On the mechanism of anti-ischemic effects of afobazole.

The anti-ischemic effect of synthetic and pharmacologically tested anxiolytic afobazole (10 mg/kg intravenously) was studied on anesthetized rats with acute endocardial ischemia caused by isoproterenol infusion (20 mg/kg/min). A calcium antagonist verapamil (1 mg/kg intravenously) belonging to the group of phenyl alkyl amine derivatives was used as the reference drug. Afobazole and verapamil were shown to exhibit anti-ischemic activity in this experimental model, which was seen from significant decrease in ST segment depression on ECG. The neuroprotective effect of afobazole is to a great extent related to its affinity for σ1 receptors. Therefore, a special series was performed to evaluate the anti-ischemic effect of afobazole after blockade of these receptors with haloperidol (0.5 mg/kg intravenously). Afobazole exhibited no anti-ischemic activity under these conditions. σ1 receptor blockade had no effect on anti-ischemic activity of verapamil. Our results suggest that the agonistic effect of afobazole on σ1 receptors in cardiomyocytes contributes to anti-ischemic activity of this agent.

[Heart rate reduction due to selective specific inhibition of the If current opens new possibilities in treatment of basic cardiovascular diseases].

It is shown that the heart rate (HR) is a predictor of the general and cardiovascular death rate. Ivabradine, being the If current inhibitor, induces a selective reduction in the HR and produces related positive effects on the course of basic cardiovascular diseases including ischemic heart disease, arterial hypertension, chronic heart failure, atherosclerosis, etc. Ivabradine is the powerful antiischemic and antianginal drug that acts by means of selective HR decrease. It can be used both in monotherapy and in a combination with beta-adrenoblockers. Ivabradine improves the function of left ventricule at chronic heart failure, increases stroke volume, and maintains cardiac output on a higher level. It optimises the energy consumption by myocardium and reduces heart electrophysiological and structural remodeling at patients with chronic heart failure and left ventricular systolic dysfunction. The drug also produces a pronounced antiatherogenic effect.

[Specific effects of selective anxiolytic afobazole on the cardiovascular system].

Experiments in narcotized rats showed the new selective anxiolytic afobazole, a derivative of 2-mercaptobenzimidazole, to cause a small bradycardia with almost no effect on the important parameters of heart hemodynamics and cardiac performance such as the arterial pressure, cardiac output, and mean aorta blood flow acceleration. Afobazole decreased the rate of ventricular fibrillations during 7-min occlusion followed by 3-min reperfusion of the left coronary artery in narcotized rats. Afobazole administered in rats for 21 days under conditions of experimental myocardial infarction had no effect on the pump and contractile cardiac functions. The drug normalized the reaction of mean aorta blood flow acceleration to the volume load suppressed by myocardial infarction, which was indicative of an increase in the adaptive capacity of myocardium.

[Effects of zatebradine on the course of experimental myocardial infarction under long-term treatment conditions in rats].

A long-term (21 days) administration of the specific bradycardic agent zatebradine to rats with experimental myocardial infarction led to a decrease in the intensity of necrotic changes in the cardiac muscle as evaluated from the ECG-recorded QS complex incidence rate. Morphological studies provided evidence for reduced intensity of the dystrophic processes in myocardium. Under these conditions, the drug did not affect the pump and contractile heart functions. At the same time, zatebradine normalized the reaction of mean aorta blood flow acceleration to volume load (which was inhibited at myocardial infarction), that is, prevented the development of latent heart failure. Zatebradine restored the infarction-decreased norepinephrine (NE) level in cardiac muscle and increased NE content in hypothalamus and brainstem. Along with that, the ratios of deoxyphenylacetic acid/dopamine and homovanillic acid/dopamine were reduced.

[Specific bradycardic drug zatebradin: cardiac rhythm variability, antifibrillatory, and antiischemic effects].

The results of experiments on narcotized cats and rats showed that the drug zatebradin produces a specific bradycardic action by reducing the heart rate and the double product, while virtually not influencing vitally important parameters of the heart activity such as the cardiac output and the mean acceleration of the aorta blood flow. The drug reduced the rise of ST segment recorded in multiple epicardial ECG leads made in narcotized cats during a 5-min occlusion of the anterior descending branch of the left coronary artery. Zatebradin was found to increase the cardiac rhythm variability in narcotized rats and decrease the rate of ventricular fibrillations during a 7-min occlusion with the subsequent 3-min coronary artery reperfusion.

[Selective and specific reduction in the heart rate: a promising direction in the creation of new cardiovascular drugs].

Numerous data indicate that a high heart rater (HR) is a risk factor in various cardiovascular diseases. The effects of HR on the energetics of myocardium, contractility function, collateral coronary blood circulation, and atherogenesis are considered. A special attention is devoted to specific bradycardic drugs and their mechanisms of action on the electrophysiological processes in the sinus node and on the HR. The new drug ivabradin (a specific selective blocker of the If current) can produce a bradycardic effect and exhibit a pronounced antiischemic action on the myocardium. The creation of such drugs offers an alternative to beta-adrenoblockers and calcium antagonists and opens new possibilities in the pharmacological protection of ischemized myocardium.

[Cardiomyocyte culture as a highly sensitive system for testing pharmacological activity of specific bradycardic agents].

Two antiarrhythmic agents were studied: verapamil and bradizole, a new bradycardic drug. It was found that both drugs exhibit a dose-dependent negative chronotropic effect on the culture of contractile cardiomyocytes of newborn rats. Bradizole showed more pronounced bradycardic properties than verapamil.

[Activation of the sympathetic nervous system influences the antifibrillatory effect of class I antiarrhythmic drugs]. / Vliianie aktivatsii simpaticheskoi nervnoi sistemy na protivofibrilliarnoe deistvie antiaritmicheskikh sredstv I klassa.

The experiments with anesthetized rats showed that drugs belonging to various subclasses of class I antiarrhytmic agents (novocainamide, IA; lidocaine, IB; ethacizine, IC) produce a pronounced antifibrillatory and antiarrhythmic action under the conditions of a 7-min occlusion followed by reperfusion of the anterior descending branch of the left coronary artery. In the arrhythmia model with beta-adrenoreceptors stimulated by isoproterenol, novocainamide (IA) and lidocaine (IB) retained their efficacy, in contrast to ethacizine (IC). This difference in the behavior of antiarrhythmic drugs may be related to their different antiarrhythmogenic potentials.

[Antiischemic and antiarrhythmic effect of esafosfina]. / O protivoishemicheskom i antiaritmicheskom deistvii preperata ezafosfina.

Esafosfina, a new preparation based on fructose 1,6-diphosphate, supported the pumping ability of the heart in experiments with a 40-min occlusion followed by 60-min reperfusion of the anterior descending branch of the left coronary artery in anesthetized cats. Esafosfina also exhibited a pronounced antifibrillatory and antiarrhythmic action in anesthetized rats with ventricular fibrillation model.

[Antifibrillatory effect of antiarrhythmic drugs of various classes under conditions of activation of the parasympathetic nervous system]. / Protivofibrilliarnoe deistvie antiaritmicheskikh sredstv razlichnykh klassov v usloviiakh aktivatsii parasimpaticheskoi nervnoi sistemy.

The experiments on anesthetized rats under the conditions of a 7-min occlusion of the anterior descending branch of the left coronary artery followed by reperfusion showed that drugs belonging to various classes of antiarrhythmic agents (ethacizine, IC; cardiocyclide, III; verapamil, IV; bradizol, V) produce a pronounced antifibrillatory and antiarrhythmic effects. The cholinomimetic carbacholine produced practically the same effect. Cardiocyclide, verapamil, and bradizol retained their antifibrillatory properties upon combined administration with carbacholine, while the effect of ethacizine administered jointly with carbacholine was decreased.

[Pharmacology of antiarrhythmia agents: the new aspects]. / Farmakologiia antiaritmicheskikh sredstv: novye aspekty.

The paper describes new original drugs created at the Zakusov Institute of Pharmacology (Moscow). Cardiocyclide is a class III antiarrhythmic drug, producing a frequency-independent action; is a promising agent for the treatment of dangerous tachyarrhythmias. Bradizol is a class V antiarrhythmic drug producing a special bradycardiac action.

[Pharmacodynamics and pharmacokinetics of the new specific bradycardic preparation bradizole]. / Sopostavleniie farmakodianmiki i farmakokinetiki novogo spetsificheskogo bradikardicheskogo sredstva bradizola.

The new drug Bradizol (SM-345), a 2-mercaptobenzimidazole derivative producing a specific bradycardic effect, is quite rapidly eliminated upon intravenous bolus in anaesthetiezed cats. After a combined injection (bolus followed by a 60-min infusion), a constant bradizol concentration in the blood plasma is observed over a time period of 90 min. The bradizol-induced bradycardic effect and the drug concentration in the blood plasma are tightly correlated. Upon per os administration of bradizol to the experimental animals, neither the drug is detected in the blood plasma, nor the bradycardic effect is observed. It is suggested that bradizol, possessing antiarrhythmic, antifibrillator, and antiischemic properties, can be used (by intravenous injections) for the therapy of patients with diverse tachyarrhythmia geneses, including those with the ischemic heart disease.

[Effect of the sympathetic nervous system activation on the antifibrillatory efficacy of various anti-arrhythmia agents]. / Vliianie aktivatsii simpaticheskoi nervnoi sistemy na antifibrilliatornoe deistvie protivoaritmicheskikh sredstv raznykh klassov.

Experiments with a 7-min occlusion followed by reperfusion of the left coronary artery in narcotized rats showed that antiarrhythmic drugs of various classes--ethacizin (class I), AL-275 (class III), and CM-345 (class V)--produce pronounced antifibrillatory and antiarrhythmic effects. AL-275 and CM-345, in contrast to ethacizin, retained their efficacy under the conditions of isoproterenol-induced stimulation of beta-adrenoceptors. This difference in behavior is probably explained by dissimilar effects of the antiarrhythmics on the ion channels of cardiomyocite membranes.

[The pharmacology of the new combined anti-arrhythmia preparation metatsizin]. / K farmakologii novogo kombinirovannogo antiaritmicheskogo preparata metatsizina.

The combined antiarrhythmic effect of ethmosin and ethacisin in various dose ratios was studied in conscious dogs with two-stage ligation of the coronary artery (after Harris). A 6:1 ratio was found to be optimal for manifestation of the antiarrhythmic effect. In such a ratio of the doses the antiarrhythmic effect of a combination of ethmosin and ethacisin is essentially higher than the activity of each component. On the grounds of these data a combined antiarrhythmic drug methacisin was developed. It possesses a broad spectrum of antiarrhythmic activity. The drug is effective on models of arrhythmias specific of class I, III, and IV antiarrhythmics. Metacisin does not change hemodynamics and activity of the heart. Study of metacisin pharmacokinetics showed that it possesses bioavailability twice that of ethmosin tablets taken separately and four times that of ethasicin.

[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.

[The anti-ischemic properties of new specific bradycardic agents, derivatives of 2-mercaptobenzimidazole]. / Protivoishemicheskie svoistva novykh spetsificheskikh bradikardicheskikh sredstv proizvodnykh 2-merkaptobenzimidazola.

Experiments on narcotized cats demonstrated that the derivatives of 2-mercaptobenzimidazole possessing the properties of specific bradycardic agents and coded as CM-251, CM-266, and CM-345, reduce the mean rise of segment ST on numerous leads of the epicardial electrogram during 5-min occlusion of the anterior descending branch of the left coronary artery. The agents stabilize the heart pumping and contracting functions under conditions of 30- and 60-min reperfusion of the coronary artery, respectively. It is concluded on the grounds of the obtained data that the 2-mercaptobenzimidazole derivatives possess a marked anti-ischemic action.

[Derivatives of 2-mercaptobenzimidazole--a new group of specific bradycardic drugs]. / Proizvodnye 2-merkaptobenzimidazola--novaia gruppa spetsificheskikh bradikardicheskikh sredstv.

Experiments on anesthetized cats and rats showed that 2-mercaptobenzimidazole derivatives, known as SM-266 and SM-345, induced marked and long-term bradycardia, increased the stroke output, and reduced the requirements of the heart of oxygen. The drugs had practically no effect on systemic arterial pressure, cardiac output, and heart contractility. Studies on isolated frog venous sinuses disclosed that bradycardia induced by the drugs under study was related to the decrease caused by them in the velocity of slow diastolic depolarization directly in the pacemaker cells on the sinus node. On grounds of the obtained results it is concluded that the drugs under study may be related to a new group of specific bradycardiac agents.

[Anti-arrhythmic properties of specific bradycardic agents from the group of 2-mercaptobenzimidazole derivatives]. / Antiaritmicheskie svoistva spetsificheskikh bradikardicheskikh sredstv iz gruppy proizvodnykh 2-merkaptobenzimidazola.

It was shown in experiments on aconitine, calcium chloride, and epinephrine models of heart rhythm disorders that derivatives of 2-mercaptobenzimidasole possessing the properties of specific bradycardiac agents coded as SM-251, SM-266, and SM-345 cause a marked antiarrhythmic effect. SM-266 and SM-345 reduce considerably the number of ventricular fibrillations and the life-hazardous arrhythmia occurring during 7-min occlusion and subsequent reperfusion of the coronary artery in anesthetized rats. The agents under study reduced the ectopic heart rate in Harris' conscious dogs. It is concluded that the studied 2-mercaptobenzimidasole derivatives exert a marked antiarrhythmic and antifibrillatory effect.

[The participation of the prostacyclin-thromboxane system in the mechanism of the action of calcium antagonists]. / Ob uchastii prostatsiklin-tromboksanovoi sistemy v mekhanizme deistviia antagonistov kal'tsiia.

The experiments with isolated rat aortic circular segments have shown that vasocyclin (natural prostacyclin), verapamil, and diltiazem cause the relaxation of vascular smooth muscles during potassium-induced contracture. The impaired endothelium and acetylsalicylic acid-induced blockade of cyclooxygenase dramatically reduce the relaxant action of verapamil and diltiazem under these conditions. It is concluded that the system of prostaglandin synthesis plays an important role in the vasodilator effects of calcium antagonist.