[Afobazole effect on heart rate variability in rats with different behaviors in the "open field" test].

The course of cardiovascular diseases is known to depend upon vegetative nervous system condition. The heart rate variability is the quantitative indicator of vegetative nervous system activity. The emotional stress reaction in rats tested in the "open field" was assessed by measuring the heart rate variability, which allowed the chronotropic cardiac function to be studied in detail and showed which part of the vegetative system (either sympathetic or parasympathetic) prevails in animals with different phenotypes of the emotional stress reaction. In rats demonstrating different behaviors in the "open field" test, changes in the heart rate variability were examined under conditions of the emotional stress response development and the treatment with non-benzodiazepine anxiolytic afobazole. It was established that the sympathetic nervous system tone prevails in stress-resistant rats, whereas in non-resistant animals, the parasympathetic system is predominating. In non-resistant rats exposed to stress, the heart rate variability decreased due to reduced power of very low frequencies, in contrast to stress-resistant animals, which showed increased power of very low frequencies. Afobazole was found to increase the heart rate variability in both animal groups. In non-resistant rats, afobazole also raised the vagus tone.

[The role of vagal control in the action of propranolol on the chronotropic cardiac function].

The effects of propranolol on the heart rate variability was studied in anesthetized outbred male rats, to which the drug was administered as intracisternal and intraperitoneal injections. Propranolol was found to increase the power of low- and high-frequency components of the heart rate. In influencing the heart rate variability, propranolol has the central mode of action. It is suggested that the ability of propranolol to increase the power of the low and high frequency components of the heart rate is related to its enhancing effect on the central cardiac vagal control.

[Comparative study of the electrophysiological properties of class iii medicinals (cardiocyclide, nibentan, sotalol) and evaluation of their efficacy in atrial fibrillation produced by auricular and vagal stimulation].

The electrophysiological properties of cardiocyclide, nibentan and sotalol and their efficacy on a model of atrial fibrillation were compared in experiments in anaesthetized dogs. The electrophysiological parameters of drugs were investigated using the method of programmed electrical stimulation of myocardium on the background of excitation of the peripheral segment of the right vagus nerve with current pulses of increasing frequency. The atrial fibrillation was produced by short stimulation (10 pulses) of the right auriculum (10 Hz, 4 thresholds). Cardiocyclide was injected in a dose of 2.5-5.0 mg/kg; nibentan, 0.25 mg/kg; and sotalol, 2.5 mg/kg. Cardiocyclide was found to prevent vagotonic atrial fibrillation in 80% of cases; under vagal stimulation this drug maintained the electrophysiological attributes and exhibited the frequency-independent action inherent in this agent. Nibentan completely retained its ability to prolong the ventricular repolarization under vagal stimulation conditions, increased the effective atrial and ventricular refractory periods, and showed the ability to prevent and eliminate the vagotonic atrial fibrillation in 80-90% of cases. Under vagal stimulation, sotalol increased the repolarization and prolonged the effective refractory atrial and ventricular periods, reduced the heart rate, and suppressed the sinus node function. The action of sotalol was frequency-dependent. Sotalol was found to prevent the vagotonic atrial fibrillation in 60% of cases.

[Effect of the class III antiarrhythmic drug nibentan in vagotonic atrial fibrillation].

Nibentan, the class III antiarrhythmic drug, was experimentally investigated in anaesthetized dogs using the model of vagotonic atrial fibrillation. Under the conditions of vagus nerve stimulation, nibentan retained the ability to prolong the ventricular repolarization and increase the effective refractory periods and to maintain the frequency-independent action on the effective refractory periods of the atrium. At the same time, nibentan did not affect conduction via the His-Purkinje system and prevented bradycardia induced by vagus stimulation. The drug was found to depress the conduction in atrium, this effect being retained on the background of vagus nerve stimulation. Nibentan has proved to be effective in preventing the vagotonic atrial fibrillation.

[Effect of cardiocyclide on the electrophysiological parameters of heart in experiments with vagus nerve excitation in narcotized dogs].

The new class III antiarrhythmic agent cardiocyclide effectively suppresses atrioventricular fibrillations caused by the vagus nerve excitation in narcotized dogs. The electrophysiological effect of cardiocyclide was studied by method of programmed electric stimulation of myocardium on the background of excitation of the a peripheral segment of the right vagus by current pulses of increasing frequency. On this background, cardiocyclide exhibited characteristic effects manifested primarily in the repolarization and the AV node conduction. In addition, the drug eliminated suppression of the sinus and atrioventricular nodes and changes in the atrioventricular conduction caused by the vagus nerve. This drug effect was dose-dependent. The action of cardiocyclide in response to activation of the parasympathetic nervous system was independent of the frequency of the induced heart rate.

Ethmozine and ethacizine--new antiarrhythmic drugs with defibrillating properties.

Ventricular fibrillation (VF) is a life-threatening arrhythmia that leads to death unless electrical defibrillation is applied in time. Recent publications indicate that VF can be either sustained (SVF), requiring electrical defibrillation, or transient (TVF), reverting spontaneously into sinus rhythm. Since VF cannot be totally prevented by drugs, a new antiarrhythmic therapeutic approach has been proposed: drug-induced enhancement of the ability of the heart to defibrillate by itself. In this study we examined the defibrillating potency of two antiarrhythmic phenothiazines, ethmozine (ETM) and ethacizine (ETA), as well as their effects on catecholamine uptake and on the electrophysiological properties of the myocardial cell membrane. The antiarrhythmic-defibrillatory activity was examined in cats; the inhibitory effect on [3H]-norepinephrine (NE) uptake was examined in rat brain synaptosomes, and the electrophysiological membrane effects were examined by microelectrode recordings in perfused strips of heart ventricle from guinea-pigs. The results indicate that: 1. ETA exhibits similar but stronger antiarrhythmic-defibrillating and NE reuptake inhibitory effects than ETM; 2. ETA at 10-6 M decreases ventricular conduction time and increases Vmax while ETM at this concentration does not change them; 3. The defibrillating ability of the drugs can be related to their inhibitory potency on NE reuptake. We suggest that the risk of sympathomimetic arrhythmogenicity is prevented by the previously described, membrane stabilizing Class 1 antiarrhythmic properties of these drugs.

[Characteristics of the anti-arrhythmic action of 3-carbethoxyamino-5-dimethylaminoacetyl-imino-dibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015)]. / Besonderheiten der antiarrhythmischen Wirkung von 3-Carbethoxyamino-5-dimethylaminoacetyl-imino-dibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015).

The action of GS 015, a substance out of the series of the novel 5-(dialkyl-amino-acyl)-3-carbalkoxyamino-10,11-dihydro-5H-dibenz[b ,f]azepines, on the alteration of the bioelectric activity in the sympathetic nerves of the heart in case of disturbed cardiac rhythm and ventricular fibrillation was tested on anaesthetized cats. The arrhythmias were induced by two different methods: Artificial electric induction by high-frequency electrical stimulation of the ventricles, occlusion and reperfusion of the anterior descending branch of the arteria coronaria sinistra. GS 015 decreases the tonic bioelectric activity in the sympathetic nerves of the heart and prevents their activation in case of disturbed rhythm which is provoked or by electric stimulation or by occlusion of the coronary artery. With an electric stimulation of the ventricles GS 015, given at doses of 0.5, 1.0, and 2.0 mg/kg, decreases the maximally reproducible frequency in dependence on the dose, which corresponds to an increase of the effective refractory period. At the same time the fibrillation threshold of the ventricles is enhanced in a very intense and long-lasting manner excelling considerably the action of the reference preparations Ethmozin and lidocaine. It may be concluded from the present results that the antiarrhythmic and antifibrillatory effects of GS 015 are basing not only on its immediate action on the myocardial cell but also on a decrease of the activity in the sympathetic nerves of the heart.

[Circulatory action and adverse effects of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) in the dog and cat]. / Kreislaufwirkungen und Nebenwirkungen von 3-Carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015) an Hund und Katze.

The haemodynamic and cardiac effects of GS 015, a substance of the series of the novel 5-(dialkyl-aminoacyl)-3-carbalkoxyamino-10,11-dihydro-5H-dibenz-[b ,f]-azepines with very potent antifibrillatory and antiarrhythmic actions, are studied on anaesthetized dogs and cats by means of the catheter technique. The clinical symptoms and the therapeutic range were tested on conscious animals. On the strength of the present results it can be stated that GS 015, given at pharmacodynamically effective doses, does not cause any circulatory side effects. A negative inotropic effect appears only at increased doses. Like other antiarrhythmic drugs, GS 015 possesses a limited therapeutic range which should be taken into consideration particularly in case of cardiac insufficiency. But an application seems possible also in patients during the acute stage of myocardial infarction.

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.

[Antifibrillatory and anti-arrhythmic action of 3-carbethoxyamino-5-dimethylamino-acetyl iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) on models of myocardial ischemia]. / Antifibrillatorische und antiarrhythmische Wirksamkeit von 3-Carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015) an Modellen der Myocardischämie.

The intense antifibrillatory and antiarrhythmic actions of GS 015, a derivative of the novel structure series of the 5-(beta-aminoacyl)-3-carbalkoxyamino-iminodibenzyles, are demonstrated on models of myocardial ischaemia: antifibrillatory action on the acute coronary occlusion in the conscious rat (1.0 mg/kg i.v.) and antiarrhythmic action on the two-step coronary ligature in the conscious dog according to Harris (2.0 mg/kg i.v. and 5.0 mg/kg orally). On the strength of the present results it is discussed that GS 015 is first of all suitable for influencing "early arrhythmias" with re-entry mechanism and only in the second line for taking an influence on "late arrhythmias" which arise from the occurrence of ectopic focuses. The substance seems suitable for preventing terminal arrhythmias in patients with ischaemic heart disease as well as for treating arrhythmias in the acute stage of myocardial infarction.

[Pharmacokinetics and pharmacodynamics of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) in the cat]. / Pharmakokinetik und Pharmakodynamik von 3-Carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015) an der Katze.

The antiarrhythmic action of GS 015 was studied proportionally to its plasma concentrations ascertained in parallel, using the model of the electrofibrillation of the cat's heart. Blood levels of about 1.3 micrograms/ml after i.v. injection of 2 mg/kg caused a marked short-term increase of the fibrillation threshold which then remained at the increased level for a longer period yet, observing GS 015 concentrations between 0.8 and 0.5 micrograms/ml. Individual differences existed in the height of the blood level as well as in its proportion to the effect.

[Pharmacokinetics and pharmacodynamics of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) in the dog]. / Pharmakokinetik und Pharmakodynamik von 3-Carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015) am Hund.

The antiarrhythmic action of GS 015 was studied in proportion to its plasma concentrations ascertained in parallel, making use of the model of the two-step coronary ligature in the conscious dog. Blood levels of 1.0 microgram/ml (2 mg/kg i.v.) or of 0.8 microgram/ml (5 mg/kg orally) brought about a complete suppression of ectopic arrhythmias. The limit concentration for this effect is about 0.5 microgram/ml.

[Antiarrhythmic effectiveness of 3-carbalkoxyamino-5-(omega-aminoacyl)-10,11-dihydro-5H-dibenz-[b,f]- azepines]. / Antiarrhythmische Wirksamkeit von 3-Carbalkoxyamino-5-(omega-aminoacyl)-10,11-dihydro-5H-dibenz-[b,f]- azepinen.

The derivatives of a novel structure series of dibenzazepines dispose of intense antiarrhythmic properties. The relations between structure and effect in comparison with the antiarrhythmically active derivatives of phenothiazine (Ethmozine) are discussed. When substituting the beta-aminopropionyl chain with cyclic residue by means of a dimethylaminoacyl chain there appears a marked antifibrillatory action besides of the intense antiarrhythmic one. The compound 17, the 3-carbethoxyamino-5-dimethylaminoacetyl-dibenzazepine, proved to be the most efficacious compound in the course of the basic screening on two models: action on the effective refractory period in the rabbit's atrium and aconitin-induced arrhythmia in the conscious rat. In comparison with Ethmozin, an antiarrhythmic agent of the phenothiazine type, 17 shows a somewhat lower efficacy in case of i.v. application, but a distinctly intenser one was stated after oral administration. A profound test on the models: two-step coronary ligature in the dog according to Harris and electrofibrillation in the cat's heart, revealed an equally intense antiarrhythmic action but a considerably intenser antifibrillatory one. Therefore the compound 17 (abbreviated designation in the USSR: GS 015 or in the GDR: AWD 19-166) was provided for a thorough pharmacological and toxcological study.

[Dependence of calcium influx in squid axons on rhythmic excitation frequency]. / Pogloshchenie kal'tsiia nervnymi stvolami kal'mara v zavisimosti ot chastoty ritmicheskogo vozbuzhdeniia.

Calcium-45 influx was measured in squid axons during excitation. Different stimulation frequencies changed this influx and general concentration of calcium ions in squid axons. The maximum influx was recorded at the frequency 10 imp/s and 30 imp/s. Calcium influx and general content of calcium ions in axoplasma during excitation was independent of the number of excitation impulses. The role of sodium and calcium channels during excitation is discussed.

[A new class-III antiarrhythmic preparation among the dicyclohexylamides of aminocarboxylic acids]. / Novyi antiaritmicheskii preparat III klassa sredi ditsiklogeksilamidov aminokarbonovykh kislot.

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.

[Comparison of the effect of ildamen and nonachlazin on the blood supply and activities of the heart]. / Sopostavlenie vliianiia il'damena i nonakhlazina na krovosnabzhenie i deiatel'nost' serdtsa.

Instravenous infusion of ildamen (0.8-1 mg/kg) into anesthesized cats caused an increase in coronary blood flow and oxygen consumption by the heart to an approximately equal degree; the resistance of the coronary vessels diminished. The values of cardiac activity (cardiac output, contractions, pulse rate) increased simultaneously with increase of the coronary blood flow. In distinction to ildamen, nonachlasin (6 mg/kg) reduced the arterio-venous difference in oxygen and increased the content of oxyhemoglobin in the draining coronary blood. In anesthesized animals cardiac activity altered in two stages. Since beta-adrenergic blocking agents prevented the increase in coronary blood flow and the intensification of cardiac contractions induced by both drugs it is assumed that their effect is caused through stimulation of the beta-adrenergic structures. Besides, ildamen and nonachlasin possess the property of inhibiting cardiac activity. The combination of these two opposite effects evidently plays an important role in the realization of the antianginal effect of the substances studied.

[Anti-arrhythmic properties of ethmosine (clinico-experimental study)]. / Antiaritmicheskie svoistva etmozina (kliniko-eksperimental'noe issledovanie).

The antiarrhythmic activity of some acyl derivatives of phenothiazine was studied. Ethmozine proved to be the most effective among them. It produced a marked antiarrhythmic effect both in experiments and in the clinic. The effect of ethmozine is similar to that of quinidine, but it has a wider therapeutic range and is less toxic. The drug has practically no effect or arterial pressure, myocardial conduction and myocardial contraction. These properties of ethmozine as well as its ability to prolong the refractory period and reduce myocardial excitability allow it to be recommened for the management of tachyarrhythmic a-rhythmia.

[Characteristics of the anti-arrhythmia effect of phosphocreatine in the acute stage of experimental myocardial infarction]. / Osobennosti antiaritmicheskoi aktivnosti fosfokreatina v ostroi stadii éksperimental'nogo infarkta miokarda.

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.

[Effect of exogenous phosphocreatine on the size of experimental myocardial infarction]. / Vliianie ekzogennogo fosfokreatina na razmer éksperimental'nogo infarkta miokarda.

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.

[Ethacizin: pharmacologic properties and prospects for clinical application]. / Etatsizin: farmakologicheskie svoistva i perspektivy klinicheskogo primeneniia.

The study of the regularities between the chemical structure and pharmacologic action of phenathiazine dialkylaminoacyl derivatives led to the identification and investigation of a new drug called ethacizine-phenothiazin-2-carbethoxyamino-10 (beta-diethylamino-propionyl) hydrochloride. Ethacizine exceeds its structural analogue ethmozin by two times in terms of intensity and by 4-5 times in terms of the duration of antiarrhythmic effect. Ethacizine has marked antianginal properties. It shows a prolonged inhibitory effect on the average elevation of the ST interval at multiple leads of the epicardial electrogram during coronary occlusion, increases the threshold of myocardial ischemia development, and reduces the size of experimental infarction. The combination of potent antiarrhythmic activity, already confirmed by clinical observations, with antianginal properties and a capacity to limit the size of infarction makes in possible to consider ethacizine a promising means for treating coronary heart disease.