Antiarrhythmic properties of estrogens.
Estrone, estriol, and estradiol valerate exhibited antiarrhythmic activity in rats with aconitine-induced arrhythmia. Estrone was most effective in this respect.
Animals↗
Biomedical subjects
N V Kaverina
Publications and source records attributed to N V Kaverina.
New aminocarboxamides with class III anti-arrhythmic activity.
In the search for new anti-arrhythmic substances we discovered the class III activity of aminocarboxamides. These compounds show a prolongation of the effective refractory period. With some of them the prolongation is more pronounced after faster than after slower stimulation of the guinea pig papillary muscle. They should therefore be of interest in the treatment of cardiac arrhythmias after myocardial infarction and atrial fibrillation. The chemical synthesis, the structure-activity relationships of the new derivatives, their efficacy on the action potential duration (APD) and the effective refractory period (ERP) in vitro of isolated guinea pig papillary muscles are described and discussed in this paper. Since AWD 160-275 (13) and AWD 23-111 (14) exerted a pronounced APD90 and ERP prolongation at faster stimulation, they were selected for further electrophysiological characterization in vitro and in vivo. Anti-arrhythmic and pro-arrhythmic effects were determined in several animal models in comparison with dofetilide, sematilide, and sotalol. 13 was found to be effective in preventing programmed electrical stimulation-induced arrhythmias in anaesthetized dogs and may therefore contribute to the therapy of dysrhythmias after myocardial infarction. The pro-arrhythmic effect of 14, investigated in a model of triggered activity in chloralose-anaesthetized rabbits under methoxamine infusion, is low in comparison with other class III anti-arrhythmics.
Action Potentials↗
[A new class-III antiarrhythmic preparation among the dicyclohexylamides of aminocarboxylic acids].
The Institute of Pharmacology, Academy of Medical Sciences, jointly with AWD (Germany) has synthesized and tested a novel class III antiarrhythmic coded AWD-160-275, a derivative of dicyclohexylamides of aminocarboxylic acids. The compound was shown to prolong cardiac repolarization, to increase atrial and ventricular refractory periods, to decrease sinus nodal automatism, and to unchange intraventricular conduction. The compound proved to be superior to the reference drugs in the rate and duration of antiarrhythmic and antifibrillatory action. In therapeutical doses it has no antiarrhythmic effect. The specific feature of the agent is that there is no relation of longer effective refractory periods to the frequency of stimulation. This property may be useful in treating tachyarrhythmias.
Action Potentials↗
New 5-aminoacyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones with antiarrhythmic activity.
A series of new 5-substituted tricyclic 5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepin-11-ones was identified as potential antiarrhythmic agents against bradyarrhythmias [1, 2]. The in vitro and in vivo interactions of the compounds with muscarinic receptors and the antiarrhythmic activity were examined. In receptor binding studies some derivatives showed a high affinity to the cardiac M2 receptor (Ki 10 nmol/l), an equal or smaller affinity to cortical M1 receptor and a lower affinity to the glandular M3 binding site. Functional experiments showed the derivatives as competitive antagonists with high affinity to the cardiac and smaller affinity to the intestinal muscarinic receptor. In vivo experiments correspond with the M2 selectivity. First the vagal or agonist-induced bradycardia was inhibited in rats and guinea pigs while the McNA-343 induced increase of blood pressure, methacholine-induced bronchi and bladder constriction as well as the salivation were inhibited only at higher doses. In conscious cats the tachycardia was examined in comparison with pupillomotoricity. The effect duration and the therapeutical range were determined in comparison to the M2 selective blocking agent AF-DX116. The antiarrhythmic activity was examined compared to quinidine sulfate in CaCl2-arrhythmia of rats, in atrial fibrillation and atrial flutter in dogs according to Scherf [2] and in electric induced atrial fibrillation under vagal stimulation in cats. In the atrial arrhythmias the derivatives are clearly longer effective than quinidine sulfate. The antiischemic activity was examined in the two-stages coronary ligature in dogs according to Harris. The long-running regularization of ectopies (about 2 h after i.v. injection) occurred without decrease of the heart rate, an effect particularly convenient to therapy of bradycardic dysrhythmias.
Animals↗
Pharmacology and clinical use of a new group of antiarrhythmic drugs: derivatives of tricyclic nitrogen-containing systems.
This paper is concerned with a new group of antiarrhythmic drugs: derivatives of phenothiazine and dibenzazepine which belong to tricyclic nitrogen-containing systems. It has been discovered that the transition from omega-aminoalkyl to omega-aminoacyl phenothiazine derivatives results in a decrease in psychotropic activity and an increase in cardiovascular, particularly antiarrhythmic, action. Based on structural and antiarrhythmic activity studies, the new and effective drugs ethmozine, ethacizine and bonnecor have been selected and extensively studied. Data on spectra and mechanisms of their action, obtained in different arrhythmia models, have been confirmed by clinical studies. Correlation between pharmacological properties and electrophysiological mechanisms, and differences in action of the drugs studied on brain and heart plasma membrane receptors may serve as a starting point for the further directed search for new antiarrhythmic drugs among tricyclic nitrogen-containing structures.
Animals↗
[Electrophysiologic study of the anti-arrhythmic mechanism of action of phosphocreatine in acute myocardial ischemia and reperfusion].
To determine the possible application of exogenous phosphocreatine (ePC) to protect the ischemic myocardium from reperfusion abnormalities in cardiac rhythm, the antiarrhythmic and antifibrillatory activities of the agent were studied in an acute myocardial ischemia model and reperfusion-induced cardiac damage. It was shown that ePC produced a pronounced antifibrillatory effect in acute coronary occlusion and subsequent reperfusion. The agent substantially increased the threshold of electric ventricular fibrillation and the frequency of spontaneous defibrillation. The highest activity was shown by ePC in ischemic myocardial reperfusion. The agent suppressed both rapid inward Na+ current and slow inward Ca2+ current. The effects of ePC on transmembrane ion currents suggest that the agent has a unique electrophysiological mechanism of action involving the properties of Classes I and IV antiarrhythmics, making ePC promising in clinical application in patients with impaired conduction and automatism.
Acute Disease↗
[Differences in the efficiency of their interaction with membrane receptors of the dialkylaminoalkyl and dialkylaminoacyl derivatives of phenothiazine].
New dialkylaminoacyl phenothiazine derivatives (DAC) were compared with their dialkylaminoalkyl analogues (neuroleptics chlorpromazine, trifluoperazine and fluphenazine) as well as with anti-arrhythmia drugs ethmozine and ethacizine for their receptor-blocking potencies. It was established that DAC are significantly less potent with dopamine alpha 1-adrenergic and H1-histamine receptors of calf and rabbit brain, which can explain the absence of neuroleptic effect of DAC drugs. DAC affinities to muscarinic and alpha-adrenergic receptors of both types are very similar to those of ethmozine and ethacizine. New DAC substance G-512 (chlorpromazine analogue) demonstrated high affinity to M1-muscarinic receptors of rabbit brain cortex (Ki = 4.2 nM) and to M2-muscarinic receptors of the rabbit heart (Ki = 48 nM).
Animals↗
Ultrastructure of Purkinje cells in the subendocardium and false tendons in early experimental myocardial infarction complicated by fibrillation in the dog.
The effect of regional myocardial ischemia complicated by ventricular fibrillation (VF) on the ultrastructure of subendocardial (SE) and false tendon (FT) Purkinje cells (PC) was studied in anesthetized dogs. In all cases of early ischemia with spontaneous VF, many PC exhibited ultrastructural damage as early as 2 min after the onset of ischemia. The changes noted were: intercalated disk dissociation, sarcoplasmic reticulum vacuolization (SRV), supercontraction, mitochondrial swelling, and sarcolemmal defects (rigor cells). The appearance of at least some rigor PC seemed to precede spontaneous VF, since these cells were absent from the conduction systems in control hearts in which VF was induced by electric shock or reperfusion, from hearts from sham-operated dogs, or from hearts subjected to longer periods of uncomplicated myocardial infarction. These observations indicate that alterations in SE and FTPC may play a role in the pathogenesis of sudden death due to early myocardial ischemia. The mechanism of this rapid damage of PC remains obscure.
Animals↗
Ethacizin metabolism in humans.
1. The major metabolites of ethacizin (ethyl 10-[3-diethylaminopropionyl]phenothiazine-2-carbamate) have been isolated from human urine by h.p.l.c. and identified by determination of u.v., i.r., n.m.r. and mass spectra and comparison with spectra of synthetic standard compounds. 2. The pathways of metabolism of ethacizin include N-de-ethylation, sulphoxidation, N-10 amide hydrolysis, aromatic hydroxylation and conjugation.
Anti-Arrhythmia Agents↗
Receptor binding potencies of chlorpromazine, trifluoperazine, fluphenazine and their 10-N-substituted analogues.
Receptor interactions of three pairs of phenothiazine derivatives, namely chlorpromazine, trifluoperazine, fluphenazine and their dialkylaminoacyl analogues were investigated. The data indicate that neuroleptic derivatives are less effective at dopamine (D2), alpha 1-adrenoceptors (AR) and histamine receptors (H1). No differences in affinity to alpha 2-AR were observed. The chlorpromazine analogue was more effective at muscarinic receptors of both types.
Animals↗
[Characteristics of the anti-arrhythmia effect of phosphocreatine in the acute stage of experimental myocardial infarction].
Antiarrhythmic and antifibrillatory effects of exogenous phosphocreatine, administered to animals at different dates after the onset of experimental myocardial infarction, were examined. Experiments were carried out on anesthetized dogs with acute one-step coronary artery ligation or in waking dogs 24 to 48 hours after two-step ligation of the descending branch of the left coronary artery (Harris's method). Major cardiac functional and hemodynamic parameters and ECG were recorded. The values obtained, using these models, show that exogenous phosphocreatine possesses high antiarrhythmic and antifibrillatory activities within first hours of coronary occlusion and is less effective after 24 hours of infarction.
Animals↗
[Effect of exogenous phosphocreatine on the size of experimental myocardial infarction].
The purpose of the study was to investigate the effect of exogenous phosphocreatine on the infarction size in experimental occlusion of a coronary artery. Experiments were carried out in anesthetized cats, in which the descending branch of the left coronary artery was ligated. Damaged zone was visualized by intravenous administration of fluorescent Thioflavin T dye. Tissue samples were taken from the heart 3, 6 and 72 hours after the ligation. Exogenous phosphocreatine was administered as a bolus injection (200 mg/kg body weight) 5 minutes before the ligation and was followed by continuous infusion for 3-6 hours at the rate of 5 mg/min/kg body weight. Administration of exogenous phosphocreatine remarkably decreased the size of severe and relative ischemia (by 37% and 71%, respectively, after 3 hours, and by 59% and 86%, respectively, after 6 hours). The size of the necrotic zone, determined after 72 hours, was decreased by 63% in the phosphocreatine experiments.
Animals↗
[Use of mathematical methods of analysis of ECG data for evaluating the effectiveness of treatment of alcoholic cardiomyopathies with preparations of the phenothiazine group].
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Adult↗
[Electrophysiologic research on the anti-arrhythmia properties of bonnecor--a new dibenzazepine derivative].
A new dibenzepin derivative, bonnecor, showed marked antiarrhythmic and antifibrillation properties in anesthetized cats. One and 2 mg/kg doses of the drug reduce cardiac assimilation of imposed ventricular electric stimuli, increase ventricular fibrillation threshold with a strong and lasting effect and prevent arrhythmias and fibrillation due to 10-minute occlusion and subsequent reperfusion of the anterior descending branch of the left coronary artery. Experimental holding of atrial trabecular membrane potential in a frog, in conditions of a double saccharose bridge, showed bonnecor, in 5 X 10(-7) and 1 X 10(-6) g/ml concentrations, to inhibit rapid sodium inflow and slow calcium inflow. It is expected that bonnecor can be used clinically to control critical arrhythmias and prevent sudden cardiac death.
Animals↗
[Current aspects of the search for and preclinical study of anti-arrhythmia agents].
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Animals↗
[Correlation between the anti-arrhythmia effect of ethacizin and pharmacokinetic parameters in a model of rhythm adoption by the heart].
Pharmacokinetics and pharmacodynamics of ethacizin were studied in a model of rhythm adoption by the heart, with the drug administered intravenously to anesthetized cats. A relation was demonstrated between blood ethacizin pattern and the drug's biphasic effect on the adoption of stimulation-imposed pace by the heart and ventricular fibrillation threshold. The estimated correlation coefficients, reflecting the relationship between the development of ethacizin anti-arrhythmic and antifibrillation effects and variation of its plasma levels between 10 and 120 min after the administration, were rather high (-0.85 and +0.93, respectively). Ethacizin shows anti-arrhythmic and antifibrillation activity when its plasma levels are between 2400 and 200 ng/ml.
Animals↗
[Anti-arrhythmia and antifibrillatory properties of dibenzazepine derivatives].
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.
Aconitine↗
[Ultrastructure of the Purkinje cells in the subendocardium and pseudo-tendons of the left ventricle in dogs with experimental infarct complicated by fibrillation].
Ultrastructural changes of Purkinje cells located on the periphery of the cardiac conductive system (subendocardium and false tendons) were studied in dogs in the presence of ventricular fibrillation developed in 30 minutes after coronary artery ligation. Ventricular fibrillation at the early stages of experimental myocardial infarction was invariably associated with the development of multiple ultrastructural lesions in the conductive Purkinje cells of subendocardium and false tendons. These changes are without any doubt important for the pathogenesis of ventricular fibrillation in myocardial infarction and they possibly take place in cases of sudden cardiac death.
Animals↗