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. FIG. 1. Chemical structure of aprindine Rapid intravenous injection of epine 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