Antiarrhythmic Effects of Coronary Vasodilators on Canine Ventricular Arrhythmia Models

Sadayoshi KOMORI, Masaaki ISHII and Keitaro HASHIMOTO*

Department of Pharmacology, Yamanashi Medical College, 1110 Tamaho-mura, Nakakoma-gun, Yamanashi 409-38, Japan

Accepted February 7, 1985

Abstract-Antiarrhythmic effects of intravenous coronary vasodilators (verapamil, diltiazem, bepridil, trimetazidine and nicorandil) were evaluated using two canine ventricular arrhythmia models (halothane-adrenaline arrhythmia and digitalis ar

rhythmia), and the minimum effective plasma concentrations of the drugs were

determined for each arrhythmia model. Verapamil (0.1 mg/kg), diltiazem (0.1

mg/kg), bepridil (1 mg/kg) and high dose trimetazidine (10 mg/kg) were effective

on halothane-adrenaline arrhythmia; and the minimum effective plasma concen

trations of the above drugs were less than 30•}10 ng/ml, less than 18•}5 ng/ml,

0.38•}0.11 ƒÊg/ml and 7.0•}1.5 ƒÊg/ml, respectively. Nicorandil (1 mg/kg) did not suppress halothane-adrenaline arrhythmia. Verapamil, diltiazem and bepridil

must have suppressed the halothane-adrenaline arrhythmia by blocking the Ca

channel. Verapamil (1 mg/kg), diltiazem (1 mg/kg), bepridil (5 mg/kg), trime

tazidine (3 mg/kg) and nicorandil (3 mg/kg) were ineffective on digitalis arrhythmia,

even though their maximum hypotensive doses were used.

Coronary vasodilators have been used to rhythmias are thought to be unrelated to treat ischemic heart diseases, which are often myocardial ischemia, we chose adrenaline complicated by ventricular arrhythmias. arrhythmia as a Ca channel related arrhythmia Though these arrhythmias sometimes require because drugs directly suppressing the Ca antiarrhythmic drug therapy using class 1 channel, like verapamil, or indirectly sup antiarrhythmic drugs (1) which block the Na pressing the channel, like (3-blockers, were channel, coronary vasodilators sometimes quite effective on this arrhythmia (6, 7). On have been reported to suppress such ven the other hand, the digitalis arrhythmia seems tricular arrhythmias (2, 3). The mechanisms to be Na channel related from our previous of generation of these arrhythmias resulting studies because class 1 antiarrhythmic drugs from myocardial ischemia have not yet been suppressed this arrhythmia (8-10). clarified, but Ca ion related oscillatory We chose different types of coronary afterpotential or slow depolarization resulting vasodilators, i.e., verapamil, diltiazem, in re-entry seems to play an important role bepridil, trimetazidine and nicorandil. Vera (4). Since some of the coronary vasodilators pamil and diltiazem are typical Ca antagonists have Ca antagonistic effects, and even have having Na channel blocking action in high additional Na antagonistic effects in high concentrations in in vitro cardiac tissues (11 ). doses (5), those drugs may be effective on Bepridil is a new Ca antagonist which has various arrhythmias. Therefore, we examined been reported to have Na channel blocking coronary vasodilators on two canine ven action in therapeutic concentrations (12, tricular arrhythmia models: halothane 13). Trimetazidine has been reported to have adrenaline and digitalis arrhythmias. Though ,3-blocking and Ca antagonistic actions in the generation mechanisms of these ar high concentrations (14), but its beneficial effects on ischemic heart diseases have been * To whom reprint requests should be addressed . reported to be due to the reduction of the venous return (15). INicorandil, 2-nico was usually produced with a total dose of 70 tinamidoethyl nitrate (SG-75), is a newly to 80 /cg/kg ouabain. Coronary vasodilators synthesized coronary vasodilator chemically were injected in a bolus into the femoral vein. related to nitrates and has been reported not Lead II ECG, the atrial electrogram from to have a Ca antagonistic effect (16, 17). the catheter tip electrodes in the right atrium Unlike many previous animal studies, we and blood pressure were continuously assayed the drug plasma concentrations recorded. The venous blood samples were simultaneously while examining their anti drawn from the jugular vein 5 min before and arrhythmic effects in order to correlate the 1, 3, 5, 10, 15, 30 and 60 min after the effectiveness of drugs on the arrhythmias to injection of the drugs. their already known concentrations of Ca or 3) Plasma drug assay Na channel blocking or of ;3-blocking actions Venous blood samples were centrifuged, in vitro. and the plasma was stored in a freezer at about -25'C before plasma drug concen Materials and Methods tration analysis. 1) Halothane-adrenaline arrhythmia Verapamil: The plasma verapamil assay Mongrel dogs of either sex, weighing 8 was carried out at the Experimental Thera to 15 kg, were anesthetized initially with peutic Research of the Eisai Co., Ltd. (Tokyo, 30 mg/kg of thiopental Na. After intubation, Japan) using a gas chromatography, mass 1.0% halothane, vaporized with 100% 02, spectrometric method similar to an assay was administered using a volume-limited developed by Spiegelhalder and Eichelbaum ventilator. After 30 min, adrenaline was (19). infused for 18 min into the femoral vein using Diltiazem: Plasma diltiazem assay was a Harvard infusion/withdrawal pump. As carried out at the Research Laboratories of reported previously, ventricular arrhythmia the Tanabe Seiyaku Co., Ltd. (Osaka, Japan) was usually induced by 2 to 3 ng/kg/min of using a high performance liquid chromato adrenaline infusion within 2 min, and the graphic method. A plasma volume of 1 ml arrhythmia lasted for the 18 min of infusion was shaken twice with 10 ml ethylether. The (7). Three minutes after the start of adrenaline aqueous phase was discarded, and the infusion, coronary vasodilators were injected organic phase was evaporated at 40°C under in a bolus into the femoral vein. a nitrogen stream. To the samples, 2 ml of Lead II ECG, the atrial electrogram from 0.2 N HCI was added and shaken with 10 ml the catheter tip electrode in the right atrium, ethylether. One ml of 0.4 N NaOH and 1 ml and blood pressure were continuously of 0.5 N NaH2PO4 were added to the recorded. Venous blood samples were taken aqueous phase, and this was shaken twice from the jugular vein 1 min before and 1, 3, with 8 ml ethylether. The organic phase was 5, 10 and 15 min after the injection of the evaporated at 40'C under a nitrogen stream drugs. and dissolved with 0.3 ml of 500 ng/ml The doses of drugs chosen in the present tipepidine hibenzate 0.02 N HCI as an experiment were determined as the minimum internal standard solution. effective dose or the maximal tolerable Two hundred pl of this solution was hypotensive doses for ineffective drugs. injected onto the column (Hypersil 5-ODS, 2) Digitalis arrhythmia 4 mm i.d. x 300 mm length) of the high Mongrel dogs of either sex, weighing 8 to performance liquid chromatograph (Hewlett 15 kg, were anesthetized with 30 mg/kg Packard 1084B). pentobarbital Na. Modifying the method of Bepridil: Plasma bepridil assay was carried Lucchesi and Hardman (18), 40 pg/kg of out at the Nippon Organon K.K. (Tokyo, ouabain was injected into the femoral vein, Japan) using a gas chromatographic method followed by an additional dose of 10 ;cg/kg with nitrogen-sensitive detection according ouabain every 20 min until stable arrhythmia to the method of Vink and Vanhol (20). of more than 1 hr duration was produced as Trimetazidine: Plasma trimetazidine assay reported previously (9, 10). Stable arrhythmia was carried out at the Research Laboratories

I n order to express the severity of ar rhythmia, the arrhythmic ratio, a ratio of the number of ventricular ectopic beats divided by the total number of beats counted from the lead II ECG (total heart rate), was used. The last minute of statistically significant decrease (P<0.05) in the arrhythmic ratio compared with that at zero time was determined. Then, the corresponding plasma concentration was calculated from the experimentally derived plasma concentration time equations, and this was regarded as the minimum effective plasma concentration. The concentration time equation was derived by the two compartment open model theory in the case of digitalis arrhythmia and by the one compartment open model theory in the case of adrenaline arrhythmia.

of the Inabata & Co., Ltd. (Osaka, Japan) diltiazem was effective in suppressing the using a gas chromatographic method. To adrenaline arrhythmia. As shown in Fig. 1, 2 ml plasma, 4 ml 0.5 N NaOH and 20 ml the arrhythmic ratio decreased soon after C6H6 were added. The mixture was shaken injection, and this effect lasted up to 15 min. and then centrifuged at 15000 rpm for 10 min. Parameters of the diltiazem concentration Eighteen ml of the aqueous phase was time equation are shown in Table 1. The evaporated, and 0.5 ml (CH3CO)2O was minimum plasma concentration was less added. After 1 hr, 4 ml 1 N HCI and 4 ml than 18±5 ng/ml. This dose of diltiazem CH2CI2 were added and then shaken and reduced the total heart rate and atrial rate centrifuged at 3000 rpm for 5 min. Three without a significant change in the blood grams of NaCI was added to 3 ml of the pressure. aqueous phase and the pH was adjusted to Bepridil (n=7): A dose of 1 mg/kg 9 with 1 N NaOH. Then 20 ml of CH2CI2 was bepridil transiently suppressed this arrhy added, the samples were shaken, and they thmia. As shown in Fig. 2, the arrhythmic were centrifuged at 3000 rpm for 10 min. ratio was reduced soon after injection and was To 15 ml of the lower layer, 500 ng of accompanied by a reduction in the total heart trimetazidine butylester was added as an rate, atrial rate and blood pressure. The internal standard and evaporated to 0.5 ml. antiarrhythmic effect continued for 5 min. Five al of this solution was injected onto Parameters of the bepridil concentration-time the column (2.6 mm i.d. x1.5 m length) of a equation are shown in Table 1. The minimum gas chromatograph (Shimadzu GC-7A-FTD). plasma concentration was 380±110 ng/ml. Nicorandil: The plasma nicorandil assay Trimetazidine (n=6): A dose of 10 mg/kg was carried out at the Chugai Pharmaceutical trimetazidine showed a transient, 2 min, Co., Ltd. (Tokyo, Japan) using a high antiarrhythmic effect as shown in Fig. 3, performance liquid chromatographic method while it markedly reduced the blood pressure according to the method developed by and total heart rate. The atrial rate was not Kamiyama et al. (21). changed. Parameters of the trimetazidine 4) Determination of the minimum effective concentration-time equation are shown in plasma concentrations Table 1. The minimum plasma concentration was 7.0±1.5 ,gig/ml. Nicorandil (n=8): A dose of 1 mg/kg nicorandil was not effective on this ar rhythmia, even though this dose markedly decreased the blood pressure as shown in Fig. 4. The atrial rate transiently increased without a change in the total heart rate. Parameters of the nicorandil concentration time equation are shown in Table 1. The maximum plasma concentration 1 min after injection reached to 2.2±0.9 ,.cg/ml. 2) Effects on digitalis arrhythmia Verapamil (n=7): A dose of up to 1 mg/kg verapamil, a maximal hypotensive dose, was ineffective on digitalis arrhythmia as shown in Fig. 5. The total heart rate, atrial rate and blood pressure markedly decreased for up to 60 min. Parameters of the verapamil concen tration-time equation are shown in Table 2. Results The peak plasma concentration 1 min after 1) Effects on the halothane-adrenaline arrhy injection reached 930±440 ng/ml. thmia Diltiazem (n=6): A dose of up to 1 mg/kg Diltiazem (n=7): A dose of 0.1 mg/kg diltiazem was also ineffective on digitalis Fig. 1. Summary of the effects of diltiazem on adrenaline arrhythmia (left) and digitalis arrhythmia (right). Diltiazem, 0.1 mg/kg, i.v., was effective on adrenaline arrhythmia, i.e., decreased the arrhythmic ratio, without significant decrease in the blood pressure. Diltiazem, 1 mg/kg, i.v., was ineffective on digitalis arrhythmia even though this dose markedly decreased the blood pressure. ": P<0.05, ": P<0.01 from the 0 time value. Bars represent the S.D.

Table 1. Pharmacokinetic parameters of vasodilators in dogs with halothane-adrenaline arrhythmia

arrhythmia as shown in Fig. 1. The total Bepridil (n=8): A dose of up to 5 mg/kg heart rate, atrial rate and blood pressure bepridil was also ineffective on this ar markedly decreased. Parameters of the rhythmia as shown in Fig. 2. Bepridil also diltiazem concentration-time equation are reduced the total heart rate, atrial rate and shown in Table 2. The peak concentration blood pressure. Parameters of the bepridil reached 930±280 ng/ml. concentration-time equation are shown in Fig. 2. Summary of the effects of bepridil on adrenaline arrhythmia (left) and digitalis arrhythmia (right). Bepridil, 1 mg/kg, i.v., was effective on adrenaline arrhythmia, but the higher dose of 5 mg/kg, i.v., was not effective on digitalis arrhythmia.

Table 2. Pharmacokinetic parameters of vasodilators in dogs with digitalis arrhythmia

Table 2. The peak plasma concentration this digitalis arrhythmia experiment. The reached to 2.6±1.3 /-ig/ml. pharmacokinetic parameters were not ob Trimetazidine (n=7): A dose of up to 3 mg/ tained for trimetazidine, because only the kg trimetazidine did not reduce the arrhythmic plasma concentrations 1 and 3 min after ratio, total heart rate and atrial rate as shown injection were measured. The peak plasma in Fig. 3. Though 10 mg/kg was used in the concentration reached 3.8±0.5 ,ag/ml, 1 adrenaline arrhythmia experiment, 3 mg/kg min after injection. markedly reduced the blood pressure and was Nicorandil (n=6): A dose of up to 3 mg/kg regarded as the maximal hypotensive dose in nicorandil did not suppress digitalis ar Fig. 3. Summary of the effects of trimetazidine on adrenaline arrhythmia (left) and digitalis arrhythmia (right). Trimetazidine, 10 mg/kg, i.v., was effective on adrenaline arrhythmia, but 3 mg/kg, i.v., which induced severe hypotension, was ineffective on digitalis arrhythmia. rhythmia as shown in Fig. 4. It only decreased markedly decreased the blood pressure as the blood pressure without changing the might be expected from the word "vaso total heart rate and atrial rate. Parameters of dilator". the nicorandil concentration-time equation We reported that 3-blocking agents and are shown in Table 2. Peak plasma concen verapamil were effective on halothane tration reached 8.3+2.8 og/ml. adrenaline arrhythmia (7), and this was confirmed by the present study that other Ca Discussion antagonists are also quite effective. Since The present study showed that the Ca all the vasodilators used in the present study antagonistic coronary vasodilators, verapamil, decreased the blood pressure, regardless of diltiazem and bepridil, were effective on their mechanism of action, these anti halothane-adrenaline arrhythmia, but were arrhythmic effects of Ca antagonists might ineffective on digitalis arrhythmia. Trime have been due to the direct or indirect tazidine, which has been reported to have 4 blocking of Ca influx into the cell. It was also blocking and Ca antagonistic effects in high confirmed by measuring the drug plasma concentrations, had almost the same effects concentrations that the minimum effective as Ca antagonists when a high dose was and the clinical therapeutic plasma concen used. Nicorandil was not effective on both trations of the Ca antagonists were almost halothane-adrenaline and digitalis arrhy equal to the concentrations, which suppress thmias. Regardless of differences in their the Ca channel of in vitro cardiac tissues (11, effectiveness on arrhythmias, all drugs 12). Though we have reported that the Fig. 4. Summary of the effects of nicorandil on adrenaline arrhythmia (left) and digitalis arrhythmia (right). Nicorandil at 1 and 3 mg/kg, i.v., was ineffective on both adrenaline and digitalis arrhythmias, respectively. Blood pressure was decreased significantly by both doses. supraventricular rate plays an important role conditions, where the resting potential of the in the genesis of the halothane adrenaline ventricular muscle is thought to elevate, the arrhythmia using the atrial stimulation tech slow inward current may become important nique (22), it does not seem to be the only in generating action potential. So Ca an mechanism, because the atrial rate was not tagonists can also be expected to suppress changed dramatically by those Ca antagonists. ischemia induced ventricular arrhythmias. Direct i3-receptor stimulation on the ventricle However, as previously reported (24), by adrenaline through the Ca channel and its verapamil (0.3 mg/kg) did not suppress two suppression must also play a role in the stage coronary ligation arrhythmias, even the genesis and suppression of the adrenaline less severe 48 hr arrhythmia. Contrary to our arrhythmia. results on model arrhythmias, there are In the present study, Ca antagonists were reports that Ca antagonists suppressed experi ineffective on the digitalis arrhythmia. mental arrhythmias (25-27) and clinical Digitalis arrhythmia has been proposed to be ventricular arrhythmias not directly related due to increased intracellular Ca, resulting in to adrenaline (3). Whether all those ar oscillatory afterpotential (23). It was reported rhythmias were produced by an abnormality that Ca antagonists suppressed the oscillatory in the Ca channel such as supraventricular afterpotential of an in vitro preparation (23), arrhythmias related either to A-V node or so Ca antagonists are thought to suppress in S-A node (3, 28-30) would be difficult to ,iivo digitalis arrhythmia. Also in ischemic clarify. electrophysiological phenomena. Na channel blockers may act on the normal myocardium to suppress the response to abnormal impulse generation, whatever the cause of its electrophysiological mechanisms. The effects of a high dose of trimetazidine were the same as those of Ca antagonists, but the duration of its effect was brief. The minimum effective plasma concentration of trimetazidine was 6.9 erg/ml, which is markedly lower than the reported concen tration for the Ca antagonistic effect and the 3-blocking effect in vascular smooth muscle (14), There is no report of a Ca-antagonistic concentration of trimetazidine using cardiac preparations. Nicorandil suppressed neither halothane adrenaline arrhythmia nor digitalis arrhy thmia. This was to be expected because nicorandil had no effect on Na and Ca channels (16, 17). As a vasodilator, nicorandil reduced the blood pressure as markedly as other coronary vasodilators. Applying our present study to clinical use of vasodilators in patients with ventricular Fig. 5. Summary of the effects of verapamil, 0.1 arrhythmia, Ca antagonists may have mg/kg, i.v., on digitalis arrhythmia. Verapamil therapeutic value only in those related to decreased the total heart rate, atrial rate and blood sympathetic drive, but may be of limited value pressure, but the number of conducted beats and in ventricular arrhythmias when compared to arrhythmic ratio were not changed. Na channel blocking drugs because verapamil (24), diltiazem (26) and trime According to our previous experiments (8), tazidine (our unpublished observation) were all class 1 antiarrhythmic agents are effective not effective on two-stage coronary ligation on digitalis arrhythmia at concentrations arrhythmia. However, there are possibilities blocking the Na channel. The Na channel that Ca antagonists may be effective for blocking concentrations in vitro are reported prophylaxis of ventricular arrhythmias because to be about 10 ,ug/ml, 10 /cg/ml and 4 pretreatments of experimental animals with ,ug/ml for verapamil, diltiazem and bepridil, verapamil were reported to increase the toxic respectively (11, 12). Since we could not doses of digitalis(31 ) and preventfibrillation increase the doses of Ca antagonists beyond following acute coronary occlusion (32). the dose which induced profound hypotensive Acknowledgements: The authors thank Eisai Co., effects, the maximum doses used did not Ltd.; Tanabe Seiyaku Co., Ltd.; Nippon Organon Co., raise the plasma concentration of the drug Ltd.; Inabata & Co., Ltd. and Chugai Pharmaceutical to Na channel blocking concentrations. This Co., Ltd for plasma drug assays, and we also thank must be the reason for their ineffectiveness on Mr. J. Sendoda and Mrs. A. Tezuka for preparing the digitalis arrhythmia. The fact that the manuscript. blocking of the Ca channel did not suppress digitalis arrhythmia may indicate that either References generation of digitalis arrhythmia is not 1 Vaughan Williams, E.M.: Electrophysiologica related to the slow inward current or anti basis for a rational approach l to antidysrhythmic arrhythmic drugs do not suppress the ar drug therapy. In Advances in Drug Research, rhythmia by directly acting on abnormal Edited by Harper, N. J. and Simmonds, A.B., Vol. 9, p. 69-101, Academic Press, London , 193-203 (1980) (1974) 14 Toda, N., Usui, H., Osumi, S., Kanda, M. and 2 Fazzini, P.E., Marchi, F. and Ducci, P.: Effects of Kitao, K.: Influence of trimetazidine, an anti verapamil on ventricular premature beats of anginal drug, on isolated dog arteries and veins. acute myocardial infarction. Acta Cardiol. 33, Arch. Int. Pharmacodyn. Ther. 260, 230-243 25-29 (1978) (1982) 3 Schamroth, L., Krikler, D.M. and Garrett, C.: 15 Taira, N., Imai, Y. and Hiwatari, M.: Differential Immediate effects of intravenous verapamil in effects of nitroglycerin, trimetazidine, verapamil cardiac arrhythmias. Br. Med. J. 11, 660-662 and SK&F 24260 on venous return as revealed (1972) by the open-loop method in the dog. Japan. J. 4 Lazzara, R., EI-Sherif, N., Hope, R.R. and Pharmacol. 30, 449-461 (1980) Scherlag, B.J.: Ventricular arrhythmias and 16 Yanagisawa, T., Satoh, K. and Taira, N.: electrophysiological consequences of myocardial Circumstantial evidence for increased potassium ischemia and infarction. Circ. Res. 42, 740-749 conductance of the membrane of cardiac muscle (1978) by 2-nicotinamidoethyl nitrate (SG-75). Japan. 5 Hashimoto, K., Nakagawa, Y., Nabata, H. and J. Pharmacol. 29, 687-694 (1979) Imai, S.: In vitro analysis of Ca-antagonistic 17 Satoh, H. and Hashimoto, K.: Effects of nicorandil effects of prenylamine as mechanisms for its on the membrane currents of the rabbit sino cardiac actions. Arch. Int. Pharmacodyn. Ther. atrial node cells. Japan. J. Pharmacol. 34, 411 231, 212-221 (1978) 415 (1984) - 6 Hashimoto, K., Tsukada, T., Matsuda, H., 18 Lucchesi, B.R. and Hardman, H.F.: The influence Nakagawa, Y. and Imai, S.: Antiarrhythmic effects of dichloroisoproterenol (DCl) and related of bupranolol against canine ventricular ar compounds upon ouabain- and acetylstrophan rhythmias induced by halothane-adrenaline or thidin-induced cardiac arrhythmias. J. Phar two-stage coronary ligation. J. Cardiovasc. macol. Exp. Ther. 132, 372-381 (1961) Pharmacol. 1, 205-217 (1979) 19 Spiegelhalder, B. and Eichelbaum, M.: Deter 7 Shibuya, T., Hashimoto, K. and Imai, S.: mination of verapamil in human plasma by mass Effective plasma concentrations of antiarrhythmic fragmentography using stable isotope-labelled drugs against sustained halothane-adrenaline verapamil as internal standard. Arzneimittel arrhythmias in dogs. J. Cardiovasc. Pharmacol. forsch. 27, 94-97 (1977) 5, 538-545 (1983) 20 Vink, J. and Vanhol, H.J.M.: Determination of 8 Hashimoto, K., Shibuya, T., Satoh, H. and Imai, the anti-ischemic drug bepridil in human plasma S.: Quantitative analysis of the antiarrhythmic using gas chromotography with nitrogen effect of drugs on canine ventricular arrhythmias sensitive detection. J. Chromatogr. 272, 87-94 by the determination of minimum effective plasma (1983) concentrations. Japan. Circ. J. 47, 92-97 (1983) 21 Kamiyama, H., Hinohara, Y., Nakano, H., Tohira, 9 Hashimoto, K., Ishii, M. and Komori, S.: Anti Y., Sawada, M., Tamura, H., Uchiyama, T., arrhythmic plasma concentrations of mexiletine Otani, T., Ishizaki, T. and Chiba, H.: Metabolism on canine ventricular arrhythmias. J. Cardiovasc. of N-(2-hydroxyethyl) nicotinamide nitrate (SG Pharmacol. 6, 213-219 (1984) 75) (4) Pharmacokinetic studies in rats - and 10 Hashimoto, K., Komori, S., Ishii, M. and Kamiya, dogs. Oyo Yakuri 23, 261-266 (1982) J.: Effective plasma concentrations of aprindine 22 Hashimoto, K. and Hashimoto, K.: The mecha in canine ventricular arrhythmias. J. Cardiovasc. nism of sensitization of the ventricle to epine Pharmacol. 6, 12-19 (1984) phrine by halothane. Am. Heart J. 83, 652-658 11 Nabata, H.: Effects of calcium-antagonistic (1972) coronary vasodilators on myocardial contractility 23 Ferrier, G.R.: Digitalis arrhythmia: Role of and membrane potentials. Japan. J. Pharmacol. oscillatory afterpotentials. Prog. Cardiovasc. 27, 239-249 (1977) Dis. 19, 459-474 (1977) 12 Labrid, C., Grosset, A.G., Bureng, G., Mironneau, 24 Hashimoto, K., Satoh, H., Shibuya, T. and J. and Duchene-Marullaz, P.: Some membrane Imai, S.: Canine-effective plasma concen interactions with bepridil, a new antianginal trations of antiarrhythmic drugs on the two agent. J. Pharmacol. Exp. Ther. 211, 546-554 stage coronary ligation arrhythmia. J. Phar- (1979) macol. Exp. Ther. 223, 801-810 (1982) 13 Kane, K.A. and Winslow, E.: Antidysrhythmic and 25 Schmid, J.R. and Hanna, C.: A comparison of electrophysiological effects of a new antianginal the antiarrhythmic actions of two new synthetic agent, bepridil. J. Cardiovasc. Pharmacol. 2 compounds, iproveratril and MJ 1999, with quinidine and pronethalol. J. Pharmacol. Exp. D.P.: Effects of intravenous and chronic oral Ther. 156, 331-338 (1967) verapamil administration in patients with supra 26 Yamada, K., Shimamura, T. and Nakaiima, H.: ventricular tachyarrhythmias. Circulation 62, Studies on a new 1, 5-benzothiazepine derivative 996-1010 (1980) (CRD-401). V. Antiarrhythmic actions. Japan. J. 30 Wakasa, Y., Ikeda, T., Oshiro, Y., Numa, T. and Pharmacol. 23, 321-328 (1973) Sugimoto, T.: Beneficial effects of diltiazem on 27 Bergey, J.L., McCallum, J.D. and Nocella, K.: re-entrant tachycardia involving A-V conduction. Antiarrhythmic evaluation of verapamil, In Proceedings of the Vlth World Symposium on nifedipine, perhexiline and SKF 525-A in four Cardiac Pacing, Chap 5 (1979) canine models of cardiac arrhythmias. Eur. J. 31 Melville, K.T., Shister, H.E. and Huq, S.: Ipro Pharmacol. 70, 331-338 (1981) veratril: Experimental data on coronary dilatation 28 Krikler, D.M. and Spurrell, R.H.J.: Verapamil in and antiarrhythmic action. Can. Med. Assoc. J. the treatment of paroxysmal supraventricular 90, 761-770 (1964) tachycardia. Postgrad. Med. J. 50, 447-453 32 Kaumann, A.J. and Aramendia, P.: Prevention of (1974) ventricular fibrillation induced by coronary 29 Rinkenberger, R.C., Prytowsky, E.N., Heger, ligation. J. Pharmacol. Exp. Ther. 164, 326-332 J.J., Troup, P.J., Jackman, W.M. and Zipes, (1968)