Pronounced Antiarrhythmic Effect Research Articles

Assessment of impact of a new derivative 2-(diethylamino)-N-(o-toluyl) acetamide, manifesting antiarrhythmic effect in heart rhythm disorders of peripheral origin, on cardiovascular system

Objective. To study the effect of a new derivative of arylamides of aminocarboxylic acids, which has a high antiarrhythmic activity on the state of the cardiovascular system.
 Materials and methods. To study the antiarrhythmic activity of the compound, the experiment was carried out on a model of arrhythmia caused by intravenous administration of aconitine. The effect was evaluated by its ability to prevent the occurrence of arrhythmia or to prolong the survival time of animals. In addition, an analysis of the electrocardiogram of awake rats and rabbits was carried out. The test compound and the comparison drug, lidocaine, were intravenously administered to animals in effective antiarrhythmic doses.
 Results. Diethylaminoacetic acid ortho-toluidide nitrate under conditions of aconitine arrhythmia shows a pronounced antiarrhythmic effect; under its influence, there is a statistically significant reduction in the duration of arrhythmia attacks in animals by 2.4 times compared with the control as well as protection from death. The compound does not change the parameters of electrocardiogram of animals, no statistically significant differences from the control results were found.
 Conclusions. 1. A new compound, diethylaminoacetic acid ortho-toluidide nitrate, exhibits a pronounced antiarrhythmic effect. Probably, it can be attributed to class IB antiarrhythmic drugs, since it exhibits high activity on calcium chloride and aconitine models of arrhythmia.
 2. Given that the studied compound combines high antiarrhythmic activity with no negative effect on ECG parameters, a drug based on it can be used as an effective antiarrhythmic drug.

Chastota porushen rytmu i providnosti ta antyarytmichna efektyvnist upstream-terapii u khvorykh na hostryi infarkt miokarda z komorbidnymy metabolichnym syndromom i endotelialnoiu dysfunktsiieiu sudyn

Context. Cardiac arrhythmias and conduction disorders are the most common reperfusion complications in patients with myocardial infarction (MI) in both acute and late postinfarction periods, which significantly complicates the course of the disease and often leads to an unfavorable prognosis for the early and distant periods. Objective. To evaluate the frequency of arrhythmias and conduction and the antiarrhythmic efficacy of upstream therapy in patients with acute MI with comorbid metabolic syndrome (MS) and endothelial vascular dysfunction. Materials and methods. The experimental group consisted of 42 patients with acute myocardial infarction in combination with MS, who underwent urgent coronary angiography followed by balloon angioplasty and stenting of the infarct-dependent coronary artery, as well as standard drug therapy according to the MOH protocol. Patients in the experimental group also received 5 intravenous infusions of arginine-carnitine mixture (4.2 g and 2.0 g, respectively) in 100 ml of solvent. The nature of the clinical course of MI was compared with that in 38 patients with MI in combination with MS (control group), who did not receive additional treatment and were comparable in age (56.64 ± 0.91 and 54.85 ± 0.76 years, respectively). Results. It was found that patients with MI with comorbid MS on percutaneous coronary intervention most often developed reperfusion syndrome with manifestations of arrhythmias and conduction. Under the influence of standard drug treatment in patients of the control group there was a significant clinical and functional improvement, though sinus tachycardia, ventricular extrasystole of high grades and supraventricular extrasystole remained resistant to treatment. There was also a pronounced endothelial vascular dysfunction, which in the process of standard treatment in patients of the control group did not reach the level of healthy individuals (p-value less than 0.05). Conclusions. In patients with acute MI with comorbid MS, who underwent balloon angioplasty and stenting of the infarct-dependent coronary artery, a pronounced vascular endothelial dysfunction and electrical instability is observed, accompanied by reperfusion arrhythmias and arrhythmias. The use of arginine-carnitine mixture as upstream therapy helped to restore endothelial function and showed a pronounced antiarrhythmic effect, which significantly reduced the incidence and severity of complications of acute MI such as reperfusion arrhythmias.

CARDIOPROTECTIVE EFFICIENCY OF REMOTE ISCHEMIC PRECONDITIONING DURING ISCHEMIA-REPERFUSION IN RATS WITH EXPERIMENTAL DYSLIPIDEMIA

The search for new effective methods of preventing or reducing ischemic myocardial injury and its mechanisms of realization is an actual problem of modern experimental and clinical medicine. The aim of the study was to determine the reproducibility of antiischemic and antiarrhythmic effects of the remote ischemic preconditioning myocardium of rats with dysrlipidemia (DLE). It was found that remote ischemic preconditioning is not effective in terms of necrosis zone size limits in the left ventricle during ischemia-reperfusion in rats with DLE. At the same time, after the reproduction of remote ischemic preconditioning in rats with DLE, a pronounced antiarrhythmic effect takes place, as evidenced the decrease in the duration of ischemic heart rhythm disturbances by 85 % (p < 0.05). The findings indicate the need for a differentiated approach to the appointment of remote ischemic preconditioning in patients with acute myocardial infarction. The existence of such a risk factor for cardiovascular diseases such as DLE can be a criterion for exclusion remote ischemic preconditioning as a way of reducing ischemic and reperfusion injury of the myocardium in patients with acute myocardial infarction.

2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1 H-indole hydrochloride (SS-68): Antiarrhythmic and cardioprotective activity and its molecular mechanisms of action (Part I)

Introduction. The problem of heart rhythm disturbances is one of the most urgent topics of modern cardiology. According to the currently available concepts, 1,2- and 1,3-disubstituted aminoindole derivatives, which compound 2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1H-indole hydrochloride (SS-68) belongs to, are a promising chemical group in terms of their cardio-pharmacological activity.
 Materials and methods. To study the anti-arrhythmic activity of SS-68 compound, the following models were used: 1) Models of cardiogenic arrhythmia: aconitine-inducedic, calcium chloride-induced, barium chloride-induced, cesium chloride-induced, adrenaline model of arrhythmia, strophanthine-induced arrhythmias, as well as arrhythmias caused by electrostimulation and acute myocardial ischemia; 2) neurogenic arrhythmias: arrhythmias caused by administration of aconitine, strophanthine K, cesium chloride into the IV ventricle of the brain and also by applying carbachol on the somatosensory cortex. To assess the antianginal activity of SS-68 in various models, the effect of this drug and comparators on the intact and ischemic myocardium was studied.
 Results. It was found that with cardiogenic arrhythmias, SS-68 compound exhibits a pronounced antiarrhythmic effect and brings to normal the electrophysiological pattern of the heart, in most cases exceeding the analogous effect of reference drugs (amiodarone, lidocaine, aymaline, ethacizine, etmozine, quinidine anaprilin). In neurogenic arrhythmias, SS-68 also had a stopping effect, and, in addition, reduced the epileptiform activity of the brain in the model with the application of carbachol on the somatosensory cortex. In the study of antianginal and coronary vasolidating activities, SS-68 demonstrated pronounced thrombolytic and anti-ischemic activities, manifested in an increase in the coronary blood flow, a positive effect on ST-segment depression, and a decrease in the area of necrosis in experimental myocardial infarction.
 Discussion. The antiarrhythmic and antianginal activities of SS-68 compound create the prerequisites for further study of the pharmacological properties of this molecule. In addition, it seems appropriate to continue studying the pharmacodynamics, pharmacokinetics and molecular mechanisms of SS-68 action.
 Conclusions. SS-68 compound is a promising pharmacological agent with a high activity towards various electrophysiological disorders in the heart, and, in addition, it has significant antiischemic and coronary vasolidating properties.

Prospects of Using of κ-Opioid Receptor Agonists U-50,488 and ICI 199,441 for Improving Heart Resistance to Ischemia/Reperfusion.

We studied the ability of the agonist of κ1-opioid receptors U-50,488 in doses of 0.1 and 1 mg/kg to simulate ischemic pre- and postconditioning of the heart and κ-opioid receptors ICI 199,441 in a dose of 0.1 mg/kg to simulate the antiarrhythmic effect of heart preconditioning. The duration of ischemia was 10 or 45 min and the duration of reperfusion was 10 min or 2 h. Administration of 1 mg/kg U-50,488 both before ischemia and 5 min before reperfusion produced a pronounced antiarrhythmic effect. U-50,488 injected 5 min before reperfusion 2-fold reduced the ratio of infarction to risk area. Administration of ICI 199,441 in a dose of 0.1 mg/kg 15 min before ischemia produced a potent antiarrhythmic effect. Antiarrhythmic effect of κ-opioid receptor agonists depended on activation of κ-opioid receptors.

Differential Effects of Furnidipines’ Metabolites on Reperfusion-Induced Arrhythmias in Rats In Vivo

We previously established that furnidipine (FUR) and oxy dihydropyridines prevent rats mortality by strong reduction of the lethal arrhythmias in reperfusion. Therefore we decided to study the influence of three main metabolites (M-2, M-3, M-8) of FUR on ischemia-and reperfusion- induced arrhythmias and hemodynamic parameters in rat model to examine their independent activity. The metabolites (M-2, M-3, M-8) were given orally 20 mg/kg (24 and 1 h before ischemia). Mortality was significantly diminished in M-2 and M-3 treated groups with M-3 preventing animal mortality entirely. All three examined substances significantly reduced the duration and incidence of ventricular fibrillation (VF) with M-3, once again, completely preventing VF. Moreover, only M-3 significantly decreased the duration of ventricular tachycardia but had no influence on their incidence. Through the occlusion and reperfusion periods, M-2 and M-3 were markedly less hypotensive than M-8 and did not influence on heart rate. We conclude that two tested metabolites of FUR, M-3 and M-2 exhibited the most pronounced anti-arrhythmic effect being at the same time the most normotensive and therefore caused the most beneficial effects.

Synthesis and antiarrhythmic activity of n-(1-methyl-2-phenylethyl)aminoethanesulfonic acid isopropylamide hydrochloride

The synthesis and pharmacological properties of a new taurine amide derivative, N-(l-methyl-2-phenylethyl) aminoethanesulfonic acid isopropylamide hydrochloride (I), are described. Pronounced antiarrhythmic effect of compound I was observed in animals with experimental ventricular arrhythmias (early postocclusive and calcium chloride models). The drug significantly decreased the frequency and intensity of paroxysmal tachycardia attacks and ventricular fibrillation after coronary artery occlusion. Simultaneous administration of calcium chloride and compound I increased the arrhythmogenic dose of calcium chloride, inducing lethal heartbeat disorder and asystolia, and decreased the frequency of ventricular flutter and fibrillation. The antiarrhythmic effect of the drug was similar to that of lidocaine. The antifibrillatory activity is the most important manifestation of the antiarrhythmic action of the taurine derivative studied. These data suggest that compound I is a potential drug for urgent aid in myocardial infarction.

Effect of thyrotropin-releasing hormone on the development of cardiac arrhythmias during stimulation of sensorimotor cortex in cats.

Preliminary intravenous injection of thyrotropin-releasing hormone in a dose of 20 g/kg to cats with developing myocardial ischemia during stimulation of the cerebrocortical sensorimotor zone had a pronounced antiarrhythmic effect.

Effect of TRH on the development of ischemic cardiac arrhythmias in cats.

Acute experiments on cats showed that intravenous injection of thyrotropin-releasing hormone prevented blood pressure drop and produced a pronounced antiarrhythmic effect.

Antiarrhythmic effect of GABA derivative TZ-50-2 in neurogenic atrial fibrillation

In experiments on anesthetized cats, GABA derivative TZ-50-2 (4-oxy-3-benzylamino-N-benzylbutanamide hemisuccinate) produced a pronounced antiarrhythmic effect during neurogenic atrial fibrillation, in which the key role was played by a depriming action on vagal innervation of the heart.

Effects of opioid peptides on the development of ischemic cardiac arrhythmias under conditions of partial sympathetic denervation and laser irradiation

The effects of intravenous administration of different opioid peptides on the development of ischemic cardiac arrhythmias under conditions of intraatrial laser irradiation (λ=632.8 nm) were studied in cats with transected cardiac branches of the right stellate ganglion and preserved sympathetic innervation of the ischemized area. Ischemia was caused by occlusion of the circumflex branch of the left coronary artery. It was found that the protective effects of dalargin were most powerful when sympathetic influences on the ischemic area were intestified by laser irradiation. Under these conditions DAGO showed more pronounced antiarrhythmic effects than DSLET.

Antiarrhythmic activity of GABA derivative TZ-50-2

The GABA derivative TZ-50-2 exerted pronounced antiarrhythmic effects on a variety of arrhythmias (atrial, ventricular, and mixed). The drug was superior (or at least comparable) to quinidine, procainamide, lidocaine, verapamil, bonnecor, and other reference drugs in antiarrhythmic activity and therapeutic range, and showed no cardiotoxicity. The antiarrhythmic effects of TZ-50-2 were due to modulation of calcium and sodium channels.

Role of σ-opiate receptors in development of ischemic arrhythmias

In acute experiments on anesthetized cats, the selective σ-opiate receptor agonist DSLET has a pronounced antiarrhythmic effect on ischemic heart rhythm disturbances. This effect is probably related to inhibition of the sympathetic heart rhythm regulation, because the antifibrillation effect of DSLET is not mediated via the vagus nerves, but on the other hand DSLET considerably modulates cardiac adrenoreactivity.

Opiatergic mechanisms of cardioprotective and antiarrhythmic effects of adaptation

Adaptation to hypoxia and short-term immobilization stress, as well as preconditioning with Rhodiolae rosea extract produces pronounced antiarrhythmic and cardioprotective effects in the model of adrenergic damage to the heart. Preliminary blockade of opioid receptor significantly decreases the protective effect of adaptation. Using selective opiate receptor antagonists (naltrindole, ICI 174,864, and norbinaltorphimine) we show that the antiarrhythmic effect of adaptation is mediated predominantly via activation ofk-receptors, and to a lesser extent μ-and σ-receptors.

Role of vagus nerves in antiarrhythmic effect of DAGO in acute myocardial ischemia

Acute experiments on cats show that DAGO, a selective μ-opiate receptor agonist, elicits a pronounced antiarrhythmic effect in ischemia-induced arrhythmias. The protective effect of DAGO is observed only under conditions of intact parasympathetic innervation of the heart and apparently depends on then. vagus activity and stimulating effect of DAGO on acetylcholine release.

Bradykinin and Endothelial-Cardiac Myocyte Interactions in Ischemic Preconditioning

Myocardial ischemia results in the release of a variety of vasoactive substances from coronary vascular endothelial cells and/or from cardiac myocytes. Some of these substances appear to be protective and include nitric oxide and bradykinin. One hypothesis for the pronounced antiarrhythmic effects of preconditioning involves the early generation of bradykinin and, subsequently, nitric oxide. Evidence for early bradykinin release has come from clinical studies involving patients undergoing coronary angioplasty where, in 4 of 5 patients, there was evidence for elevated kinin levels in coronary sinus blood either during balloon inflation (i.e., ischemia) or deflation (reperfusion). The levels reached are sometimes considerable (increases 10–20 fold). The second piece of evidence comes from dogs subjected to a preconditioning stimulus (2 × 5 min periods of ischemia), followed 20 min later by occlusion of the same artery for a 25-min period. This preconditioning procedure markedly reduces ischemia-induced ventricular arrhythmias and, although under resting conditions there was little difference between arterial and coronary sinus bradykinin levels (125 ± 22 and 157 ± 41 pg/mL, respectively), there was a marked increase in coronary sinus levels in preconditioned dogs before the prolonged occlusion (637 ± 293 pg/mL compared with 114 ± 18 pg/mL in nonpreconditioned dogs); levels at the end of the prolonged occlusion in the preconditioned dogs were also higher (577 ± 305 pg/mL compared with 162 ± 34 pg/mL in control dogs). Other evidence for the involvement of bradykinin and nitric oxide comes from studies in which the generation, or effects, of these mediators have been suppressed (e.g., with the bradykinin B2 receptor blocking agent icatibant, with inhibitors of the l-arginine-nitric oxide pathway, and by methylene blue). The conclusion is that early bradykinin release is protective under conditions of ischemia, is presumably enhanced during therapy with angiotensin-converting enzyme (ACE) inhibitors and is suppressed under conditions of endothelial dysfunction.

Different antiarrhythmic effects of dalargin and β-endorphin in severe myocardial ischemia during stimulation of the sensorimotor cortex

The effects of the opiate receptor agonists dalargin and β-endorphin on the occurrence of idioventricular arrhythmias, including ventricular tachycardia and fibrillation, are studied in acute experiments on Nembutal-anesthetized cats. Dalargin administered in the dose crossing the blood-brain barrier produces a pronounced antiarrhythmic effect, while β-endorphin is effective only against ventricular fibrillation.

Pronounced antiarrhythmic effects preconditioning in anaesthetized dogs: is adenosine involved?

Although there is good evidence that adenosine contributes to the ability of ischaemic preconditioning to reduce myocardial ischaemic damage (infarct size) there is no evidence that it contributes to the marked antiarrhythmic effects of this endogenous protective mechanism. We have examined this in anaesthetized open-chest mongrel dogs by administering the non-selective adenosine receptor blocking drug 8-sulfophenyltheophylline (8-SPT) (1 mg/kg) given by intracoronary administration 10 min before both 5 min preconditioning coronary artery occlusions and also before the prolonged 25 min LAD occlusion i.e. in a total dose of 3 mg/kg. The only haemodynamic effect of 8-SPT was a reduction in coronary (LAD) blood flow and an increase in cardiovascular resistance. It was difficult to precondition dogs in the presence of 8-SPT; the number of ventricular premature beats was significantly higher (61 +/- 6 v 8 +/- 4; P < 0.01) during the initial preconditioning occlusion and the incidence of ventricular fibrillation during the preconditioning procedure was higher in the presence of the drug (5/11 v 4/20; P < 0.05). Nevertheless, it was still possible to precondition these dogs in the presence of the drug. No VF occurred during the prolonged occlusion (cf. 50% in the controls) and the number of episodes of ventricular tachycardia, and the number of ventricular premature beats in dogs preconditioned in the presence of 8-SPT was similar to those in dogs preconditioned without 8-SPT and significantly (P < 0.01 or P < 0.05) less than in control, non-preconditioned dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Pronounced antiarrhythmic effects of ischaemic preconditioning—are there possibilities for pharmacological exploitation?

Pronounced antiarrhythmic effects of ischaemic preconditioning—are there possibilities for pharmacological exploitation?

Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B2 receptors.

1. The possibility that bradykinin is involved in the pronounced antiarrhythmic effects of ischaemic preconditioning in anaesthetized mongrel dogs was examined with the use of the selective B2 antagonist, icatibant (Hoe-140). 2. Preconditioning, achieved by two 5 min occlusions of the left anterior descending coronary artery, followed 20 min later by a 25 min occlusion of the same artery resulted, during this prolonged occlusion, in less severe arrhythmias (VF 0% versus 47% in control non-preconditioned dogs), reductions in the incidence and number of episodes of ventricular tachycardia (VT) and in the number of ventricular premature beats and increased survival following reperfusion (50% versus 0% in the controls). 3. Hoe-140 was given in a dose of 300 micrograms kg-1 either before the preconditioning procedure or after preconditioning but before the prolonged occlusion. This dose of Hoe-140 had insignificant haemodynamic effects and failed to modify the increase in coronary blood flow that occurred in the circumflex coronary artery when the anterior descending branch was occluded. 4. It was difficult to precondition dogs in the presence of Hoe-140. There were more ventricular arrhythmias during the initial 5 min occlusion (44 +/- 12 versus 10 +/- 3) and a higher incidence of ventricular fibrillation (50% versus 21%) during the preconditioning procedure. There was also a more pronounced ST-elevation (recorded from epicardial electrodes) during the preconditioning occlusions in those dogs given Hoe-140. 5. In those dogs that survived to the long (25 min) occlusion, Hoe-140 prevented the antiarrhythmic effects of preconditioning (reduction in ventricular premature beats and in VT) although all the dogs survived the occlusion period. However on reperfusion, survival in the preconditioned dogs given Hoe-140 was less than in those dogs preconditioned without the B2 antagonist.6. Changes in the degree of inhomogeneity of conduction within the ischaemic area, which were markedly suppressed by preconditioning, were attenuated in those dogs preconditioned in the presence of Hoe-140.7. These results suggest that bradykinin acts as both a 'trigger' for preconditioning and as one of the mediator protective (antiarrhythmic) substances generated by the myocardium under these conditions.Since the protection afforded both by preconditioning and by local intracoronary infusions of bradykinin is markedly attenuated by an inhibitor of the L-arginine nitric oxide pathway, we suggest that much of the protection afforded by ischaemic preconditioning results from the generation of nitricoxide, and that bradykinin, released early during ischaemia, acts as a stimulant for this generation.