Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties.

A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride-induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents.

Protective effects of estrogen against reperfusion arrhythmias following severe myocardial ischemia in rats.

BACKGROUND: Female sex hormones may have protective effects against arrhythmias, including reperfusion arrhythmias (RAs), but the mechanisms are still not completely known. METHODS AND RESULTS: Serial changes in rat hearts (rhythm, apoptosis and the its infuencing factors; cardiac vinculin mRNA expression and connexin43 (Cx43) dephosphorylation) were examined during periods of ischemia-reperfusion with and without estrogen treatment. After reperfusion, although the incidence of arrhythmias became higher in both the vehicle-group and estrogen-group, compared with the ischemia period, estrogen prevented reperfusion-induced upregulation of the incidence of arrhythmias, especially ventricular premature beats (VPB) and ventricular tachycardia (VT). The duration of VT and fibrillation, and the number of VPB and VT, were all significantly decreased in the estrogen-group. The expression of cardiac vinculin mRNA decreased significantly in the vehicle-group but not in the estrogen-group. Cx43 dephosphorylation and myocyte apoptosis increased in both groups, but the values for the estrogen-group were all markedly lower than those for the vehicle-group. A selective estrogen receptor (ER) beta agonist prevented reperfusion-induced upregulation of the incidence of both VPB and VT significantly; a selective ERalpha agonist had no significant influence. CONCLUSIONS: Estrogen can protect the heart against RAs, at least in part, mediated through gap junctions. Upregulation of ERbeta but not ERalpha mediated most of the estrogen-induced cardioprotection against RA.

[Palpitations in competitive athletes. Risks from premature beats, nonsustained tachycardia and preexcitation]. / Palpitationen beim Leistungssportler. Risiken durch Extrasystolen, nichtanhaltende Tachykardien und Präexzitation.

Cardiovascular screening tests to prevent sudden cardiac death in athletes are discussed controversially, but they should include diligent patient history and physical examination as well as registration of an ECG. If palpitations or tachycardias are described or if preexcitation, supraventricular or ventricular arrhythmias are documented, further risk stratification is mandatory. Specifically the origin and the complexity of the arrhythmia need to be analyzed and any form of structural cardiac pathologies has to be ruled out. Sinus tachycardia, supraventricular and ventricular premature beats, atrial fibrillation as well as supraventricular and ventricular tachycardia may serve as substrate for palpitations. Each of these arrhythmias is associated with a different amount of cardiac risk and can be evidence for certain forms of structural cardiac disease. Recommendations to limit physical activity and specific treatment options depend on the type of the arrhythmia and the presence and the nature of underlying cardiac disease.

Defibrillator shock due to ventricular trigeminy.

A 56-year-old lady with arrhythmogenic right ventricular cardiomyopathy had a shock for ventricular trigeminy. The device diagnosed this as ventricular fibrillation because of its binning algorithm, which does not use a consecutive, or a proportional counter. A beat is binned as a fibrillation beat only if the current cycle length is in the fibrillation zone and the running average of the previous four cycle lengths are in the fibrillation or ventricular tachycardia zone. Reprogramming the device into a single detection zone will help prevent shocks in this situation.

An unusual mechanism causing inappropriate implantable cardioverter defibrillator shocks: transient reduction in R-wave amplitude.

Inappropriate shocks delivered by the implantable cardioverter defibrillator (ICD) are an increasingly recognized complication. The most frequent cause is related to supraventricular rhythms associated with fast conduction to the ventricles that are incorrectly detected as ventricular tachycardia leading to inappropriate antitachycardia pacing and/or shocks. Oversensing is a frequent cause of inappropriate shocks usually due to increased amplitude of the T-wave secondary to ischaemia or electrolyte disorders that lead to T-wave double counting. We describe an unusual case of T-wave double counting during sinus rhythm caused by transient reduction in R-wave amplitude with no changes in T-wave amplitude resulting in inappropriate shocks.

Carvedilol can restore the multifractal properties of heart beat dynamics in patients with advanced congestive heart failure.

INTRODUCTION: Human heart beats in an extremely inhomogeneous and non-stationary manner. Recent study has demonstrated that it belongs to a class of signals called multifractal. Loss of multifractality was also uncovered in patients with congestive heart failure. We investigated whether carvedilol could restore the multifractal properties in a group of patients with advanced congestive heart failure. METHODS AND RESULTS: A Holter ECG recording was obtained before and 1 and 3 months after titrated addition of carvedilol therapy in 10 patients with advanced congestive heart failure. Multifractal spectrum, detrended fluctuation analysis (DFA) as well as the traditional time- and frequency-domain heart rate variability (HRV) parameters were compared before and after carvedilol therapy together with those in age and sex-matched normal control. The results showed that the multifractal spectrum tau(q) vs. q of N-N interval time series returned toward normal during carvedilol treatment. All the traditional HRV parameters and the short-term DFA improved significantly after 3 months of carvedilol therapy. CONCLUSION: We concluded that the deteriorated multifractal properties could be reversed by carvedilol treatment in patients with advanced congestive heart failure.

[Effect of combined application of nitrogen baths and 6 month physical training on physical work capacity and extrasystole in patients with ischemic heart disease and stable stenocardia]. / Vliianie kombinirovannogo primeneniia azotnykh vann i fizicheskikh trenirovok s prodolzheniem poslednikh do 6 mes na fizicheskuiu rabotosposobnost' i ékstrasistoliiu u bol'nykh ishemicheskoi bolezn'iu serdtsa so stabil'noi stenokardiei.

AIM: To study effects of combined use of general artificial nitric baths and bicycle exercise for 6 months on physical performance (PP) and extrasystole (ES) in patients with coronary heart disease (CHD) and stable angina pectoris (SAP) of functional class I-II. MATERIAL AND METHODS: A total of 129 CHD with SAP patients entered the study. Of them, 44 patients received balneotherapy (a course of general artificial nitric baths); 37 patients took the baths and exercised on bicycle ergometer; 48 patients took the baths, exercised on bicycle ergometer in the outpatient clinic and continued the exercises for 6 months. The patients were examined with spiroveloergometry and ambulatory Holter ECG monitoring. RESULTS: The latter group of patients achieved the highest training effect manifesting with increased PP and coronary heart reserve, an antiarrhythmic effect (a 73.3% fall in the mean number of ventricular ES for 24 hours, a 72.2% one in this number of supraventricular ES). CONCLUSION: A significant efficacy is shown of combined use of general nitric baths and bicycle exercise with prolongation for 6 months in CHD patients and SAP of functional class I-II with ES.

NO-ergic mechanisms are implicated in a disturbed cardiac rhythm after systemic application of lipopolysaccharide E. coli to rats.

In acute experiments on nembutal-urethan-anaesthetized rats, a slow infusion of subseptic dose of lipopolysaccharide (LPS) Escherichia coli (1 mg/ml) via the right jugular vein immediately led to bradycardia and extrasystoles. Preliminary administration of 20 mg/kg N(G)-nitro-L-arginine methyl ester (L-NAME) or 30 mg/kg aminoguanidine hydrochloride prevented the LPS-induced extrasystoles but did not affect the pattern of bradycardia. We conclude that nitric oxide (NO)-ergic mechanisms are involved in provoking electrical instability of the heart in conditions of endotoxemia.

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.

Preventive effect of rilmenidine on the occurrence of neurogenic ventricular arrhythmias in rabbits.

BACKGROUND: Centrally acting antihypertensive drugs bearing an imidazoline or a related chemical structure inhibit sympathetic nervous output to the heart and vascular beds, and enhance parasympathetic tone. Cardiac ischaemia and ventricular arrhythmias that can result from hypertension are likely to benefit from such effects. OBJECTIVE: To investigate the effects of rilmenidine, an oxazoline with antihypertensive properties, in a model of neurogenically induced ischaemic ventricular arrhythmias. METHODS AND RESULTS: Bicuculline, a alpha-aminobutyric acid (GABA(A)) receptor antagonist, was administered intracisternally in pentobarbitone anaesthetized rabbits; 10 microg/kg intracisternal bicuculline induced polymorphic ventricular ectopic beats and ventricular tachycardia, while blood pressure increased by about 50-60% and heart rate in sinus rhythm decreased by about 20%. Rilmenidine pretreatment (10 min), either administered intravenously (0.01, 0.1, 1 mg/kg) or intracisternally (3, 10, 30 microg/kg), dose-dependently prevented the occurrence of bicuculline-induced arrhythmias and, because of a lower baseline, the blood pressure values reached were less when compared with controls. Intracisternal idazoxan (15 microg/kg) had no significant antiarrhythmic effect but antagonized, in part, the haemodynamic and antiarrhythmic effects of rilmenidine (1 mg/kg intravenously; 30 microg/kg intracisternally). CONCLUSION: The antiarrhythmic effects observed with rilmenidine are mainly mediated by blunting the bicuculline-induced increase in the sympathetic nervous output to the heart and the vascular beds. These effects of rilmenidine are likely to originate from action on the central as well as on the peripheral nervous systems. Direct coronary or cardiac effects might also play a role, in particular at low non-hypotensive intravenous doses.

Cardiac arrhythmias and left ventricular hypertrophy in systemic hypertension and their influences on prognosis.

Left ventricular hypertrophy (LVH) is the adaptative mechanism of the heart to systolic overload of the left ventricle. Nevertheless, LVH plays a role in some complications, such as cardiac arrhythmias. Patients with LVH are more likely to develop ventricular arrhythmias than the hypertensive population without LVH. Further, the relation between left ventricular mass and ventricular arrhythmias is graded and continuous. The arrhythmias described in hypertensive patients with LVH are usually isolated premature ventricular contractions. The presence of electrocardiographic criteria of LVH represents a risk of higher incidence of sudden death, especially in men. The risk is even greater in the presence of ventricular arrhythmias. The presence of late potentials has been recently characterized as more related to ventricular arrhythmias than LVH. Antihypertensive drugs that can reduce LVH also have a beneficial effect on cardiovascular morbility and mortality.

Trandolapril decreases prevalence of ventricular ectopic activity in middle-aged SHR.

BACKGROUND: Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease. METHODS AND RESULTS: Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy. CONCLUSIONS: After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.

Studies on the protective effect of azepexole on ouabain-induced cardiac arrhythmias and lethality in guinea-pig.

Azepexole, an alpha 2-adrenoceptor agonist (125, 250 and 500 micrograms/kg i.v.), was examined for its effect on ouabain-induced ventricular premature beats, ventricular tachyarrhythmias and lethality in guinea-pigs. The doses of ouabain required to cause ventricular arrhythmias and lethality were significantly higher in azepexole-treated animals. However, it did not offer any protection in reserpinised guinea-pigs. Idazoxan, the alpha 2-adrenoceptor antagonist (100 micrograms/kg i.v.) inhibited the protective action of azepexole while corynanthine, the alpha 1-adrenoceptor antagonist (1 mg/kg i.v.), potentiated the effect. Azepexole inhibited the rate of the ouabain-induced rise in mean arterial blood pressure and the peak pressor response. In isolated paced left atria of guinea-pig, azepexole (2.76 x 10(-3) M) did not offer any protection against extrasystolic contractions induced by ouabain. Therefore the protective effect of azepexole may be mediated through the stimulation of alpha 2-adrenoceptors and the resultant suppression of the indirect neural components of ouabain toxicity.

Effects of intravenous magnesium sulphate in suspected acute myocardial infarction on acute arrhythmias and long-term outcome.

A total of 252 patients with suspected acute myocardial infarction were included in a double blind study and randomised to 50 mmol magnesium sulfate infusion under 20 h or corresponding placebo. Acute myocardial infarction was verified in 117 patients and 59% of these had concomitant treatment with thrombolysis. One-hundred ninety-four patients had Holter registrations during the first day in the coronary care unit. Intention-to-treat analysis showed an increase in long RR-intervals (> 3 s) in the magnesium treated group (P = 0.006) and a tendency toward a reduction in episodes of ventricular premature complexes in triplets (P = 0.09). During hospital stay and a mean of 22 months follow-up, 23 fatal events occurred in the magnesium allocated group and 31 fatal events among the placebo allocated group (P = 0.1). Mortality rate from cardiac disease was reduced by 54% (95% C.I. 30-99%, P < 0.05). Subgroup analysis on acute myocardial infarction patients showed a 48% mortality risk reduction in the magnesium treated acute myocardial infarction group compared to the placebo treated acute myocardial infarction group (95% C.I. 23-104%, P = 0.06). There was no significant interaction between the effects of magnesium and thrombolytic treatment on total mortality or cardiac events. This study supports the results of other small double blind placebo controlled studies regarding effects of magnesium therapy on mortality in acute myocardial infarction, but are in discordance to the conclusion from the ISIS-4 study. The reasons for these discrepancies cannot be elucidated by our data.

Magnesium substitution in elective coronary artery surgery: a double-blind clinical study.

Magnesium may be beneficial in the control of ventricular ectopy and supraventricular tachyarrhythmias after coronary artery bypass graft (CABG) surgery, but it is not known whether a high-dose magnesium regimen is superior to a regimen keeping the patient normomagnesemic. A prospective randomized and double-blind clinical comparison was performed in 81 elective CABG patients in order to assess the effects of two different magnesium infusion regimens on electrolyte balance and postoperative arrhythmias. Forty-one patients (high-dose group, H) received 4.2 +/- 0.7 g (mean +/- SD), of magnesium sulfate before cardiopulmonary bypass, followed by an infusion of 11.9 +/- 2.8 g of magnesium chloride until the first postoperative (PO) morning, and a further 5.5 +/- 1.0 g until the second PO morning. Forty patients (low-dose group, L) received magnesium sulfate only after bypass to a total of 2.9 +/- 0.5 g at the first, and 1.4 +/- 0.1 g at the second PO morning. A blood cardioplegia technique was used in both groups, including bolus doses of magnesium chloride to a total of 2.4 +/- 0.6 g and 2.3 +/- 0.6 g to H and L patients, respectively. Continuous Holter tape-recording was used for 12 to 15 hours preoperatively, and for 48 hours postoperatively. Serum magnesium peaked in H patients on the first PO morning at 1.60 +/- 0.25 mmol/L, whereafter it declined to the normal level on the third PO morning. Patients in the L group were normomagnesemic, except after the start of bypass.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of bidisomide (SC-40230), a new class I antiarrhythmic agent, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats; comparison with mexiletine and disopyramide.

We investigated the antiarrhythmic effects of bidisomide (SC-40230), a new class I antiarrhythmic drug, in early-phase ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats. The effects of bidisomide were compared with those of mexiletine (MXT) and disopyramide (DSP), established class I antiarrhythmic drugs. Drugs were administered intravenously, 5 min before induction of coronary occlusion. Bidisomide (5 mg/kg) reduced the number of premature ventricular complexes and the incidence of ventricular tachycardia and ventricular fibrillation similarly to MXT and DSP in rats with ventricular arrhythmias induced by coronary artery occlusion. In rats with ventricular arrhythmias induced by coronary artery reperfusion following a 5-min coronary occlusion, the antiarrhythmic effects of 5 mg/kg of bidisomide were similar to those of the same doses of MXT and DSP. All three drugs significantly slowed the heart rate. Our results suggest that bidisomide may effectively reduce the severity of life-threatening ventricular arrhythmias that occur during acute coronary syndrome.

Antiarrhythmic activity of oximethers.

More than sixty 2-substituted-cycloalkanone-oxim-/2-hydroxy-3-dialkylamino/- propylethers were investigated on aconitine induced ventricular arrhythmia model in rats. According to the structure-activity relationships cyclohexanes containing diisopropylamine in the basic group were the most effective derivatives. Based on the highest per os activity and lowest toxicity EGIS-3966 (ED50 values 1.21 mg/kg iv. and 27.3 mg/kg per os) was selected for further development.