Moricizine (Ethmozine) Can Break Electrical Coupling between Rat Right Atrial Working Cardiomyocytes In Vitro.

A previously popular antiarrhythmic drug moricizine (ethmozine) is known for its blocking action on the fast sodium channels in cardiomyocytes. Its effects were examined only in isolated cardiomyocytes or in vivo. Here, the effect of moricizine (10 µM) was examined in vitro on perfused right atrial preparation, where it completely reproduced all the previously observed phenomena and disturbed electrical coupling between the working cardiomyocytes in 35.3±3.4 min, which arrested generation of action potentials. During washing, the cardiomyocytes restored rhythmic firing in 34.1±3.7 min. Inhibition of firing in the working atrial cardiomyocytes was not accompanied by suppression of rhythmic activity in the pacemaker cells of sinoatrial node as attested by rhythmic miniature spikes in the records of resting (diastolic) potential of these cardiomyocytes. Thus, moricizine disturbed conduction between the working atrial cardiomyocytes without affecting the pacemaker activity.

Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block.

The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with the increase in the duration of train pulses, and was more prominent with a holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of INa induced by moricizine during depolarization to -20 mV was continuously increased with increasing the pulse duration, and was enhanced at the less negative HP. The slower component of recovery of the moricizine-induced INa block was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/- 1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP = -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and 22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or cloned hH1 had significantly higher sensitivity to moricizine than atrial INa. The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3 microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM moricizine. From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.

Moricizine, an antiarrhythmic agent, as a potent inhibitor of hepatic microsomal CYP1A.

We examined the inhibitory effect of moricizine (MOR) on hepatic cytochrome P-450 (CYP) in mice. Spectrophotometric analysis revealed that MOR had a relatively high affinity for CYP molecules. MOR most potently inhibited the CYP1A1-dependent ethoxyresorufin O-deethylation and the CYP1A2-dependent methoxyresorufin O-demethylation, among the metabolic reactions mediated by CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP3A subfamilies expressed in untreated and CYP-inducer-treated hepatic microsomes. The inhibition constants (K(i)) for ethoxyresorufin and methoxyresorufin O-dealkylations were 0.43 and 0.98 micromol/l, respectively. These K(i) values were one to three orders of magnitude lower than those of cimetidine (CIM) and mexiletine (MEX) that have been accepted as the clinical inhibitors of CYP1A2 and were below the therapeutic serum concentration of MOR. Theophylline 3-demethylation and 8-hydroxylation in untreated hepatic microsomes, clinical probes for CYP1A2 activities, were subjected to marked and competitive inhibition by MOR with K(i) values similar to that of methoxyresorufin O-demethylation, and the inhibitory potency of MOR was much higher than those of CIM and MEX. In addition, the zoxazolamine paralysis time, an in vivo measure of the hepatic CYP1A2 capacity, was markedly prolonged by pretreatment of mice with MOR rather than CIM and MEX, while the prolonging effect of MOR on the pentobarbital sleeping time, an indicator of the metabolic function of phenobarbital-inducible CYP species, was not so pronounced as compared with the zoxazolamine paralysis time. These results indicate that MOR acts as a potent and preferential inhibitor of hepatic CYP1A enzymes in vitro and in vivo.

[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.

Pharmacokinetic interactions of moricizine and diltiazem in healthy volunteers.

Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.

Effect of chronic oral moricizine and intravenous epinephrine on ventricular fibrillation and defibrillation thresholds.

The purpose of this study was to determine the effects of chronic oral moricizine therapy and physiological doses of epinephrine on ventricular fibrillation and defibrillation thresholds using an implantable transvenous/subcutaneous defibrillation system in a pig model. Thirteen pigs completed the three phases of the study. After a baseline study on day 1, the animals were randomized to receive moricizine 10-15 mg/kg tid or placebo for seven doses, at which time the protocol was repeated on day 4. The same protocol was again repeated on the same day after infusion of physiological doses of epinephrine. Multiple ventricular fibrillation and defibrillation thresholds were measured during each study. Moricizine did not alter ventricular fibrillation nor defibrillation thresholds, whereas epinephrine increased the ventricular defibrillation threshold from 20.8 J to 23.7 J (P < 0.05). In addition, we observed an increase in both ventricular fibrillation (19.7 J vs 12.6 J; P < 0.05) and defibrillation (20.8 J vs 17.8 J; P 0.05) thresholds over the 4 days of the study. These findings suggest that moricizine may be a safe antiarrhythmic agent to use in patients with implantable cardioverter defibrillators, and that elevated endogenous epinephrine may render defibrillation more difficult.

Rate-dependent anisotropic conduction property in the epicardial border zone of canine myocardial infarcts and its modification by moricizine.

We evaluated anisotropic conduction properties, different conduction velocities depending on fiber orientation, in normal and infarcted myocardium and the effects of moricizine on anisotropic conduction. Various cycle lengths of stimulation were applied to 15 mongrel dogs, and epicardial mapping was performed using a 96-channel mapping electrode. Moricizine was then administered to seven dogs and the same procedure was performed. Conduction velocities were calculated from these maps. Programmed electrical stimulations were performed before and after moricizine administration to induce ventricular arrhythmias. Before moricizine administration, a rate-dependent decrease in longitudinal conduction velocity was observed in the infarcted zone. Moricizine suppressed longitudinal conduction in the normal zone significantly at 300 msec pacing, but not at slower rates. Moricizine at a dose of 4 mg/kg, on the other hand, suppressed longitudinal conduction in the infarcted zone significantly at all pacing cycle lengths. The effect of moricizine on transverse conduction was inconsistent. In three dogs, sustained ventricular tachycardia (VT) was induced either before or after moricizine administration. The mean cycle length of sustained VT was prolonged from 202 msec to 291 msec after 4 mg/kg of moricizine. Thus, the changes in cycle length of ventricular tachycardia observed were most likely the result of slowing of conduction velocity, especially in the longitudinal direction, in the infarcted myocardium. We conclude that the electrophysiologic nature of the subacute ischemic model was modified by moricizine, leading to depression of the conduction velocity of longitudinal conduction and the inducibility of ventricular arrhythmias.

Effect of moricizine on heart rate variability in normal subjects.

We investigated the effects of moricizine HCl, a type Ic anti-arrhythmic agent, on heart rate variability. Decreased heart rate variability is a risk factor for mortality in post-MI and other patient populations, and some antiarrhythmic drugs decrease heart rate variability. Normal volunteers (10 M, 11 F, age 19-39 years) received blinded placebo and moricizine HCl at 200 mg twice daily for 5 days. On day 4, a 24-h ECG was obtained, and time and frequency domain measures of heart rate variability based on normal-to-normal intervals were computed. Moricizine decreased both time and frequency domain measures of heart rate variability. Significant reductions were seen for SDNNIDX (the average S.D. for N-Ns for each 5-min interval in ms) and pNN50 (the proportion of successive N-N differences > 50 ms in percent) in the time domain, and very low (0.0033-0.04 Hz), low (0.04-0.15 Hz) and high (0.15-0.4 Hz) frequency power. Similar patterns of change in heart rate variability were seen when data for daytime and nighttime periods were analyzed separately. rMSSD (the root mean square successive difference of N-N intervals in ms), pNN50 and high frequency power are primarily indices of parasympathetic tone. SDNNIDX, and very low and low frequency power reflect both sympathetic and parasympathetic tone and longer term variability. Thus, moricizine decreases both vagal tone and longer term components of heart rate variability. This decrease produced by moricizine is similar to that reported with other type 1 antiarrhythmics.

Electrophysiological effects of Ro 22-9194, a new antiarrhythmic agent, on guinea-pig ventricular cells.

1. Cardiac effects of Ro 22-9194 were examined in papillary muscles and single ventricular myocytes isolated from guinea-pigs and compared with those of moricizine. 2. In papillary muscles, both Ro 22-9194 (> or = 10 microM) and moricizine (> or = 1 microM) caused a significant dose-dependent decrease in the maximum upstroke velocity (Vmax) and a shortening of the action potential duration. 3. In the presence of either drug, trains of stimuli at rates > or = 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequencies. A time constant (tau R) for Vmax recovery from the use-dependent block was 9.3 s for Ro 22-9194 and 26.4 s for moricizine. 4. The curves relating membrane potential and Vmax in single myocytes were shifted by Ro 22-9194 (30 microM) or by moricizine (3 microM) in a hyperpolarizing direction by 8.4 mV and 8.0 mV respectively. 5. In myocytes treated with Ro 22-9194 (30 microM), a 10 ms conditioning clamp to 0 mV caused a significant decrease in Vmax of the subsequent test action potential; further prolongation of the clamp pulse duration resulted in a modest enhancement of the Vmax inhibition. In the presence of moricizine (3 microM), a similar conditioning clamp > 200 ms caused a significant Vmax reduction; the longer the clamp pulse duration, the greater the Vmax reduction. 6. Ro 22-9194 > or = 30 microM caused a slight decrease of calcium inward current (ICa) of myocytes without affecting the delayed rectifier potassium current (IK). 7. These findings suggest that the primary electrophysiological effect of Ro 22-9194 as an antiarrhythmicagent is, like moricizine, a use- and voltage-dependent inhibition of sodium channels. From the onset and offset kinetics of the use-dependent block, Ro 22-9194 belongs to the intermediate kinetic Class I drugs, while moricizine is a slow kinetic drug. From the state-dependence of sodium channel block, Ro 22-9194 may belong to activated channel blockers, while moricizine belongs to inactivated channel blockers.

Electrophysiological mechanisms of action of ethmozine that explain its antiarrhythmic efficacy in the late stage of experimental myocardial infarction in dogs.

The effects of intravenous ethmozine (3 mg.kg-1) on electrophysiological parameters of ischaemically damaged myocardium and induced ventricular tachyarrhythmias were studied by programmed stimulation in 17 conscious dogs with 4 to 8 day-old ligation of the left anterior descending coronary artery. Ethmozine showed a beneficial effect on sustained ventricular tachycardia by suppressing its inducibility in five of 14 animals or by slowing its rate in six of 14 animals. Ethmozine prolonged the ventricular effective refractory period in normal and infarcted myocardium, and impaired depressed conduction in ischaemically damaged tissue. The latter was indicated by significant lengthening of late potentials recorded from the infarction zone. The QT interval was only slightly increased with ethmozine. Our findings indicate an antiarrhythmic action of ethmozine in the late stage of myocardial infarction. Major mechanisms accounting for its efficacy may predominantly be associated with marked depression of slow conduction in the infarction zone, as well as with prolongation of ventricular refractoriness without significant changes of ventricular repolarization.

New classification of moricizine and propafenone based on electrophysiologic and electrocardiographic data from isolated rabbit heart.

Because the classification of propafenone and moricizine is not clear, we measured in 20 specifically equipped isolated rabbit hearts QRS duration, QT interval, action potential duration at 90% of repolarization (APD90), effective refractory period (ERP), conduction time (CT), and rise velocity (Rv) of the monophasic action potentials (AP) during exposure to moricizine and propafenone in comparison with procainamide. Propafenone and procainamide prolonged APD90 and JT. All drugs increased ERP. Propafenone demonstrated marked tonic sodium channel block. Onset of use-dependent kinetics (tau on), defined as change in Rv as fraction per beat at 300 ms cycle length (CL), were 0.047 +/- 0.004/beat for procainamide, 0.050 +/- 0.004/beat for propafenone, and 0.022 +/- 0.003/beat for miricizine. Recovery kinetics, defined as recovery of Rv after cessation of pacing, had a time constant of 5.3 +/- 0.7 s for procainamide, 6.3 +/- 0.8 s for propafenone, and 25.0 +/- 1.3 s for moricizine. Based on these data, moricizine must be classified as a Ic agent, whereas propafenone demonstrates pronounced tonic sodium channel block, in addition to its phasic block, which is similar to class Ia kinetics.

Block of Na+ channel by moricizine hydrochloride in isolated feline ventricular myocytes.

The effect of moricizine hydrochloride, a potent class I antiarrhythmic agent, on Na+ current (INa) of single feline ventricular myocytes were studied using whole cell patch clamp techniques. Moricizine inhibited INa in a concentration-dependent manner without altering the current-voltage relationship for INa. INa inhibition was expressed by the Hill equation with a Hill coefficient of 1.3 and dissociation constant of 105 microM in the resting state (holding potential = -140 mV). Moricizine 30 microM shifted the steady state inactivation curve for INa toward more negative potentials by 7.3 +/- 2.4 mV without causing significant changes in the slope factor. Recovery of INa from inactivation was retarded (time constant = 8 s) at a holding potential of -140 mV in the presence of 30 microM moricizine. When the start of INa block was studied in experiments using a double pulse protocol, moricizine reduced INa by only 4% after a 4-ms prepulse, but strongly inhibited it after prepulses longer than 200 ms. Intracellular application of 100 microM moricizine did not produce significant resting or use-dependent INa block. These results suggest that (1) moricizine blocks INa by binding to the Na+ channel with a 1:1 stoichiometry, (2) the drug has a higher affinity to the inactivated state than to the activated and resting states of the Na+ channel, (3) recovery kinetics of moricizine from Na+ channel inactivation, or drug dissociation observed during the transition from inactivated to resting state was relatively slow, (4) the drug binding site appeared to be located on the external side of the membrane.

Mechanism of interruption of atrial flutter by moricizine. Electrophysiological and multiplexing studies in the canine sterile pericarditis model of atrial flutter.

BACKGROUND: Moricizine is said to have potent effects on cardiac conduction but little or no effect on cardiac refractoriness. METHODS AND RESULTS: The effects of moricizine (2 mg/kg IV) on induced atrial flutter were studied 2 to 4 days after the creation of sterile pericarditis in 11 dogs. Ten episodes of stable atrial flutter before and after the administration of moricizine were studied in 9 dogs in the conscious, nonsedated state, and 7 episodes were studied in 6 dogs in the anesthetized, open chest state. In the conscious state, the effects of moricizine on atrial excitability, atrial effective refractory period, and intra-atrial conduction times were studied by recording during overdrive pacing of sinus rhythm from epicardial electrodes placed at selected atrial sites. Moricizine prolonged the atrial flutter cycle length in all the episodes, from a mean of 133 +/- 9 to 172 +/- 27 milliseconds (P < .001), and then terminated 7 of the 10 episodes. Moricizine increased the atrial threshold of excitability from a mean of 2.3 +/- 1.4 to 3.3 +/- 2.2 mA (P < .01) and prolonged intra-atrial conduction times (measured from the sulcus terminalis to the posteroinferior left atrium) from a mean of 58 +/- 6 to 64 +/- 5 milliseconds (P < .005). Prolongation of the atrial effective refractory period from 166 +/- 20 to 174 +/- 24 milliseconds (P < .05) was observed only at the sulcus terminalis site. In the open chest studies, administration of moricizine prolonged the atrial flutter cycle length from a mean of 150 +/- 15 to 216 +/- 30 milliseconds (P < .001) and then terminated the atrial flutter in all 7 episodes. As demonstrated by simultaneous multisite mapping from 95 bipolar sites on the right atrial free wall, the atrial flutter cycle length prolongation was either due to further slowing of conduction in an area of slow conduction in the reentrant circuit of the atrial flutter (5 episodes) or further slowing of conduction in an area of slow conduction plus the development of a second area of slow conduction (2 episodes). The change in conduction times in the rest of the reentrant circuit was negligible (10.9 +/- 8.7% of the total change). In all 7 episodes, the last circulating reentrant wave front blocked in an area of slow conduction. CONCLUSIONS: Moricizine (1) prolongs the atrial flutter cycle length, primarily by slowing conduction in an area of slow conduction in the reentrant circuit, (2) terminates atrial flutter by causing block of the circulating reentrant wave front in an area of slow conduction of the reentrant circuit, and (3) effectively interrupts otherwise stable atrial flutter in this canine model. The reason for these effects of moricizine are not readily explained by its effects on global atrial conduction times and refractoriness studied during sinus rhythm. Local changes in conduction in an area(s) of slow conduction are responsible for both cycle length prolongation and atrial flutter termination rather than the traditional wavelength concept of head-tail interaction.

Action of MgSO4 differs from moricizine and verapamil on ouabain-induced ventricular tachycardia in normomagnesemic conscious dogs.

We performed a comparative study to determine whether acute administration of MgSO4, moricizine, and verapamil to conscious dogs with normal plasma magnesium levels (0.75 +/- 0.06 mM) terminates ouabain-induced ventricular tachycardia (VT). This arrhythmia is dependent on triggered activity (TA) resulting from delayed afterdepolarizations (DADs). In animals with surgically induced complete atrioventricular (AV) block, monomorphic VT was induced by programmed ventricular stimulation during continuous intravenous (i.v.) infusion of ouabain. At the moment of drug administration, VT persisted for at least 20 min, while the rate was stable for at least 5 min. A single dose of MgSO4 (100 mg/kg i.v.) abolished only VTs with cycle lengths > or = 320 ms (335 +/- 10 ms); VTs with faster cycle lengths (300 +/- 20 ms) were merely slowed, although the increase in plasma magnesium levels was considerable and comparable in both groups (3.9 +/- 1.6 and 4.8 +/- 1.9 mM). In contrast, moricizine (2 mg/kg i.v.) and verapamil (0.5-1.0 mg/kg i.v.) terminated both fast and slow VTs. The cycle length of VT ranged from 280 to 320 ms (mean 300 +/- 15 ms) for moricizine and 260-330 ms (mean 300 +/- 25 ms) for verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme induction by moricizine: time course and extent in healthy subjects.

Moricizine.HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.

A new class of antiarrhythmic--defibrillatory compounds.

Ventricular fibrillation (VF) is a major cause of sudden cardiac death in humans. Currently used antiarrhythmic drugs are aimed at preventing initiation of VF by decreasing the incidence of arrhythmias which can lead to VF. This approach today seems to be insufficient. On the basis of reports that VF can terminate spontaneously in various mammals, and even in humans, we propose pharmaceutical enhancement of self-ventricular defibrillation as a new therapeutical approach. Data obtained over the last decade indicate that a high cardiac extraneuronal noepinephrine level during VF facilitates self-defibrillation. Dibenzazepines (tricyclic antidepressants) and phenothiazines elevate norepinephrine level by inhibiting norepinephrine reuptake and were found to exhibit defibrillatory activity. The relationship of chemical structure to defibrillatory activity was studied in a group of dibenzazepine and phenothiazine compounds.

Ethmozine and ethacizine--new antiarrhythmic drugs with defibrillating properties.

Ventricular fibrillation (VF) is a life-threatening arrhythmia that leads to death unless electrical defibrillation is applied in time. Recent publications indicate that VF can be either sustained (SVF), requiring electrical defibrillation, or transient (TVF), reverting spontaneously into sinus rhythm. Since VF cannot be totally prevented by drugs, a new antiarrhythmic therapeutic approach has been proposed: drug-induced enhancement of the ability of the heart to defibrillate by itself. In this study we examined the defibrillating potency of two antiarrhythmic phenothiazines, ethmozine (ETM) and ethacizine (ETA), as well as their effects on catecholamine uptake and on the electrophysiological properties of the myocardial cell membrane. The antiarrhythmic-defibrillatory activity was examined in cats; the inhibitory effect on [3H]-norepinephrine (NE) uptake was examined in rat brain synaptosomes, and the electrophysiological membrane effects were examined by microelectrode recordings in perfused strips of heart ventricle from guinea-pigs. The results indicate that: 1. ETA exhibits similar but stronger antiarrhythmic-defibrillating and NE reuptake inhibitory effects than ETM; 2. ETA at 10-6 M decreases ventricular conduction time and increases Vmax while ETM at this concentration does not change them; 3. The defibrillating ability of the drugs can be related to their inhibitory potency on NE reuptake. We suggest that the risk of sympathomimetic arrhythmogenicity is prevented by the previously described, membrane stabilizing Class 1 antiarrhythmic properties of these drugs.

Antifibrillatory and electrophysiologic actions of moricizine alone and in combination with lidocaine: a prospective, randomized trial.

OBJECTIVE: The Cardiac Arrhythmia Suppression Trial II showed that moricizine acutely increases the occurrence of sudden cardiac death. Thus the objective of this investigation was to evaluate the antifibrillatory properties of moricizine (a new antiarrhythmic agent) alone and in combination with lidocaine (an established antifibrillatory agent). DESIGN: Prospective, double-blind, randomized, placebo-controlled trial. SETTING: Laboratory at a large, university-affiliated medical center. SUBJECTS: Eighteen domestic farm swine with a mean weight of 39 +/- 5 kg. INTERVENTIONS: After pentobarbital anesthesia, the animals were instrumented. A bipolar pacing catheter was placed in the right ventricular apex and a pig-tail catheter was placed in the aortic arch for induction of ventricular fibrillation and aortic blood pressure monitoring. Subsequently, the pigs were randomized to moricizine or control (0.9% saline) groups. Each group underwent three treatment phases: baseline, drug (moricizine 2 mg/kg loading dose, 1.5 mg/kg/hr infusion, or saline bolus and infusion), and drug combined with lidocaine (5 mg/kg loading dose, 4 mg/kg/hr infusion). Ventricular fibrillation threshold was determined every 5 to 10 mins over a 1-hr period during each treatment phase. RESULTS: Ventricular fibrillation threshold values in the animals randomized to control were 16.8 +/- 7.6, 18.1 +/- 8.9, and 23.9 +/- 10.4 mA at baseline during saline infusion, and when saline was combined with lidocaine, respectively. The values during the saline-lidocaine combination treatment phase were significantly greater than the values at baseline and during saline treatment alone (p < .001). Ventricular fibrillation threshold values in the animals randomized to receive moricizine were 15.5 +/- 4.4, 18.1 +/- 5.1, and 21.1 +/- 8.4 mA at baseline, during moricizine infusion, and when moricizine was combined with lidocaine. The values during the lidocaine-moricizine combination treatment phase were significantly greater than values at baseline (p = .005), but not during moricizine treatment alone (p = .16). The increase in ventricular fibrillation threshold from baseline to moricizine (17%) was similar to the increase from baseline to saline (7%), p = .37. The increase in ventricular fibrillation threshold when lidocaine was added to moricizine (13%) was less than the increase with lidocaine alone (32%), p = .05. CONCLUSION: In this experimental model, moricizine, at the dose studied, lacked antifibrillatory properties. Moreover, moricizine did not contribute to the antifibrillatory effects of lidocaine.