Local anesthetic and negative chronotropic effects of diltiazem on canine cardiac Purkinje fibers

The electrophysiologic effects of diltiazem, a drug with antianginal, antihypertensive, and antiarrhythmic actions, were studied on transmembrane action potentials recorded from isolated canine cardiac tissues by means of standard microelectrode techniques. Recordings were made from normal canine cardiac Purkinje fibers in major false tendons, from normal Purkinje fibers partially depolarized by treatment with Tyrode's solution containing 7 mmol/L potassium chloride, from subendocardial Purkinje fibers of the left ventricle of normal hearts, and from subendocardial ventricular muscle preparations. Diltiazem, 1 and 2 mumol/L, exerted local anesthetic effects and decreased the action potential plateau duration in normal Purkinje fibers. In contrast, diltiazem, 1 mumol/L, did not affect the action potentials of potassium-depolarized Purkinje fibers, subendocardial Purkinje fibers, or ventricular muscle cells. Diltiazem, 1 and 2 mumol/L, did not decrease normal or high potential automaticity or catecholamine-enhanced high potential automaticity in canine Purkinje fibers with maximum diastolic potentials greater than -80 mV. In contrast, diltiazem, 1 mumol/L, rapidly terminated low potential automaticity in barium-treated Purkinje fibers with maximum diastolic potentials of -40 to -60 mV. The local anesthetic effects of diltiazem, as well as the effect on low potential automaticity, can explain the antiarrhythmic effects of the drug.     

Electrophysiologic properties of a new antiarrhythmic drug--tocainide

Tocainide (Astra W36095) is an orally active antiarrhythmic drug that is structurally related to lidocaine. This paper describes in vivo and in vitro studies undertaken to assay the electrophysiologic properties of this compound. Ouabain-induced ventricular ectopic activity was abolished by this drug in both isolated canine Purkinje fibers and in intact dogs. Similarly, the ventricular ectopic activity that occurs 24 hours after the two stage Harris coronary arterial ligation procedure also was abolished by tocainide. The amount of current necessary to evoke an action potential by intracell stimulation during diastole was Increased in direct relation to drug concentration. Similarly, in dogs anesthetized with pentobarbital sodium, tocainide increased the ventricular fibrillation threshold up to 150 percent above control values during normal supraventricular rhythm and up to 285 percent after premature ventricular beats. The transmembrane action potential duration and effective refractory period of isolated canine Purkinje fibers were shortened by tocainide. Tocainide depressed atrioventricular nodal conduction in anesthetized dogs, an effect that was magnified in the presence of premature atrial beats but had no effect on His, Purkinje or ventricular muscle conduction. These results Indicate that tocainide is a potentially effective antiarrhythmic agent and deserves further investigation in patients.     

Acute effects of amiodarone on the electrophysiologic properties of isolated neonatal and adult cardiac fibers

The acute cellular electrophysiologic actions of amiodarone on isolated neonatal and adult canine ventricular muscle and Purkinje fibers were evaluated using standard microelectrode techniques. Amiodarone, 10(-6) to 5 X 10(-5) M (0.68 to 34 micrograms/ml), significantly (p less than 0.05) prolonged adult ventricular muscle action potential duration and voltage-dependent refractoriness at all concentrations, thereby demonstrating typical class III antiarrhythmic effects. Similar concentrations had no significant effects on neonatal ventricular muscle. Amiodarone significantly shortened action potential duration and refractoriness of both neonatal and adult Purkinje fibers, with neonatal fibers having a greater sensitivity to the drug. At the standard stimulation rate of 1 Hz, amiodarone had no effects on action potential amplitude or maximal rate of rise of phase 0 of the action potential (Vmax) of any tissues. At faster stimulation frequencies (2 to 4 Hz), amiodarone produced frequency-dependent decreases in action potential amplitude and Vmax of all neonatal and adult preparations. The data indicate that amiodarone exhibits a complex aggregate of electrophysiologic actions that include significant frequency-related class I effects. Compared with adult myocardium, neonatal tissues demonstrated altered responsiveness to amiodarone, a feature common to many antiarrhythmic compounds.     

Electrophysiologic effects of beta blockers in ventricular arrhythmias

Beta-adrenergic receptor blocking agents are effective antiarrhythmic drugs in patients with ventricular arrhythmias. However, these agents exert little or no measurable electrophysiologic effect on normal Purkinje and ventricular muscle fibers when administered acutely. They prevent catecholamine-induced increases in Purkinje fiber automaticity and may interfere with catecholamine-dependent slow responses. beta-adrenergic blocking drugs also prevent the decrease in ventricular fibrillation threshold induced by catecholamines. In the acutely ischemic ventricle, some beta blockers selectively depress conduction within the ischemic zone. The long-term administration of some beta blockers has, in contrast to their short-term effects, been shown to prolong action potential duration and effective refractory period in the ventricle. Which of these observed electrophysiologic effects, either alone or in combination, contributes to the ventricular antiarrhythmic effects of beta-blocking drugs in man is at present unknown.     

In vitro electrophysiological effects of sodium dantrolene on isolated preparations of Purkinje fibers and ventricular myocardium of sheep

Dantrolene sodium is a drug used in the treatment of spasticity and malignant hyperthermia. It is known to have a myorelaxant effect related to inhibition of the "release" of calcium by the sarcoplasmic reticulum of striated skeletal muscle. A direct cardiac effect which has only recently been suspected was demonstrated in vitro on isolated preparations of sheep Purkinje fibres and ventricular myocardium. Dantrolene caused a spectacular lengthening of the duration of the action potential of Purkinje fibres. This could be due either to an action on the slow calcium current or to stimulation of an ingoing sodium current sensitive to tetrodotoxin (TTX). This effect on the cardiac action potentials could explain the antiarrhythmic properties of dantrolene sodium during attacks of malignant hyperthermia.     

Electrophysiological actions of disopyramide phosphate on canine ventricular muscle and purkinje fibers.

Disopyramide phosphate is a new antiarrhythmic drug that has been shown to possess significant antiarrhythmic effects in animals and man. In the present investigation, the effects of 2, 5, and 10 mug/ml of disopyramide phosphate were studied on the electrophysiological properties of canine Purkinje fibers and ventricular muscle superfused in vitro. Transmembrane action potentials were recorded from Purkinje fibers in the region of maximum action potential duration (gate), from Purkinje fibers proximal and distal to the gate, and from ventricular muscle. Disopyramide phosphate produced a concentration-dependent decrease in the slope of phase 4 diastolic depolarization of spontaneously beating Purkinje fibers. In all electrically stimulated fibers, the drug decreased the amplitude and the maximum upstroke velocity of the action potential. This depression of phase 0 characteristics was accompanied by a decrease in conduction velocity. In Purkinje fibers located at the gate, a concentration-dependent parallel shift to the right and a depression of the maximum of the membrane responsiveness curve occurred. Effects on action potential duration were variable. Repolarization was altered so that action potentials with dissimilar durations recorded from sites proximal to, at, and distal to the gate became equal. The total action potential duration and the effective refractory period of gate Purkinje fibers were prolonged, but the change in action potential duration was always greater than the change in effective refractory period so that the ratio of the change in duration to the change in refractory period was always greater than one.     

Comparative mechanisms of action of antiarrhythmic drugs

The antiarrhythmic actions of different compounds are best compared in terms of their dominant electrophysiologic effects on myocardial fibers from different parts of the heart. Such primary actions may be modified considerably by changes in the serum electrolyte concentrations, pH, interactions with serum proteins, or other extracardiac factors. Clinically, however, it appears useful to categorize antiarrhythmic drugs into four groups in terms of their currently known mechanisms of action. Quinidine is the prototype of Group 1 drugs. Its main effect is the reduction of the maximal rate of depolarization of the cardiac action potential so that it slows conduction velocity and increases the effective refractory period with only minor effects on repolarization. Procainamide, disopyramide, carbamazepine, and Kö 1173 all have similar effects to those of quinidine on heart muscle. Lidocaine and diphenylhydantoin may be considered to constitute a subgroup (Group 1B) of “quinidine-like” drugs. In small concentrations they increase membrane responsiveness but in concentrations in the therapeutic range they have a quinidine-like depressant action on the cardiac membrane, particularly if serum levels of potassium are physiologically appropriate. Group 2 drugs are exemplified by β-adrenergic receptor blocking compounds. In blocking concentrations their only electrophysiologic effect is the reduction in the slope of the pacemaker potential; in very much higher concentrations they reduce the maximal rate of depolarization of the cardiac action potential but the precise clinical significance of this is still uncertain. Amiodarone and bretylium prolong the duration of the action potential in the ventricular muscle and Purkinje fibers without causing a significant change in other electrophysiologic parameters. This leads to a “pure” prolongation of the absolute refractory period which may be regarded as an independent antiarrhythmic mechanism (Group 3). Verapamil, a novel antiarrhythmic compound, is a specific calcium antagonist in the heart. It does not reduce the maximal rate of depolarization of the action potential but slows the spontaneous diastolic depolarization in heart muscle. The effects of verapamil are sufficiently different from those of other known agents to allow the tentative conclusion that its fundamental mode of action represents a fourth (Group IV) class of antiarrhythmic action.     

Effects of flecainide on the cellular electrophysiology of neonatal and adult cardiac fibers

The acute cellular electrophysiologic actions of flecainide acetate on isolated neonatal and adult canine ventricular myocardium and Purkinje fibers were evaluated with standard microelectrode techniques. Flecainide, 0.1 to 10.0 micrograms/ml, produced concentration-dependent decreases in action potential amplitude, overshoot, and phase O Vmax of adult ventricular myocardium and Purkinje fibers. The greatest effects were on Vmax. Neonatal action potential characteristics were affected to a lesser degree by flecainide. Flecainide had disparate effects on myocardial and Purkinje fiber repolarization and refractoriness. In adult ventricular myocardium, action potential duration (APD) and effective refractory period (ERP) increased progressively with drug concentration. APD and ERP were increased to a lesser degree in neonatal myocardium. In adult Purkinje fibers, APD decreased progressively with increasing flecainide concentrations. ERP decreased at 0.1 and 1.0 microgram/ml, but returned to control values at 10.0 micrograms/ml. APD and ERP of neonatal Purkinje fibers responded to a lesser degree. At faster stimulation frequencies (2 to 4 Hz), flecainide produced significant frequency-dependent decreases in Vmax in adult Purkinje fibers. Such use-dependency was not evident in neonatal fibers. These data indicate a significantly lower sensitivity of immature cardiac tissues to the electrophysiologic effects of flecainide.     

Electrophysiologic effects of a new antiarrhythmic agent, recainam, on isolated canine and rabbit myocardial fibers

Recainam (Wy 42,362) is a new antiarrhythmic agent undergoing clinical evaluation, but its electrophysiologic effects in cardiac muscle are poorly defined. With microelectrode techniques, its profile in isolated preparations of dog and rabbit hearts was determined using drug concentrations of 10 to 300 microM. Recainam induced a concentration- and frequency-dependent decrease in the maximal rate of rise of the phase 0 of the action potential (Vmax), action potential amplitude and overshoot potential, with little or no change in the effective refractory period except in Purkinje fibers, in which it was markedly reduced. At a 300 microM concentration, Vmax was reduced 51% (p less than 0.001) in ventricular muscle and 44% (p less than 0.001) in atrial muscle, with no change in action potential duration or effective refractory period. At the same drug concentration in Purkinje fibers, Vmax was decreased by 41% (p less than 0.01), action potential duration at 90% repolarization by 36% (p less than 0.01) and effective refractory period by 34% (p less than 0.01). Recainam had no significant effect on the sinoatrial node, but it depressed phase 4 depolarization in isoproterenol-induced automaticity in Purkinje fibers. The drug had no effect on slow channel potentials induced by high concentrations of potassium and isoproterenol. The data indicate that the electrophysiologic profile of recainam in isolated cardiac muscle is consistent with the overall effects of class IC agents without having an effect on the slow calcium channel. Its major action is to depress Vmax, with little effect on refractoriness.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antifibrillatory versus antiectopic therapy

The concept of antifibrillatory action distinct from antiarrhythmic effect has recently been recognized. An antiarrhythmic (antiectopic) action leads to a decrease in the frequency of ventricular ectopic beats. In contrast, an antifibrillatory drug action increases myocardial electric stability, decreasing the propensity for ventricular fibrillation. Agents with predominant antiarrhythmic action (designated class I) include lidocaine, quinidine, procainamide and disopyramide. Bretylium is an agent with predominant antifibrillatory action (class III). Amiodarone and sotalol are experimental class III drugs. The beta-blockers (class II) also possess antifibrillatory action, particularly in ischemic heart disease. The rationale for the use of agents with antiarrhythmic (antiectopic) effects is the reduction of triggering events for more complex ventricular tachyarrhythmias. These agents act by slowing conduction, decreasing abnormal automaticity and affecting phase IV depolarization. In contrast, agents with antifibrillatory action may exert little effect on cardiac conduction and automaticity. However, they raise the energy threshold required for premature electrical discharge to initiate ventricular fibrillation (ventricular fibrillation threshold). The inhomogeneity of electrophysiologic properties and adrenergic tone in different portions of the heart may be reduced or eliminated. Direct electrophysiologic effects of agents such as bretyllum include a general lengthening of the refractory period and the action potential duration in the heart and a diminution in the disparity of their durations between normal and abnormal myocardium.Clinical studies are incomplete, but they support the concept of antifibrillatory therapy. In postmyocardial infarction patients at intermediate risk of sudden death, the broad use of oral antiarrhythmic agents has not decreased the incidence of sudden death, whereas high-dose β-blocker therapy, which exerts experimental antifibrillatory effects, may reduce sudden death by 30 to 70%. For survivors of sudden death and sustained ventricular arrhythmias at high risk of recurrence, clinical evidence suggests that antifibrillatory therapy with amiodarone is generally more effective in reducing recurrence than is therapy with both standard and newer antiarrhythmic agents. In therapy or prophylaxis of acute ventricular fibrillation, bretylium is unexcelled. Unlike standard antiectopic agents, bretylium reduces the experimental defibrillation threshold. Ventricular fibrillation recurring despite standard therapy responds to bretylium in up to 75 % of patients, based on several clinical studies.     

Effects of propafenone on sinus nodal and ventricular automaticity: in vitro and in vivo correlation

The electrophysiologic effects of the new antiarrhythmic drug, propafenone, were evaluated in anesthetized closed-chest dogs and on isolated cardiac tissues with the microelectrode technique. Propafenone (2 to 4 mg/kg intravenously) had no effect on sinus rate or on sinus nodal recovery time, but caused a dose-dependent significant decrease in the rate of idioventricular rhythm and increased the duration of ventricular overdrive suppression in dogs (n = 8) with complete atrioventricular block. On isolated canine Purkinje fibers (n = 8) manifesting automaticity with resting membrane potential less negative than -70 mV, propafenone reduced the slope of phase 4 depolarization and reduced the rate of automatic impulse initiation in a concentration-dependent manner (10(-6) M-4.10(-5) M). At these concentrations, propafenone had no effect on rabbit sinus nodal automaticity (n = 8) or on sinoatrial conduction. However, significant depression of sinus nodal automaticity occurred with propafenone concentrations above 5.10(-6) M in the presence of cholinergic or complete autonomic blockade with atropine (10(-6) M) and propranolol (5.10(-5) M). Propafenone caused a concentration-dependent decrease in the disparity of Purkinje fiber-ventricular muscle action potential duration (APD), mainly by shortening Purkinje fiber APD. We conclude: that propafenone suppresses idioventricular rhythm in the intact dog, most likely by depressing Purkinje fiber automaticity; the depressant effect of propafenone on sinus nodal automaticity is evident only during cholinergic receptor blockade; and the antiarrhythmic properties of propafenone may include removal of APD disparity by selective shortening of Purkinje fiber and not of ventricular muscle APD.     

OPC-88117 suppresses early and delayed afterdepolarizations and arrhythmias induced by cesium, 4-aminopyridine and digitalis in canine Purkinje fibers and in the canine heart in situ

The effects of OPC-88117, a new investigational antiarrhythmic drug, on early and delayed afterdepolarizations (EAD and DAD, respectively) were assessed in vitro in canine Purkinje fibers and in vivo in the canine right ventricle. OPC-88117 had similar electrophysiologic properties to class I antiarrhythmic agents in that it decreased Vmax. OPC-88117 decreased the amplitude and prolonged the coupling interval of DAD induced by acetylstrophanthidin. Likewise, OPC-88117 suppressed EAD induced in vitro by 4-aminopyridine. In vivo, cesium-induced EAD, ventricular arrhythmia, and atrioventricular block were suppressed by OPC-88117. In summary, OPC-88117 suppressed DAD and EAD in vitro and inhibited EAD and triggered activity in the in situ canine heart.     

Electrophysiologic effects of imipramine and doxepin on normal and depressed cardiac Purkinje fibers

The tricyclic antidepressant drug imipramine may cause ventricular arrhythmias and intraventricular conduction disturbances in clinical use, particularly in patients who have ingested toxic doses or who have preexisting heart disease. Such effects have not been reported with doxepin, another tricyclic antidepressant drug. In this study, the electrophysiologic effects of these two drugs on normal and depressed canine Purkinje fibers were examined. Fiber depression was achieved by elevating potassium concentration [K⁺] in the perfusate to 10 mM. In normal Purkinje fibers both imipramine and doxepin were tested in concentrations of 50, 250, 500 and 1,000 ng/ml. Both drugs had no effect on resting membrane potential but caused similar, dose-related reductions in action potential amplitude, maximal velocity of phase 0 depolarization (V_max), action potential duration, conduction velocity and effective and functional refractory periods. Depressed fibers were exposed to only 250 ng/ml of imipramine and doxepin. Both drugs reduced conduction velocity and failed to alter the refractory periods of the depressed fibers whereas at the same concentration in normal fibers they caused no change in conduction velocity but shortened the refractory periods. The other electrophysiologic effects of the two drugs on depressed fibers were similar to those on normal fibers. These observations indicate that depressed fibers are more sensitive than normal fibers to certain electrophysiologic effects of both imipramine and doxepin, and that the different incidence rates of arrhythmias and conduction disturbances associated with the clinical use of these drugs is probably not due to differences in their direct electrophysiologic effects on the ventricular specialized conduction system.     

Cardiac Electrophysiologic Effects of 9-Deoxydoxorubicin

Electrophysiology of 9-Deoxydoxorubicin. Introduction : The purpose of this investigation was to use standard microelectrode techniques to study the actions of the anthracycline antibiotic, 9-deoxydoxorubicin (9-DOD), on cellular electrophysiologic properties of canine Purkinje fibers and on ouabain-induced ventricular tachycardia (VT) in intact dogs. Methods and Results : 9-DOD, 1-5 μM, suppressed delayed afterdepolarizations and prolonged repolarization and the effective refractory period in Purkinje fibers. It had no effect on maximum diastolic potential, V?_max of phase 0, or action potential overshoot through a 10 μM concentration. Although 9-DOD did augment early afterdepolarizations (EAD) induced by cesium, it did not induce EAD. In six of eight intact dogs with ouabain-induced VT, 9-DOD, 0.32-1.28 mg/m² IV, brought conversion to sinus or junctional rhythm. In its cellular and intact animal antiarrhythmic actions, 9-DOD is about 50 times more potent than the parent compound, doxorubicin. Like doxorubicin, it is highly selective for delayed afterdepolarization-induced rhythms, suppressing these at concentrations lower than those required to reduce the rate of automatic rhythms. Moreover, it has a greater Class III action than doxorubicin and prolongs the duration of normal and calcium-induced (slow response) action potentials. Hence, this subtle variation on the doxorubicin molecule adds greatly to the antiarrhythmic action of the drug. Conclusions : Although useful as an investigative tool, clinical development of 9-DOD as an antiarrhythmic is not possible because the antitumor activity of the parent compound, which results in lipid peroxidation and cardiotoxicity, persists.     

Electrophysiological effects of some antidepressant drugs on canine cardiac Purkinje fibres

The electrophysiological effects of several antidepressant drugs, imipramine, metapramine, minanserin, nomifensine, and amineptine, were studied in canine cardiac Purkinje fibres at concentrations between 10(-6) mol.litre-1 and 10(-4) mol.litre-1. Metapramine (10(-5) mol.litre-1) decreased the action potential amplitude, the action potential duration, and Vmax. In addition, imipramine or metapramine induced a pronounced increase of conduction time and conduction block at 10(-4) mol.litre-1, whereas with mianserin and nomifensine a 10(-4) mol.litre-1 concentration was necessary to induce a decrease of Vmax and conduction velocity. With the exception of conduction time and action potential duration, amineptine was not able significantly to change the electrophysiological indices of canine Purkinje fibres. The decrease of Vmax observed with imipramine, metapramine, and with high concentration of mianserin and nomifensine confirms that the antiarrhythmic action of these agents might be related principally to their class I antiarrhythmic effects. The fact that amineptine, which is not antiarrhythmic, does not decrease Vmax reinforces this suggestion.     

Placement of moricizine in the selection of antiarrhythmic drug therapy

The selection of antiarrhythmic drug therapy requires a careful assessment of the benefits of ventricular arrhythmia suppression compared with the risks of antiarrhythmic drug use. Since reduction in sudden cardiac death from ventricular arrhythmia suppression has not been demonstrated, the only indications for antiarrhythmic drug suppression involve the reduction of hemodynamic symptoms such as syncope (a major benefit) or the reduction of nonhemodynamic symptoms such as palpitations or dizziness (a minor benefit). Noncardiac adverse effects and organ toxicity as well as cardiac side effects must be considered when antiarrhythmic drug therapy is initiated. For reduction of nonhemodynamically important symptoms in patients with benign or potentially lethal ventricular arrhythmias, beta blockers are chosen as first-line therapy. Because of moricizine's relatively high effectiveness in suppressing ventricular arrhythmias and its low potential for noncardiac adverse effects and organ toxicity as well as a low incidence of induced proarrhythmia and heart failure, moricizine is selected as the next drug in line. All other class I antiarrhythmic drugs either have been shown to have the potential for increasing sudden cardiac death or have major rates of noncardiac adverse effects or organ toxicity that preclude their use in these patient groups except in special circumstances. In patients with malignant ventricular arrhythmias who present with hemodynamic consequences such as syncope or worse, moricizine also is preferred as an initial drug for consideration. When compared to drugs with class IA and IB action, moricizine has comparable efficacy yet lower rates of noncardiac adverse effects, organ toxicity, proarrhythmia and heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic effects of propafenone on canine ischemic cardiac cells

The electrophysiologic effects of propafenone were studied by conventional microelectrode techniques in ischemic myocardial and Purkinje fibers from 1-day-old myocardial infarction in the dog. Propafenone reduced the amplitude and rate of rise of normal myocardial and Purkinje action potentials and had little effect on the resting potential. In the control state, both ischemic myocardial and Purkinje fibers had reduced resting potential, action potential amplitude and upstroke velocity. These fibers were more susceptible to the depressant effects of propafenone than normal fibers. Ischemic myocardial fibers were particularly sensitive to the actions of propafenone that resulted in marked depression of action potential characteristics, with little effect on resting potential. These changes resulted in cycle length-dependent conduction disorders in ischemic epicardial preparations. However, in ischemic endocardial preparations in which triggered activity could be initiated, propafenone reversibly suppressed the triggered activity. Termination of the triggered activity was preceded by slowing of the rate, which was attributed to a decrease in the rate of rise of the delayed afterdepolarizations. This activity terminated when the delayed afterdepolarization failed to attain threshold potential. This study suggests that propafenone has a membraneanesthetic effect, with the abnormal fast channel in ischemic cells being more sensitive; propafenone depresses delayed afterdepolarizations in ischemic Purkinje fibers; and the actions of propafenone could result in an antiarrhythmic effect in vivo on both reentrant ventricular rhythms in ischemic myocardium and triggered rhythms in ischemic Purkinje fibers.     

Cardiac electrophysiologic effects of etafenone hydrochloride (Dialicor), a new antiarrhythmic agent.

The electrophysiologic effects of etafenone hydrochloride (Dialicor) were studied in isolated rabbit hearts and canine or rabbit cardiac tissues with intracellular microelectrode techniques. The concentration range used was 0.25-10 mg/L, except in experiments with direct addition of etafenone into the tissue bath. Etafenone depressed automaticity in the sinus node, atrioventricular junction and Purkinje fibers at concentrations not affecting the action potential contour. In both atrial and ventricular fibers, etafenone prolonged the action potential duration and total refractory period. The action potential upstroke was slowed and conduction time increased. Higher concentrations reduced the resting potential, causing incomplete depolarization. Atrial action potentials were affected at lower concentrations than ventricular and Purkinje action potentials. Occasi-nally, etafenone produced localized conduction block within the atria, usually sparing internodal conduction. In electrically driven hearts, direct recording of His bundle potential as well as surface electrograms revealed marked prolongation of intraatrial and intranodal conduction times, with some increase in His-Purkinje and ventricular conduction times. Depression of atrioventricular conduction was insignificant under sinus rhythm. Possible therapeutic implications of these electrophysiologic effects are discussed.     

Electrophysiology of Ethacizin: Effects on Arrhythmias in the In Situ Heart and Transmembrane Action Potentials of Purkinje Fibers and Ventricular Muscle Cells

Therapeutic and Toxic Effects of Ethacizin. Ethacizin is a new antiarrhythmic drug that is a derivative of ethmozine. We confirmed the early findings that ethacizin reduces the arrhythmias that occur in dogs 24 hours after ligation of the left anterior descending coronary artery. However, we found that QRS duration and R-on-T beats were increased by ethacizin, and that sudden death occurred in one-third of the dogs. In control experiments, etbmozine (n = 6) and quinidine (n = 6) produced antiarrhythmic effects comparable to those of ethacizin, but sudden death did not occur. Studies then were carried out on canine cardiac tissues using standard microelectrode techniques. Ethacizin 300 ng/mL decreased dV/dt_max in Purkinje fibers and ventricular muscle. These decreases were rate dependent. Ethacizin decreased action potential plateau duration (APD-60 mV) in false tendon Purkinje fibers, and increased it in ventricular muscle. In spontaneously firing Purkinje fibers, ethacizin consistently decreased high-potential (normal) and low-potential (abnormal) automaticity to 14% and 12% of control, respectively. The effects of ethacizin on catecholamine-enhanced high-potential automaticity were more variable. Automaticity decreased in about half of the fibers, but did not change greatly in the remainder. The antiarrhythmic actions of ethacizin may result from reduction of impulse initiation or conduction in Purkinje fibers or myocardial cells. (J Cardiovasc Electrophysiol, Vol. 1, pp. 411–425, October 1990)