male; Manganese; Manganese Compounds; Valinomycin; Ventricular Fibrillation

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.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dinoprost; Dinoprostone; Epoprostenol; Female; Male; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Blood Pressure; Cimetidine; Dogs; Heart; Heart Rate; Injections, Intraventricular; Propranolol; Pyrilamine; Receptors, Histamine

The 2-n-propyl- and 2-n-butyl-3-dimethylamino-5,6-methylenedioxyindene hydrochlorides are intracellular calcium antagonists with coronary dilating and antiarrhythmic effects against ouabain- and calcium-induced arrhythmias. In the present study, pretreatment with these tertiary methylenedioxyindenes afforded significant protection against the calcium-dependent arrhythmias induced by chloroform in mice. On the other hand, their antiarrhythmic activity against aconitine- and methacholine-induced arrhythmias in rats (in which calcium does not play a primary etiological role) was suggestive but not impressive. The quaternary derivative, 2-n-butyl-5,6-methylenedioxy-3-trimethylammonium iodide, which was synthesized with the expectation of being devoid of antiarrhythmic activity owing to its exclusion from the intracellular compartment, unexpectedly demonstrated greater antiarrhythmic potency than the tertiary analogues against calcium-induced arrhythmias in rats and chloroform-induced arrhythmias in mice. Like the tertiary methylenedioxyindenes, the protective activity of the quaternary analogue against arrhythmias induced by aconitine or by methacholine in rats was suggestive but not impressive. Because of the relative inactivity of the quaternary methylenedioxyindene in vitro, it is proposed that its in vivo activity may be due either to metabolic activation or to concentration in cardiac tissue in sufficient quantity to allow diffusion into cardiac cells down a concentration gradient or to alter membrane electrophysiological properties to the extent of exerting antiarrhythmic activity.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Chloroform; Indenes; Male; Methacholine Compounds; Rats; Rats, Inbred Strains

In anaesthetized open-chest dogs, cardiac arrhythmias (CA) were induced by cumulative intravenous doses of aconitine or ouabain. Aconitine in a dose which did not induce CA had no influence on the PGE and PGF2 alpha effluxes into coronary sinus blood (CSB), whereas the PGE efflux into CSB increased after a subtoxic dose of ouabain. However, both PGE and PGF2 alpha effluxes were increased, when CA had developed. During aconitine induced CA, the PGE efflux was 6.5-fold and that of PGF2 alpha had increased by 80%. During ouabain induced CA, the effluxes of both PGs were about 3-fold. Propranolol and lidocaine decreased the PGF2 alpha efflux into CSB by about 50% and the PGE efflux was doubled after lidocaine and decreased after propranolol by about a third. The increased PGE efflux into CSB during CA was normalized after propranolol and quinidine if the CA was abolished or the cardiac rhythm improved. Lidocaine did not modify the increase in PGE efflux, despite the abolishment of CA. The increase in PGF2 alpha efflux was not influenced by antiarrhythmic drugs. The cyclic AMP and cyclic GMP in CSB remained unchanged during ouabain induced arrhythmias or after propranolol. The increased efflux of PGE into CSB during aconitine and ouabain induced CA and its abolishment by propranolol support the hypothesis that PGE participates in the modulation of increased sympathetic tone during CA.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Cyclic AMP; Cyclic GMP; Dinoprost; Dogs; Female; Male; Ouabain; Prostaglandins; Prostaglandins E; Prostaglandins F

Topics: Aconitine; Aconitum; Alkaloids; Animals; Arrhythmias, Cardiac; Blood Pressure; Female; Male; Mice; Rats; Structure-Activity Relationship

Topics: Aconitine; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Benzylisoquinolines; Calcium Chloride; Female; Guinea Pigs; Male; Ouabain; Rabbits; Rats

Topics: Aconitine; Adult; Aged; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Chloride; Carbamazepine; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Male; Middle Aged; Rats

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium; Disease Models, Animal; Female; Male; Manganese; Metals; Mice; Verapamil

The antidysrhythmic effects of a new antianginal agent, bepridil, were compared with those of disopyramide, a known antidysrhythmic drug. Bepridil (20, 50, and 100 mg/kg, i.p.) conferred little protection against aconitine-induced dysrhythmias in mice, whereas similar doses of disopyramide exerted a marked dose-dependent antidysrhythmic effect. Intravenous administration of either bepridil (2 mg/kg) or disopyramide (10 mg/kg) significantly reduced the number of ventricular extrasystoles and completely abolished the occurrence of ventricular fibrillation following coronary artery ligation in the rat. Local anesthetic and electrophysiological effects in vitro of bepridil were also investigated. A marked but slowly developing reduction in action potential height of desheathed frog sciatic nerves was observed at concentrations of 0.01-0.05 mM. In sheep Purkinje fibres, a similar decrease in action potential height, associated with a pronounced reduction in the maximum rate of depolarization of phase zero of the action potential (MRD) was seen with bepridil (0.5-2 X 10(-5) M). Higher concentrations (2-8 X 10(-5) M) were required to reduce MRD of guinea pig ventricular muscle. The antidysrhythmic actions of bepridil may at least in part be explained by the electrophysiological effects observed.

Topics: Aconitine; Action Potentials; Anesthesia; Angina Pectoris; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bepridil; Coronary Vessels; Dose-Response Relationship, Drug; Hemodynamics; In Vitro Techniques; Ligation; Male; Mice; Purkinje Fibers; Pyrrolidines; Rats; Rats, Inbred Strains; Sheep

The present study was undertaken in order to investigate the possibility of cardiac hypersensitivity to norepinephrine (NE) after propranolol withdrawal in rats. The effect of NE was studied on heart rate and left intraventricular pressure development (maximal dP/dt) in the isolated perfused heart at various time periods after termination of the propranolol feeding. Also, the influence of propranolol withdrawal on vulnerability to aconitine-induced arrhythmias in vivo was evaluated in anesthetized rats. No hypersensitivity to NE was seen in the perfused rat heart 1 and 3 days after propranolol withdrawal. Rather, a depressed response to NE was registered suggesting a long half-life for the disappearance of beta adrenoceptor blockade. Increased vulnerability to aconitine-induced arrhythmias was observed 1 and 3 days after treatment with propranolol had ceased. Rats receiving propranolol continuously until experimentation exhibited an elevated threshold to aconitine-induced arrhythmias. These data indicate that a hypothetical rebound phenomenon after withdrawal of propranolol is not associated with an increase in mechanical performance of the heart in response to NE. A decreased threshold for development of arrhythmias appears, however, to be at hand, perhaps due to an inbalance in the transmembrane sodium flux in the heart in the early time course after propranolol withdrawal.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Body Weight; Eating; Heart; Humans; Male; Norepinephrine; Organ Size; Propranolol; Rats; Receptors, Adrenergic; Receptors, Adrenergic, beta; Substance Withdrawal Syndrome

In guinea-pig Langendorff hearts, a benzotriazinium derivative, 2-n-propyl-4-p-tolylamino-1,2,3-benzotriazinium iodide (TnPBI), increased the ventricular refractory period, increased the ventricular fibrillation threshold to electrical stimulation and converted persistent ventricular fibrillation to sinus rhythm. TnPBI also converted aconitine-induced tachyarrhythmias to sinus rhythm in the same preparation. In mice pretreated with TnPBI, both acutely and chronically, the amount of intravenous aconitine necessary to produce cardiac arrhythmias was increased. In guinea-pigs anaesthetised with halothane. TnPBI converted adrenaline-induced arrhythmias to sinus rhythm.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Epinephrine; Female; Guinea Pigs; Halothane; In Vitro Techniques; Male; Mice; Quinidine; Triazines; Ventricular Fibrillation

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Digoxin; Dogs; Female; Glycogen; Male; Myocardium; Phosphorylases

Topics: Aconitine; Action Potentials; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Epinephrine; Female; Heart Conduction System; Hemodynamics; Male; Ouabain; Piperidines; Time Factors; Ventricular Fibrillation

1 Antagonism of aconitine-induced dysrhythmias in mice as a method of detecting and assessing antidysrhythmia activity was evaluated. 2 Aconitine-induced dysrhythmias in mice appear to be selectively sensitive to antidysrhythmia agents (administered intraperitoneally) which reduce the inward sodium current in cardiac cells. 3 Antidysrhythmic agents whose mechanism of action is thought to depend on beta-adrenoceptor blockade, prolongation of cardiac monophasic action potentials or calcium antagonism are ineffective in delaying the onset of aconitine-induced dysrhythmias in mice. The inactive drugs were practolol, sotalol, bretylium, amiodarone and verapamil. 4 Comparisons of anti-dysrhythmic activities of test drugs should be based on more than one ED value and should take account of efficacy as well as potency. 5 The mouse aconitine test is a useful and rapid method of evaluating oral antidysrhythmic activity in terms of potency, efficacy and duration of action. 6 With respect to potency, efficacy, oral activity, duration of action and safety, 3 alpha-amino-5 alpha-androstan-2 beta-ol-17-one hydrochloride (Org 6001) offered the most satisfactory overall profile of the active drugs tested (Org 6001, aprindine, quinidine, disopyramide, lignocaine, mexiletine, procainamide and propranolol).

Topics: Aconitine; Aconitum; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Evaluation, Preclinical; Injections, Intraperitoneal; Mice

Topics: Acetylcholine; Aconitine; Adrenergic beta-Antagonists; Animals; Arrhythmias, Cardiac; Dogs; Female; Heart Atria; Male

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cinchona Alkaloids; Male; Mice; Quinidine

The beta-blocking, antiarrhythmic, and local anesthetic effects of the racemic mixture and optical isomers of bucumolol, 5-methyl-8-(2-hydroxy-3-t-butylamino-propoxy) coumarin hydrochloride, were studied in dogs, guinea-pigs and frogs. In blocking the positive chrontropic response to isoproterenol, the levo-isomer of bucumolol was about 40 times more potent in dogs, and 270 times in guinea-pigs than its dextro-isomer and twice as effective in both species as the racemic mixture. In frog sciatic nerves bucumolol was 1/10-1/15 as potent in local anesthetic action as propranolol on a weight basis. Dextro- and levo-isomers and racemic bucumolol neither elevated electrical threshold for propagated impulses nor prolonged the effective refractory period of the dog right atrium. The levo-isomer and racemic bucumolol were capable of suppressing aconitine-induced atrial arrhythmia, while the dextro-isomer was less effective. Both isomers and racemic bucumolol were capable of reversing ventricular arrhythmia caused by ouabain, but the effective dose of the levo-isomer was significantly less than that of the dextro-isomer. The results suggest that both specific beta-blocking activity and non-specific membrane action of bucumolol suppressed experimental arrhythmias in dogs produced by aconitine and ouabain.

Topics: Aconitine; Aconitum; Adrenergic beta-Antagonists; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Anura; Arrhythmias, Cardiac; Coumarins; Dogs; Female; Guinea Pigs; Heart Atria; Heart Rate; Heart Ventricles; In Vitro Techniques; Isoproterenol; Male; Ouabain; Propanolamines; Propranolol; Quinidine; Refractory Period, Electrophysiological; Stereoisomerism; Stimulation, Chemical; Structure-Activity Relationship

Intracerebroventricular administration of PGI2 or PGE2 reduced aconitine-induced cardiac arrhythmia in rats. PGF2 alpha had no antiarrhythmic effect under the same conditions. The ED50 values of PGI2 and E2 were 0.25 microgram/kg and 1.1 microgram/kg, respectively. Central mechanisms may participate in the antiarrhythmic effect of these PGs.

Topics: Aconitine; Aconitum; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Brain; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Epoprostenol; Female; Heart Rate; Injections, Intraventricular; Male; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats

The synthesis of 6'-hydroxycinchonine [8R,9S)-cinchonan-6',9-diol] was achieved by demethylating quinidine with boron tribromide in dichloromethane at -75 degrees C. The antiarrhythmic activities of 6'-hydroxycinchonine and quinidine were compared following the infusion of aconitine into the tail veins of mice to induce arrhythmias. Comparative ED50 and LD50 studies for quinidine and 6'-hydroxycinchonine revealed equivalent antiarrhythmic potencies for the two drugs but a smaller acute toxicity for 6'-hydroxycinchonine.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cinchona Alkaloids; Mice; Quinidine

The effects of lithium on the time to onset of aconitine-induced initial arrhythmia and onset of ventricular tachycardia were determined in mice. The mice were pretreated intraperitoneally with 1.73, 3.0, 5.1 and 8.8 mEq lithium chloride/kg/day for 5 days, or 8.8 mEq LiCl/kg/day i.p. for 1, 3, 5, 7 and 10 days. Lithium prolonged the onset-time to ventricular tachycardia, and this effect was both dose and time dependent. Under these conditions, lithium pretreatment had no effect on the time to onset of aconitine-induced initial arrhythmia. The LD50 was 15.3 mEq/kg. The observed prolongation of the onset of ventricular tachycardia can be explained in part by the influence of lithium on myocardial cations and catecholamines, and the pharmacologic effect of lithium on Purkinje fibers.

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Drug Interactions; Heart Ventricles; Lethal Dose 50; Lithium; Mice; Tachycardia; Time Factors

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Lidocaine; Pyrrolidines; Quinazolines; Rats; Sciatic Nerve

The activity of N-methyl-N-(beta-hydroxyethyl)guanidine O-phosphate (creatinol O-phosphate, COP) on two in vitro and in vivo experimental arrhythmias was investigated. The substance proved to be active in delaying the onset time of aconitine induced arrhythmias in guinea-pig atria. COP showed also a definite antagonizing activity against chloroform-induced ventricular fibrillation in mice.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chloroform; Creatine; Guinea Pigs; Humans; In Vitro Techniques; Male; Prenylamine; Quinidine; Ventricular Fibrillation

Involuntary ingestion of 3 mg of aconitine induces in a young woman multifocal extrasystoles and alternating periods of sinusal rhythm and junctional arrhythmia. The rhythmogenetic abnormalities disappear spontaneously within two hours. The physiopathology of arrhymias due to aconitine is discussed.

Topics: Aconitine; Aconitum; Adult; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Electroencephalography; Female; Humans

Calcification of the aorta and the coronary vessels as well as metastatic calcification of the heart muscle in the rat was produced by daily oral administration of 300,000 i.u. vitamin D2/kg for 6 consecutive days. E.C.G. tracings showed different pathological conditions. The response of the cardiovascular system to certain arrhythmogenic substances, e.g. aconitine and CaCl2 was generally reduced in comparison to non-treated rats.

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Arteriosclerosis; Calcinosis; Calcium Chloride; Electrocardiography; Ergocalciferols; 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.

Topics: Aconitine; Animals; Arrhythmia, Sinus; Arrhythmias, Cardiac; Epoprostenol; Female; Heart; Male; Prostaglandins; Rats

Prilocaine, a synthetic tertiary amine with local anesthetic properties, suppressed aconitine-induced atrial and ventricular arrhythmias in the cat. In normal animals, prilocaine decreased the heart rate. In the group of successfully treated arrhythmic cats as well as in normal animals, the drug increased the blood pressure, while the equally effective antiarrhythmic drug, lidocaine, did decrease blood pressure.

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Blood Pressure; Cats; Electrocardiography; Heart Rate; Lidocaine; Prilocaine

The neuroleptic butyrophenone, melperone, has been compared with antiarrhythmics, neuroleptics, alpha-blockers and beta-blockers in various experimental arrhythmias. Melperone 0.01--1 mg/kg intravenously antagonized ouabain-induced arrhythmias in conscious rabbits to the same degree as propranolol 2 mg/kg and quinidine 10 mg/kg intravenously probably mainly via s CNS depressive effect. It was found to be considerably weaker than propranolol 2 mg/kg, when anaesthetized guinea pigs were used. Melperone 0.1--10 mg/kg was inactive against aconitine-induced arrhythmias. Melperone 1--5 mg/kg antagonized adrenaline-induced arrhythmias in halothane-sensitized guinea pigs like phentolamine 1--5 mg/kg intravenously and was more potent than chlorpromazine, propranolol and quinidine. This study and an electrophysiological study suggest that melperone might be a type III anti-arrhythmic drug, which at the same time depresses CNS and reduces afterload.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Butyrophenones; Droperidol; Epinephrine; Guinea Pigs; Lidocaine; Male; Ouabain; Piperidines; Procainamide; Propranolol; Quinidine; Rabbits; Rats

Lorcainide hydrochloride or N-(4-chlorophenyl)-N-[1-(1-methyl-ethyl)-4-piperidinyl]benzeneacetamide mono-hydrochloride (R 15889) is a new anti-arrhythmic drug. Studies in dogs show that lorcainide is effective against post-infarction and ouabain-induced ventricular arrhythmias, and abolishes acetylcholine and aconitine-induced atrial fibrillation; it elevates the threshold of electrically induced ventricular fibrillation. In isolated dog and cow Purkinje fibers, in dog ventricular and in guinea-pig auricular muscle preparations, lorcainide decreases the rate of rise of the transmembrane action potential, the conduction velocity and spontaneous activity. It prolongs the refractory period of isolated Purkpinje and ventricular muscle preparations, and the functional refractory period of the AV node in the guinea-pig heart. It has no effect on Ca mediated electrical activity. Isometric force measurements in isolated cat papillary muscles and hemodynamic studies in anaesthetized and unanaesthetized dogs indicate that lorcainide moderately decreases myocardial contractility. Side effects observed at large doses are of central origin and include salivation, tremor and vomiting. Intravenous injection induces transient peripheral vasodilatation. Lorcainide is an antiarrhythmic of the local anaesthetic type. It is characterized by a good oral absorption, a long duration of action and a large safety factor.

Topics: Acetamides; Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cats; Cattle; Coronary Vessels; Dogs; Electrocardiography; Female; Guinea Pigs; Heart; Hemodynamics; In Vitro Techniques; Ligation; Male; Membrane Potentials; Myocardial Contraction; Ouabain; Piperidines; Refractory Period, Electrophysiological

Some dihydro- and hexahydro-2-dialkylaminoalkyl-9-phenyl-1H-indeno[2,1-c]pyridines were prepared and found to possess significant antiarrhythmic activity. Hydrogenation of the dihydro compounds 4 produced the allcis-hexahydro isomers 5 which were consistently active in three assays against induced ventricular arrhythmias. On the other hand, the H9H9a-trans isomers, which were obtained by basic equilibration of the cis isomers, were less effective.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Dogs; Female; In Vitro Techniques; Indenes; Ligation; Male; Ouabain; Pyridines; Rabbits; Structure-Activity Relationship

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium; Coronary Circulation; Electric Stimulation; Epinephrine; Guinea Pigs; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Myocardial Contraction; Myocardium; Ouabain; Time Factors

A novel benzanilide derivative, MJ 9067, has been shown to abolish experimental atrial and ventricular arrhythmiase effectively and promote the return of normal sinus rhythm in a variety of animal models. At intravenous dose levels ranging from 0.5 to 3.2 mg/kg, MJ 9067 successfully converted atrial fibrillation induced by either local application of aconitine or electrical stimulation, and ventricular tachycardia elicited by intravenous injection of ouabain or digoxin. The compound was equally effective in vagotomized or nonvagotomized dogs, and in intact cats and monkeys. The ventricular ectopic rate in conscious dogs 18 to 20 hours after two-stage ligation of a coronary artery was also markedly reduced by the drug at 2 mg/kg i.v. At antiarrhythmic dose levels, there were no undesirable effects noted on peripheral blood pressure, heart rate or the configuration of the electrocardiogram.

Topics: Aconitine; Anilides; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Blood Pressure; Cats; Digoxin; Dogs; Electric Stimulation; Electrocardiography; Female; Haplorhini; Heart Rate; Male; Ouabain; Piperidines; Saimiri; Tachycardia

Results of the pharmacological investigation of a new antiarrhythmic drug are presented. In the isolated guinea pig ileum the substance of the procainamide-quinidine type reveals strong activity in prolonging the relative refractory period. The safety index as to antiarrhythmic and negative-inotropic properties in relatively high. In the aconitine arrhythmia of the rat the substance is effective after i.v. or oral administration. Furthermore, in these experiments it shows a long-lasting action with these two modes of application. From experimental data in the conscious and anesthetized dog the oral efficacy can also be derived. An oral dose of the new substance for the first application in humans is proposed which refers to its pharmacological activity compared with procainamide and to the human dose of this latter substance.

Topics: Aconitine; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Drug Evaluation, Preclinical; Guinea Pigs; Heart Conduction System; Humans; Injections, Intravenous; Myocardial Contraction; Rats; Refractory Period, Electrophysiological

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Dogs; Female; Injections, Spinal; Male; Spinal Cord

Verapamil 0.25-1.0 mg/kg i.v. did not significantly elevate the ventricular fibrillation threshold in dogs. It did not antagonize the deslanoside arrhythmias, but inhibited transiently the arrhythmias induced by either electrical stimulation of the posterior hypothalamus or bilateral carotid occlusion in cats. Effect of verapamil on the aconitine-induced rapid firing of the isolated atria and ventricles of the young rabbit and chick embryos was also studied with the microelectrode technique. In doses of 5, 10 and 20 microng/ml, it suppressed the rapid firing of the cardiac preparations, with exception of the ventricles of the rabbit. Antiarrhythmic action of verapamil in such high concentration seems to be due to non-specific inhibitions of Na+ channels of the myocardial cells.

Topics: Aconitine; Action Potentials; Animals; Arrhythmias, Cardiac; Carotid Arteries; Cats; Chick Embryo; Deslanoside; Dogs; Electric Stimulation; Female; Heart; Hypothalamus; In Vitro Techniques; Male; Microelectrodes; Rabbits; Ventricular Fibrillation; Verapamil

A comparison was made between the effects of quinidine and quinine on experimental arrhythmias and on cardiac electrophysiologic parameters. Both drugs raised ventricular fibrillation thresholds, reversed aconitine-induced atrial fibrillation, decreased ouabain-induced abnormal ventricular beats, and increased atrial refractory periods and His-Purkinje conduction time. In contrast, only quinidine antagonized acetylcholine-induced atrial fibrillation. In addition, quinidine increased ventricular fibrillation thresholds and atrial refractory periods for a longer time period than quinine. These observations are discussed in terms of choosing an appropriate model for testing new compounds with suspected quinidine-like activity.

Topics: Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Bundle of His; Cats; Dogs; Electric Stimulation; Female; Heart Ventricles; Male; Neural Conduction; Ouabain; Purkinje Fibers; Quinidine; Quinine; Refractory Period, Electrophysiological; Time Factors; Ventricular Fibrillation

Antiarrhythmic property of a new adrenergic beta-blocking agent, dl-1-(tert.butylamino)-3[(2-propinyloxy) phenoxy]-2-propanol hydrochloride (Kö 1400-Cl) was studied, using 1) ouabain-induced arrhythmia in the guinea pig, 2) aconitine-induced arrhythmia in the rat, 3) arrhythmia induced by two-step ligation of coronary artery (Harris's method) in the dog and 4) halothane-adrenaline arrhythmia in the dog and was compared with those of propranolol, oxprenolol, procainamide and ajmaline. Procainamide and ajmaline produced a marked protective effect against aconitine-induced ventricular extrasystole, but were not so effective against aconitine-induced ventricular fibrillation, while oxprenolol and, to a lesser degree, propranolol were effective against the latter type of aconitine arrhythmias. Kö 1400-Cl proved to be ineffective. All the compounds tested produced a marked protective action against ouabain-arrhythmia. Whereas procainamide was most effective in abolishing the ventricular arrhythmia due to coronary-ligation even on the first postoperative day, Kö 1400-Cl and propranolol were almost ineffective on the first day. Even on the second postoperative day, the antiarrhythmic effects of these two beta-blockers were not remarkable, effective only in 2/4 animals in the case of Kö 1400-Cl and in 2/3 animals in the case of propranolol. On the contrary, all the beta-blockers tested produced a protective action against halothane-adrenaline arrhythmia at much lower doses than against coronary ligation arrhythmia. The potency ratio of Kö 1400-Cl and propranolol was 3 : 1, which paralleled with beta-blocking activity of these compounds.

Topics: Aconitine; Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Epinephrine; Female; Halothane; Ligation; Male; Ouabain; Rats

Intravenous application of arachidonic and linoleic acid induced strong antiarrhythmic effects demonstrated on three models of experimental arrhythmias. In contrast, linolenic and oleic acid were poorly effective. The antiarrhythmic action of the unsaturated fatty acids required 10- to 1000-fold higher doses in comparison with the most effective prostaglandins. Indomethacin decreased the antidysrhythmic action of arachidonic and linoleic acid; PG efficiency remained unaffected. Polyphloretinphosphate markedly reduced the improvement of aconitine arrhythmia by PGs, the decrease of the antidysrhythmic effects of arachidonic and linoleic acid was without statistical significance. The results suggest an important role of PG synthesis for the antiarrhythmic effect of polyunsaturated fatty acids.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arachidonic Acids; Arrhythmias, Cardiac; Barium; Fatty Acids; Female; Indomethacin; Linoleic Acids; Linolenic Acids; Male; Oleic Acids; Ouabain; Phloretin; Polyphloretin Phosphate; Prostaglandins; Rabbits; Rats

1. The relationship of antiarrhythmic to inotropic activity of the optical isomers of verapamil was studied by comparing their effects on functional refractory period and force of contraction in the isolated left atrium of the guinea pig and on maximum follow frequency and contractility in the dog heart. To evaluate the antiarrhythmic profile of the optical isomers of verapamil the relationship between threshold voltage and impulse duration in the left atrium of the guinea pig and the antagonistic action against ventricular arrhythmias in the rat were studied. 2. (-)Verapamil is nearly 10 times more effective than (+)verapamil in prolonging the functional refractory period in the isolated left atrium of the guinea pig. 3. In the dog heart (-)verapamil is about 8 times more active in reducing a maximum follow frequency at atrial pacing, as well as spontaneous heart rate and in prolonging PQ-duration. 4. In the guinea pig atrium (+)verapamil shows less negative inotropic activity than its enantiomorph. With (+)verapamil the concentration producing a 25% decrease in contractility is 3.7 times higher than that causing a 25% increase in refractory period. With (-)verapamil these concentrations are identical. 5. In the dog i.v. infusion of the isomers, at a dosage inducing identical reduction of maximum follow frequency, is accompanied by a decrease in left ventricular dp/dtmax with (-)verapamil, whereas with the (+)isomer a significant increase of dp/dtmax is observed at a certain dose level. 6. Because of the higher antiarrhythmic activity of (-)verapamil, the antiarrhythmic profile and the inotropic pattern of the racemic compound are mainly due to this isomer. 7. (+)Verapamil shifts the voltage duration curve of the isolated left atrium of the guinea pig to the right and leads to a significant increase in the chronaxie value. (-)Verapamil has no comparable effects on the excitability of the atrial myocardium. 8. In the intact animal (+)verapamil shows additional antiarrhythmic qualities. Like procainamide, but with higher activity, it antagonizes ventricular arrhythmias (ectopic beats, automaticity and flutter or fibrillation) which can be provoked in the rat by i.v. infusion of aconitine. (-)Verapamil and the racemic compound are ineffective against these ventricular rhythm disorders.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Chronaxy; Dogs; Female; Guinea Pigs; Heart Conduction System; Heart Ventricles; Male; Myocardial Contraction; Rats; Refractory Period, Electrophysiological; Stereoisomerism; Verapamil

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.

Topics: Aconitine; Aconitum; Ajmaline; Animals; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Electrocardiography; Guinea Pigs; Heart; Heart Atria; Heart Rate; In Vitro Techniques; Male; Myocardial Contraction; Rats; Tachycardia; Ventricular Fibrillation

Topics: 17-Ketosteroids; Aconitine; Androstanes; Androstanols; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Dogs; Heart Rate; Hydroxysteroids; Lidocaine; Ligation; Male; Myocardial Contraction; Ouabain; Rats

1. The aminosteroid Org. NA13 (3alpha-dimethylamino-5alpha-androstan-2beta-ol-17-one) was shown to be a more potent local anaesthetic than lignocaine in rats and guinea-pigs. 2. Experimental arrhythmias induced in mice by chloroform, in rats by aconitine and in dogs by coronary artery ligation were corrected by Org. NA13 at doses from 10 to 50 mg/kg intravenously. 3. In contrast to lignocaine, other local anaesthetics and beta-adrenoceptor blocking drugs, Org. NA 13 did not show any activity against the arrhythmias induced by ouabian in dogs. 4. The acute toxicity in whole animals and myocardial toxicity in the rabbit isolated atrium appeared to be less than that observed with lignocaine.

Topics: Acetylcholine; Aconitine; Androstanes; Anesthesia, Conduction; Anesthetics, Local; Animals; Arrhythmias, Cardiac; Chloroform; Coronary Vessels; Dimethylamines; Dogs; Dose-Response Relationship, Drug; Eye; Guinea Pigs; Heart; Lethal Dose 50; Lidocaine; Mice; Myocardial Contraction; Ouabain; Rabbits; Rats; Sciatic Nerve

Topics: Aconitine; Adrenal Gland Diseases; Animals; Arrhythmias, Cardiac; Cardiovascular Diseases; Cats; Female; Male; Nervous System Diseases

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Calcium Chloride; Cats; Disease Models, Animal; Dogs; Female; Male; Prostaglandins; Prostaglandins A; Prostaglandins E; Prostaglandins F; Rabbits; Rats

Topics: Aconitine; Aminobenzoates; Anesthetics, Local; Animals; Arrhythmias, Cardiac; Heart; In Vitro Techniques; Lidocaine; Phenyl Ethers; Procaine; Rabbits; Sulfides

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Electrocardiography; Humans; Poisoning; Toxicology

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.

Topics: Acetylcholine; Aconitine; Aconitum; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Flutter; Atropine; Brugada Syndrome; Cardiac Conduction System Disease; Dogs; Electric Stimulation; Electrocardiography; Heart Atria; Heart Conduction System; Pharmacology; Research; Toxicology; Vagus Nerve

Topics: Acetylcholine; Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Brugada Syndrome; Cardiac Conduction System Disease; Heart; Heart Conduction System; Isoproterenol; Rabbits; Strophanthins; Sympatholytics

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Atrial Fibrillation; Brugada Syndrome; Cardiac Conduction System Disease; Heart Atria; Heart Conduction System

The arrhythmias observed in isolated rabbit atria appear to be due to two actions of aconitine. One is an apparent direct stimulant effect on the sino-atrial node and the other is a depressant effect on the processes involved in intra-atrial propagation of impulses. Acetylcholine has either an inhibitory or stimulatory effect on atria pretreated with aconitine because it antagonizes the actions of aconitine both on the sinus node and on conduction. When conduction block is not apparent, acetylcholine depresses the atrial rate. On the other hand, when conduction is markedly depressed, acetylcholine increases the atrial rate.

Topics: Aconitine; Alkaloids; Animals; Arrhythmias, Cardiac; Heart; Heart Atria; Heart Block; Heart Rate; Rabbits; Sinoatrial Node

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Brugada Syndrome; Cardiac Conduction System Disease; Heart Conduction System; Humans

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Brugada Syndrome; Cardiac Conduction System Disease; Heart Conduction System; Humans

Topics: Aconitine; Aconitum; Anesthesia; Anesthesia, Conduction; Animals; Arrhythmias, Cardiac; Brugada Syndrome; Cardiac Conduction System Disease; Heart Conduction System; Rabbits; Vagus Nerve

Topics: Aconitine; Aconitum; Arrhythmias, Cardiac; Humans

Topics: Aconitine; Arrhythmias, Cardiac; Atrial Fibrillation

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Brugada Syndrome; Cardiac Conduction System Disease; Heart; Heart Conduction System; Myocardium; Procaine; Quinolines

Topics: Aconitine; Arrhythmias, Cardiac; Cardiovascular Diseases; Humans; Phenethylamines; Procainamide; Tachycardia, Ventricular