Pharmacological Study of Aprindine (A. Christiaens, AC1802; N-(3-Diethylamino) Propyl)-N-Phenyl-2-Indanamine) by Georges Et Al

Japan. J. Pharmacol. 25, 549-561 (1975) 549

ANTIARRHYTHMIC EFFECT OF APRINDINE ON SEVERAL TYPES OF VENTRICULAR ARRHYTHMIAS

Motohiko UEDA, Sadatoshi KIMOTO, Saburo MATSUDA, Masaru KAWAKAMI, Eiichi MORISHIGE, Shoichi MATSUMURA and Hiroshi TAKEDA Shionogi Research Laboratory, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553, Japan

Accepted July 31, 1975

Abstract-The antiarrhythmic effect of aprindine was compared with those of lidocaine and propranolol on several ventricular arrhythmias-epinephrine arrhythmias in cats, ouabain arrhythmias in cats and guinea pigs, ischemic ventricular arrhythmias in coronary-ligated Beagle dogs. Antiarrhythmic effects of aprindine and lidocaine were observed both in ouabain and ischemic arrhythmias, but not in epinephrine arrhythmias. While propranolol had a strong antiarrhythmic effect against epinephrine and ouabain arrhythmias, it did not increase sinus beats in ischemic arrhythmias. Marked anti arrhythmic effects of aprindine in ischemic arrhythmias were observed in dogs using either single intravenous administration (4 mg, kg) or intravenous infusion (200 pg/ kg/min, 2 mg/kg). Antiarrhythmic activity of aprindine is considered to be about twice as strong as that of lidocaine, but lidocaine is less toxic in experimental animals.

Pharmacological study of aprindine (A. Christiaens, AC1802; N-(3-diethylamino) propyl)-N-phenyl-2-indanamine) by Georges et al. (1) showed that the antiarrhythmic effects of aprindine were present both in ouabain arrhythmias and ischemic ventricular arrhythmias in dogs. These workers also reported the superior local anesthetic activity of aprindine to lidocaine, tetracaine, and procaine. Fasola (2) and Kesteloot et al. (3) clinically confirmed the antiarrhythmic effect of aprindine, i.e., prevention of premature ventricular beats. From electrocardiograms of arrhythmic patients, Gleichmann et al. (4) observed that aprindine as well as ajmaline retarded conduction in the His bundle. Orally administered aprindine is said to be more favorable than intravenously administered lidocaine for ventricular arrhythmias in patients with acute myocardial infarction (5). We compared antiarrhythmic effects of aprindine on several ventricular arrhythmias in cats, guinea pigs and dogs with those of lidocaine, propranolol, ajmaline, quinidine, and procaine amide.

MATERIALS AND METHODS Epinephrine arrhythmias: Male cats weighing 2.2-5.2 kg were anesthetized with pentobarbital-Na (25 mg/kg, i.v.) and urethane (0.6 g/kg, s.c.). Respiratory movements via a glass cannulae inserted into trachea, femoral blood pressure, and electrocardiogram (ECG II, V5_6) were recorded on an ink-writing oscillograph (WI-260, Nihon Kohden) 550 M. UEDA ET AL.

with a respiratory pick-up (MTR-ITA, N.K.), a pressure transducer (MP-24T, N.K.), and a biophysical amplifier (RB-2, N.K.), respectively. Rapid intravenous injection of epine FIG. 1. Chemical structure of aprindine hydrochloride phrine (30-50 fig/kg) elicited marked ventric ular arrhythmias lasting for 1 to 1.5 min in anesthetized cats. Five min after the intravenous administration of antiarrhythmic compounds, epinephrine was injected. In order to com pare the antiarrhythmic effect, sinus (SR) and non-sinus rates (NSR) caused by epinephrine were observed every 30 sec for a duration of 5 min before and after administration of the antiarrhythmic agent. The duration of the antiarrhythmic effects was confirmed by re peated administration of epinephrine at 30 and 60 min after the antiarrhythmic compounds. Ouabain arrhythmias in cats: Ouabain was intravenously administered to anesthetized cats until steady occurrence of ventricular rhythm-that is, the initial ouabain dose (50 fig/kg) was followed by an additional dose of 5 Pg/kg every 15 min. Antiarrhythmic compounds were intravenously or orally administered 15-30 min after the establishment of ventricular rhythm in cats. Intravenous infusion of the antiarrhythmic compound was performed with an infusion pump (STP-11, Sharp) until 3-5 min after the disappearance of arrhythmias. Ouabain arrhythmias in guinea pigs: Ouabain at a dose of 4.4 ,ug/animal was inter mittently administered every 2 min to anesthetized male guinea pigs weighing 330-430 g (urethane 1.3-1.6 g/kg, i.p.) until cardiac arrest following the method of Sekiya and Vaughan Williams (6). In order to differentiate ventricular arrhythmias, ECG II of guinea pig was continuously recorded with ink-writing oscillograph. The ouabain dose which caused ventricular extrasystole, ventricular rhythm, ventricular fibrillation, and cardiac arrest was statistically compared (F-test) between the control group and the group given antiarrhythmic compounds intravenously (5 min) or intraduodenally (10 min) before ouabain. Ischemic arrhythmias: Beagle dogs of either sex weighing 7-10 kg were anesthetized with morphine (1 mg/kg, s.c.) and pentobarbital-Na (25 mg/kg, i.p.). After thoracotomy under artificial respiration with room air, the anterior descending branch of the left coronary artery was ligated at the inferior margin of the left atrium by Harris' technique (7). Twenty four hr after the operation, marked ventricular arrhythmias were continuously noted on the ECG II in the conscious dogs. ECG II was recorded with the ink-writing oscillograph, as antiarrhythmic compounds were being injected or infused (KN-202, Natsume) into the cutaneous vein of the fore-leg. SR and NSR every I min were counted in order to evaluate the antiarrhythmic activity of the compounds. Compounds: The following compounds were used as saline solutions: aprindine HC1 (A. Christiaens), dl-propranolol• HCl (Sigma), procaine amide' HCl (K & K Labs.), quinidine• H$SO4 (Merck), lidocaine (K & K Labs.), ajmaline (Yamanouchi), epinephrine Cl (Sankyo), ouabain (Merck). Lidocaine was dissolved with 1N hydrochloric acid solution and diluted with saline solution after the pH had been adjusted to 5.5 to 7.0 with solid ANTIARRHYTHMIC EFFECT OF APRINDINE 551 sodium bicarbonate. The dosage of a given compound was determined as a base.

RESULTS Effects on epinephrine arrhythmias in cats Intravenous injection of 3 mg/kg aprindine or ajmaline caused transient apnoea and a marked fall of blood pressure with ventricular arrhythmias lasting for a few min. Though lidocaine (4 mg/kg, i.v.) caused transient apnoea as well, only a moderate fall of blood pressure was observed without noticeable changes in ECG pattern. Thus the maximal doses used for this experiment were 2 mg/kg for aprindine and 4 mg/kg for lidocaine.

TABLE1. Effects of antiarrhythmic compounds on epinephrine-induced arrhythmias in cats

1) Incidence of arrhythmias/no. of animals 2) Mean value ± standard error 552 M. UEDA ET AL.

FIG. 2. Antiarrhythmic effects of aprindine, lidocaine, and propranolol on epine phrine-induced arrhythmias in cats. Numerals in each column indicate the incidence of ventricular arrhythmias.

No antiarrhythmic effects were noticed for aprindine, lidocaine, and ajmaline even at their maximal dose, although marked antiarrhythmic effects were observed using pre treatment of propranolol (0.5 mg/kg, i.v.) and quinidine (10 mg/kg, i.v.) and some effects using procaine amide (Table 1, Fig. 2). Effects on ouabain arrhytlnnias in cats By cumulative intravenous administration of ouabain at doses of 60-75 '"g/kg, sinus rhythm was converted to ventricular rhythm via ventricular extrasystole in 6 control cats (Fig. 3). The ventricular rhythm continued for more than 3 hr in 3 cats and for about 1 hr in the other 3. In the latter group, cardiac arrest was observed after ventricular flutter or fibrillation. Spontaneous recovery from ventricular rhythm to sinus rhythm was not ANTIARRHYTHMIC EFFECT OF APRINDINE 553 observed. Intravenous infusion of antiarrhythinic compounds: Recovery from ventricular rhythm to sinus rhythm was observed with the intravenous infusion of aprindine (200 pg/kg/min, 5-7 mg/kg) in 3 out of 8 cats (Table 2). The established sinus rhythm continued for more

FIG. 3. Ouabain-induced arrhythmias in cats. B : Before, SR: Sinus rhythm, VES : Ventricular extrasystole, VR : Ventricular rhythm, VF: Ventricular flutter, VFi: Ventricular fibrillation.

TABLE 2. Effects of intravenous infusion of aprindine, lidocaine, and propranolol on ouabain-induced arrhythmias in cats

1) Mean value '-standard error 2) No. of antiarrhythmic effects/no. of animals 3) Duration of antiarrhythmic effects than 2 hr. Further infusion of aprindine was discontinued, because the characteristic pattern of ECG II by the cardiotoxic doses of aprindine-some notch on R spike, irregular height of R spike, widening of QRS complex, and depression of ST segment was observed. Lidocaine infusion (400 Pg/kg/min, 15-20 mg/kg) converted ventricular rhythm to sinus rhythm in all experiments and the established sinus rhythm was stable for more than 2 hr. Propranolol (200 pg/kg/min, 3-5 mg/kg) also caused recovery of sinus rhythm from marked arrhythmias in 4 out of 5 cats. In one cat, however, incomplete recovery to sinus rhythm with ventricular extrasystole was observed. Oral administration of antiarrhytlunic compounds: Although lidocaine did not show any antiarrhythmic activity, propranolol (20 mg/kg) converted ventricular rhythm to sinus rhythm in all cats even by oral administration. On the other hand, antiarrhythmic effects of aprindine (10, 20 mg/kg) and ajmaline (20 mg/kg) were incomplete as shown at Table 3. 554 M. UEDA ET AL.

TABLE3. Effects of oral administration of aprindine, lidocaine, propranolol, and ajmaline on ouabain-induced arrhythmias in cats

1) No. of antiarrhythmic effects/no. of animals 2) Duration of antiarrhythmic effects

Effects on ouabain arrhythmias in guinea pigs Intravenous administration of antiarrhythmic compounds: Aprindine at 4 mg/kg required significant increases in ouabain doses necessary to cause ventricular rhythm, ventricular fibrillation, and cardiac arrest. These effects were also observed with administration of lidocaine at 8 mg/kg. Antagonism to the ouabain arrhythmias was most distinctly shown by propranolol. Although ajmaline at 4 mg/kg required moderate increases in ouabain doses necessary to cause arrhythmias, these increases were not significant. Intraduodenal administration of antiarrhythmic compounds: Aprindine required moder ate increases in ouabain doses necessary to cause arrhythmias, but these increases were not significant. On the other hand, lidocaine and propranolol required significant increases

TABLE4. Effects of intravenous administration of aprindine, lidocaine, propranolol, and ajmaline on ouabain-induced arrhythmias in guinea pigs

1) Standard error, *P<0.05, **P<0.01, ***P<0.001 (Statistically significant compared to the control values) Numerals in parenthesis indicate the number of animals with ventricular fibrillation. ANTIARRHYTHMIC EFFECT OF APRINDINE 555

TABLE5. Effects of intraduodenal administration of aprindine, lidocaine, propranolol, and ajmaline on ouabain-induced arrhythmias in guinea pigs

1) Standard error, *P<0.05, **P<0.01, (Statistically significant compared to the control values) Numerals in parenthesis indicate the number of animals with ventricular fibrillation. in ouabain doses. No effect was observed upon administration of ajmaline.

Effects on ischemic arrhythmias in dogs Twenty-four hr after a ligation of the anterior descending branch of the left coronary artery, marked ventricular rhythm interspersed by a few sinus beats was observed in dogs. As shown by Fig. 4, SR and NSR were stable for longer periods.

FIG. 4. Ischemic ventricular arrhythmias of Beagle dogs 24 hr after coronary ligation according to Harris. 556 M. UEDA ET AL.

Single intravenous administration of antiarrhythmic compounds: Aprindine at a dose of 4 mg/kg significantly decreased heart rate and increased SR (Fig. 5). Negative chrono tropic effect of aprindine lasted more than one hr, but sinus beats began to decrease within about 40 min after injection. Vomiting occurred 5 min after aprindine administration in one dog. These negative chronotropic effects and increase of SR were also observed with the administration of lidocaine 8 mg/kg. But lidocaine caused such excitatory symptoms as tonic convulsion and tail raising in 3 out of 4 dogs . Lidocaine at a dose of 4 mg/kg did not show any effect. Propranolol (0.1-0.5 mg/kg) showed a moderate negative chronotropic effect, but did not increase SR. Intravenous infusion of antiarrhythmic compounds: Aprindine at a dose of 2 mg/kg (200 fig/kg/min) caused negative chronotropic effects and increased SR. Significant in creases of SR were observed for 30 min after aprindine infusion . An antiarrhythmic effect

FIG. 5. Antiarrhythmic effects of aprindine on ischemic ventricular arrhythmias in Beagle dogs. TABLE6. Effects of a single intravenous administration of aprindine, lidocaine, and propranolol on ischemic ventricular arrhythmias in Beagle dogs (24 hr after coronary ligation)

H.R.: Heart rate (beats/min), S.R.: Sinus rhythm, ( ): No. of experiments, 1) Mean+standard error, *P<0.05, **P<0.01, ***P<0.001 (Statistically significant compared to control 0). In the saline group, saline was infused for 10 min (0.8 ml/animal/min). TABLE7. Effects of intravenous infusion of aprindine, lidocaine, propranolol, and ajmaline for 10 min on ischemic ventricular arrhythmias in Beagle dogs (24 hr after coronary ligation)

H.R.: Heart rate (beats/min), S.R.: Sinus rhythm, ( ): No. of experiments, 1) Mean-standard error, *P<0.05, **P<0.01, ***P< _0.001 (Statistically significant compared to control 0). Antiarrhythmic compounds were infused for 10 min from control 0. ANTIARRHYTHMIC EFFECT OF APRINDINE 559 of aprindine was also observed in one dog at a dose of 1 mg/kg (100 fig/kg/min). Lidocaine at 4 mg/kg (400,ag/kg/min) increased SR for 20 min, but propranolol at 2 mg/kg (200 fig/ kg/min) showed negative chronotropic effects with a slight increase of SR.

DISCUSSION Antiarrhythmic effects of aprindine, lidocaine, propranolol, and ajmaline on epine phrine, ouabain, and ischemic arrhythmias are summarized in Table 8. 1) Although anti arrhythmic effects of propranolol were observed both in epinephrine and ouabain arrhy thmias, an increase of sinus beats did not appear in ischemic arrhythmias with propranolol. 2) Aprindine and lidocaine, on the other hand, did not show any antiarrhythmic effects on epinephrine arrhythmias, but significantly increased sinus beats in ischemic arrhythmias. These two points seem to be the most interesting in the present experiments.

TABLE 8. Antiarrhythmic effects of several antiarrhythmic compounds in four experimental arrhythmias

no: no effect, E : effective. (E: 3/8) means that antiarrhythmic effects were observed in 3 out of 8 animals.

In recording electrocardiograms of ischemic epi and endocardium, Wendt (8) observed that isoproterenol augmented the rise of ST segment but propranolol decreased it. Verrir et al. (9) showed that the fibrillation threshold was lowered at the time of coronary ligation and release. Since propranolol antagonized the lowering of the fibrillation threshold at the time of coronary ligation without any antagonism at coronary release, it was presumed that a release of norepinephrine was associated with the lowering of the fibrillation threshold at the time of coronary ligation. Reimer and Jennings (10) histologically examined the effect of propranolol on the posterior papillary muscle with coronary ligation. Propranolol had some preventive effect but had no therapeutic effect on the necrotic tissue. Since the norepinephrine content of the myocardium of dog (11, 12, 13) and pig (14) was markedly decreased by coronary ligation, it was presumed that norepinephrine was released upon coronary ligation and the released norepinephrine was related to eliciting ventricular arrhy thmias. Thus, propranolol would have an effect on the ventricular arrhythmias in the acute myocardial infarction. In this experiment, however, antiarrhythmic effects were 560 M. UEDA ET AL. examined on ischemic arrhythmias 24 hr after coronary ligation following Harris' technique, and it was confirmed that propranolol in the dose range of 0.1-0.5 mg;'kg had no anti arrhythmic effect on the ischemic and norepinephrine-depleted myocardium. Such findings support the observation of Reimer and Jennings (10) that propranolol had no therapeutic effect on the posterior papillary muscle 30 min after coronary ligation. Somani and Lum (15) also reported the non-effectiveness of propranolol and INPEA on ischemic arrhythmias in dogs. Constriction of the coronary artery by a-excitation following ,3-blockade may augment the ischernia in the myocardium. The antiarrhythmic effects of aprindine in the various arrhythmias were similar to those of lidocaine as shown in Table 8. Vaughan Williams (16) observed that lidocaine depressed the maximal rate of depolarization in the myocardium, but other workers (17) reported that lidocaine had no effect on the action potentials in the Purkinje fiber, atrium, and ventricular muscle. Greenspan et al. (18) observed that 1) a decrease of the maximal rate of depolarization, 2) decreases of height and duration of action potentials, 3) delayed conduction in the quiescent Purkinje fiber, and 4) depression of phase 4 depolarization in the autonomous Purkinje fiber were caused by application of aprindine. Aprindine is a No. 1 type, like lidocaine, according to the classification of antiarrhythmic agents by Vaughan Williams (19). Verdonck et al. (20) reported that these effects of aprindine were most clearly observed in the Purkinje fiber but not as markedly in the contractile myocardium. They also observed that the effect of aprindine was long-lasting and tissue concentration of aprindine became about 10 times higher than the concentration in the bathing medium. Therefore the antiarrhythmic mechanism of aprindine is presumed to be based on its in hibition of the maximal rate of depolarization (inhibition of sodium influx) and pacemaker activity. These effects of aprindine presumably suppress the ectopic focus in the ischemic myocardium. The shortening of the refractory period by aprindine (20) may explain to some extent the arrhythmogenic effect. In ouabain arrhythmias, oral administration of aprindine produced an antiarrhythmic effect in cats but not in guinea pigs, while the effects of lidocaine were vice versa. Thus, it is difficult to conclude that oral administration of aprindine is superior to that of lidocaine for antiarrhythmic activity. Intravenously administered lidocaine showed a lasting anti arrhythmic effect on ouabain arrhythmias in cats but its effect on ischemic arrhythmias in dogs did not last so long as that of aprindine. For both ouabain and ischemic arrhythmias, the antiarrhythmic dose of aprindine was about one-half that of lidocaine, but acute toxicity of aprindine in mice and rats was about twice as strong as that of lidocaine (private com munication from Dr. Y. Hayashi). In conclusion, aprindine as a potent antiarrhythmic agent seems to be equivalent to lidocaine. The marked antiarrhythmic effect of aprindine on ischemic arrhythmias, how ever, is deemed worthy of further investigation.

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