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Antiepileptic drugs (AEDs) have been associated with cardiac conduction abnormalities and arrhythmias, predominantly in patients with predisposing cardiac conditions. Ventricular late potentials (VLPs) detected in the signal-averaged electrocardiogram (SAECG) may imply an increased risk of ventricular tachycardia or fibrillation. Twenty-six AED-naïve patients with newly diagnosed epilepsy and no clinical evidence of heart disease were examined with SAECG and standard ECG. Fifteen patients were treated with lamotrigine and ten with carbamazepine. No significant abnormality was found in the standard ECG or SAECG three to nine months after initiation of AED therapy. In one patient, a VLP was detected at baseline and subsequent MRI demonstrated significant right ventricular pathology; therefore, this patient was excluded from the rest of the study. This exclusion along with only newly diagnosed patients with a low total seizure count being included in the study may explain the lack of AED-induced electrocardiographic abnormalities in this patient cohort., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The acute effects on monophasic action potentials (MAP), QT interval, and right ventricle effective refractory period (V-ERP) of propranolol 0.2 mg.kg-1 body weight have been studied in 10 patients with coronary artery disease. The median duration of MAP at 90% repolarization (MAP90) was shortened from 238 to 228 ms at a constant paced heart rate of 100 beats.min-1, while V-ERP remained unchanged. The median ratio V-ERP/MAP90 increased from 1.00 to 1.03. The electrical restitution curves of the duration of premature action potentials, normalized to those paced at constant heart rate, were more horizontal after propranolol. Isometric handgrip shortened MAP90 from 217 to 211 ms and after propranolol similar shortening was found (215 to 209 ms), although both values were slightly lower than before beta-blockade.

Electrophysiologic effects of acetylcholine (Ach) injections were compared to those obtained by vagus stimulation with and without beta-adrenoreceptor blockade during right heart catheterization in 12 dogs. Monophasic action potentials were obtained by suction electrode technique, and programmed electrical stimulation was used to determine heart rate independent changes in 50 and 90% repolarization times and the effective (V-FRP) and functional (V-FRP) refractory periods of the right ventricle. Vagus stimulation decreased heart rate with and without beta-blockade, while after Ach injections a marked increase in heart rate was found, which could be eliminated by beta-blockade. Vagus stimulation increased action potential duration and refractoriness at high sympathetic tone induced by pentobarbital anesthesia, mainly by inhibiting the effect of beta-adrenoreceptor stimulation. It is concluded that stimulation of the vagus induces antiarrhythmic effects at high sympathetic activity, while the change in ventricular electrophysiology found after Ach injections in high doses to intact animals is an effect probably induced by stimulation of beta 1-receptors.

In pentobarbital anaesthetised dogs, melperone (a neuroleptic butyrophenone) reduced mean aortic blood pressure and at lower doses (0.5 and 2.5 mg . kg-1) increased the heart rate. By means of His bundle electrography and programmed electrical stimulation, conduction velocity and refractoriness were measured at different frequencies of stimulation (170, 200, 230 and 260 beats.min-1). Melperone 0.5 and 2.5 mg.kg-1 decreased the atrioventricular nodal conduction time and refractoriness. Melperone (0.5 to 12.5 mg.kg-1) did not affect the intra-atrial or His-Purkinje conduction times or the QRS width. However, melperone increased the functional and effective refractory period of the right atrium and ventricle dose-dependently at all frequencies studied. This suggests that melperone may be a valuable drug in treating selected cardiac arrhythmias.

The aim of the present investigation was to study the modifying effect of autonomic blockade with atropine plus propranolol and atropine alone on the electrophysiologic response to digitoxin during an observation period of 8 hours. Twenty-five pentobarbital-anaesthetised Labrador dogs were used. Pacing and programmed electrical stimulation were used to determine heart rate independent changes in repolarisation times and the effective (V-ERP) and the functional (V-FRP) refractory periods. The dogs were divided into three groups and all dogs got digitoxin (2.0 mg) intravenously during 5 min. Fourteen dogs were given digitoxin without blockade, while 5 dogs were pretreated with propranolol 0.5 mg/kg plus atropine 0.05 mg/kg every hour for 8 hours and 6 dogs with atropine in the same dose and with the same interval. Digitoxin alone increased 50 and 90% repolarisation times 2-4 hours after injection of the drug. During autonomic blockade digitoxin induced a shortening of action potential duration, and thus digitoxin interacts with autonomic transmitters resulting in prolongation of action potential duration. The "direct" effects of digitoxin, the action potential shortening effect, the decrease in membrane responsiveness (i.e. V-ERP/50% repolarisation time) reached a maximum 2-3 hours after injection of the drug.

The effects of digitoxin and digoxin on right ventricular monophasic action potentials were studied in intact dogs during an 8 hour observation period. Pentobarbital anaesthesia was used, and monophasic action potential recordings were obtained with the suction electrode technique. Intravenous injection of 2.0 mg digitoxin to six dogs, 2.0 mg digoxin to two dogs and 1.0 mg digoxin to five dogs caused a rapid increase in the time taken for 90% repolarisation with return to control values after 20 to 30 min. A late increase in 50 and 90% repolarisation times was observed 2 to 4 h after digitoxin, while digoxin had no such effect. The late action potential prolonging effect was inversely correlated to serum concentrations in the early elimination phase (2 to 8 h after the injection) since it reached a maximum towards the end of the observation period. Digitoxin and digoxin thus differed in their late effects on ventricular monophasic action potentials in intact dogs and may possess different antiarrhythmic activity.

The butyrophenone neuroleptic melperone has recently been shown to possess antiarrhythmic properties in man and animals. We studied the correlation between plasma concentration of melperone and the electrophysiological and blood pressure effects of the drug in 20 pentobarbital-anaesthetized dogs. Linear correlations were found between the log melperone plasma concentration and decreases in mean aortic blood pressure and heart rate, and increases in atrial and AV nodal refractoriness. The correlations were better after pretreatment with the beta 1-blocker atenolol. There was a linear correlation between log melperone plasma concentration and increases in ventricular refractoriness only after atenolol. No correlation was found between log melperone plasma concentration and decreases in AV nodal conduction time. Apart from the effect on AV nodal conduction time, the relationship between plasma concentration of melperone and the electrophysiological and blood pressure effects after beta 1-blockade fits well into an overall log concentration-effect relationship. The poorer correlation without beta 1-blockade was probably due to a combination of direct and indirect effects of the drug.

The major metabolite of procainamide (PA) is N-acetylprocainamide (NAPA). The effect of this drug on the electrophysiology of the right ventricle was studied in the dog heart in situ by means of programmed electrical stimulation and monophasic action potential (MAP) recordings. A decrease in the beat interval caused a progressive decrease in refractoriness and MAP duration. Intravenous injection of NAPA 50 mg.kg-1 body weight increased refractoriness to a greater extent than MAP duration at shorter, while the opposite was observed at longer beat intervals. These observations are compatible with delayed recovery of excitability. On the basis of these findings, it is concluded that NAPA belongs to antiarrhythmic drugs of type I according to Vaughan Williams' classification, and NAPA may be an alternative drug for treatment of cardiac arrhythmias.

We attempted to correlate inotropic and eletrophysilogic digitoxin effects with serum digitoxin concentrations during 8 hr after a single dose. Eight pentobarbital-anesthetized Labrador dogs were given 2.0 mg digitoxin intravenously. Left heart catheterization and His bundle registration were performed. acing and programed electrical stimulation were used to determine heart rate-independant changes in dP/dt, intra-atrial, atrioventricular (AV), His-Purkinje, and intraventricular conduction velocity. The effective (A-ERP) and functional (A-FRP) refractory periods of the atrium and the functional nodal refractory period (AV-FRP) were measured. Serum digitoxin concentrations were determined by radioimmunoassay. Median serum digitoxin half-time was 5.7 hr. The dP/dt increased after digitoxin, with maximum values after 2 hr. Digitoxin concentration correlated with the inotropic response after 4 hr. Heart rate fell significantly within 2 min and remained below control values for the 8 hr observation period concimitant with an increase in AV-nodal conduction time and AV-ERP increased significantly in the late elimination phase, while A-FRP increased slightly initially and remained high. No consistent correlation was found between the electrophysilogic variables and serum concentrations. We conclude that the two main effects of digitoxin, the inotropic and electrophysiologic, are dissociated in the elimination phase after a single dose.

The effect of nifedipine, a calcium-antagonistic drug, was studied on the electrophysiology of the right ventricle in the dog heart in situ. Monophasic action potential recordings were obtained by the suction electrode technique and refractoriness was measured by means of programmed electrical stimulation. Pentobarbital anaesthesia was used. As the basic cardiac effects of nifedipine can be altered by the release of catecholamines from sympathetic nerves of the heart and vessels, the dogs were pretreated with the beta-adrenergic receptor blocking agent acebutolol which increased the action potential duration and the refractoriness. Intravenous injection of nifedipine 30 microgram/kg body weight decreased the times for 50 and 90 per cent repolarization of the monophasic action potential and to a smaller extent the effective and functional refractory period. It is suggested that nifedipine decreases the action potential duration and the refractoriness of the right ventricle of the dog heart in situ due to a direct effect of the drug on the myocardium.

We tested the electrophysiologic effects of vagus stimulation in six dogs in the presence or absence of beta-adrenoreceptor blockade. Monophasic action potentials were obtained by the suction electrode technique and programmed electrical stimulation was used to determine heart rate-independent changes in 50 and 90% repolarization times and in the effective (V-ERP) and functional (V-FRP) refractory periods of the right ventricle. Vagus stimulation decreased heart rate both in the presence and in the absence of beta-adrenoceptor blockade. It also increased action potential duration and refractoriness during high sympathetic tone induced by pentobarbital anesthesia. The effect is probably due mainly to inhibition of beta 1-adrenoreceptors, since it was decreased by beta 1-adrenoceptor blockade with atenolol. We conclude that stimulation of the vagus has antiarrhythmic effects in ventricles under high sympathetic stimulation.

Monophasic action potentials were recorded in the outflow tract of the right ventricle in patients with coronary artery disease during ventricular pacing at different basic cycle lengths and programmed stimulation. During continuous pacing (basic cycle length 600 ms) the time for 90% repolarisation (MAP90) and the QTa interval decreased exponentially during the first 1.5-2 min of pacing to 90% of control values. The reproducibility of the monophasic action potential signals and the ventricular effective refractory period were assessed as good when studied after repetitive trains of 8 beats for more than 1.5 min. The reproducibility of conduction, however, was less good. Electrical restitution of MAP90 duration of the premature beats determined at three different basic cycle lengths was different from that in single muscle preparations. The curves showed two phases with unchanged MAP90 durations despite longer coupling intervals. The first phase was close to the ventricular effective refractory period, probably because subnormal conduction left the diastolic interval constant for the earliest premature beats. This indicates that subnormal conduction may influence the premature dispersion of repolarisation.

Melperone (0.5 to 12.5 mg.kg-1) reduced mean aortic blood pressure in pentobarbital anaesthetised dogs to a greater extent after beta1-adrenergic receptor blockade with atenolol than after cholinergic blockade with atropine. Electrophysiological studies demonstrated that increased heart rate and decreased atrioventricular nodal refractoriness after lower doses of melperone (0.5 to 2.5 mg.kg-1), could be prevented by pretreatment with atenolol. The melperone-induced decrease in atrioventricular nodal conduction time was, however, not affected by pretreatment with atenolol or atropine. Intra-atrial and His-Purkinje conduction times and QRS width were not affected by atenolol or atropine plus melperone. Melperone caused a dose-dependent and very pronounced increase in ventricular and, even more, atrial refractoriness after atenolol. The ventricular and atrial refractoriness increased less after pretreatment with atropine. Some of the cardiac electrophysiological effects of melperone thus depend on the degree of beta-adrenergic stimulation. The overall cardiac electrophysiological effects of melperone results from a combination of direct and indirect actions of the drug.

We studied the effects of three different beta-adrenoreceptor-blocking drugs (atenolol, acebutolol, and propranolol) on the duration of monophasic action potentials and refractoriness of the right ventricular myocardium in closed-chest dogs. Pentobarbital anesthesia, which is known to increase the sympathetic tone, was used. Monophasic action potential recordings were obtained by the suction electrode technique, and refractoriness was measured by means of programmed electrical stimulation. A stepwise decrease in stimulation intervals from 350 to 300, 260, and 230 ms caused a progressive decrease in refractoriness as well as in the duration of the monophasic action potential. Intravenous injections of atenolol 0.5 mg/kg, acebutolol 2.0 mg/kg, and propranolol 0.5 mg/kg after pretreatment with atropine each increased the times for 50 and 90% repolarization of the monophasic action potential at each stimulation interval. The effective and the functional refractory periods paralleled the changes in the action potential duration in all experiments. We conclude that beta-adrenoreceptor blockade in the presence of adrenergic receptor stimulation prolongs ventricular refractoriness and action potential duration, and that the presence or absence of cardiac selectivity or slight intrinsic sympathomimetic activity plays no role in this process. These results suggest that if the antiarrhythmic action of beta-blocking drugs is due to prolongation of ventricular refractoriness, all types of these drugs may be expected to be equally effective as therapeutic agents.