CLINICAL INVESTIGATIONS Jpn Circ J 2001; 65: 1–6

Frequency-Dependent Electrophysiological Effects of Flecainide, Nifekalant and d,l-Sotalol on the Human Atrium

Hiromi Watanabe, MD; Ichiro Watanabe, MD; Toshiko Nakai, MD; Naohiro Oshikawa, MD; Satoshi Kunimoto, MD; Riko Masaki, MD; Toshiaki Kojima, MD; Satoshi Saito, MD; Yukio Ozawa, MD; Katsuo Kanmatuse, MD

To compare the effects of class Ic and III antiarrhythmic agents on the termination and prevention of atrial fibril- lation, the present study investigated the use-dependent electrophysiological effects of flecainide, nifekalant and d,l-sotalol on the human atrium. Flecainide significantly prolonged effective refractory period (ERP), intra-atrial conduction time (IACT) and monophasic action potential duration (MAPD), and its effects on ERP and IACT were use-dependent. Nifekalalant significantly prolonged ERP and MAPD, and these effects were reverse use- dependent; however, there was no significant change in IACT. d,l-Sotalol significantly prolonged MAPD and the effect was reverse use-dependent. It significantly prolonged ERP, but the effect was not reverse use-dependent. d,l-Sotalol increased IACT in a use-dependent manner. Thus, for atrial fibrillation, class Ic antiarrhythmic agents might be more effective in termination and class III antiarrhythmic agents might be more effective in prevention. (Jpn Circ J 2001; 65: 1–6) Key Words: Antiarrhythmic drugs; Atrial muscle; Monophasic action potential; Reverse use-dependency; Use-dependency

lass I antiarrhythmic drugs have use-dependent diac dysfunction comprised the study population. Of these effects on ventricular conduction; that is, intraven- 23 patients, 4 had paroxysmal atrial flutter or fibrillation, 4 C tricular conduction time increases according to had concealed Wolf-Parkinson-White (WPW) syndrome, 5 heart rate.1 By contrast, many class III antiarrhythmic drugs had atrial flutter or fibrillation, 5 had atrioventricular nodal have reverse use-dependent effects on the ventricular reentrant tachycardia (AVNRT), 2 had atrioventricular (AV) action potential duration (APD); that is, a decrease in the block, 2 had sick sinus syndrome (SSS), 1 had syncope, extent of prolongation of ventricular APD according to and 1 had ventricular tachycardia (VT). None of the patient heart rate.2,3 However, there are few studies on the use- had had an episode of atrial fibrillation, flutter or paroxysmal dependent effects of class I and III antiarrhythmic drugs on supraventricular tachycardia for at least 2 weeks prior to atrial APD, effective refractory period (ERP) and intra- the study and all antiarrhythmic drugs had been withdrawn atrial conduction time (IACT) in humans. Therefore,we for a period equivalent to at least 5 half-lives prior to the investigated the use-dependent electrophysiological effects study. Patients who had a left atrial diameter greater than of a class Ic antiarrhythmic drug, flecainide, and 2 class III 40mm on transthoracic echocardiography were excluded antiarrhythmic drugs, nifekalant and d,l-sotalol, on the from the study. right atrium by measuring APD, ERP and IACT. The subjects were divided in 3 groups: flecainide group (n=10), nifekalant group (n=5) and d,l-sotalol group (n=8). Prior to the study, the patients and their families gave Methods consent to the assessment of the efficacy of the new antiar- Subjects rhythmic drugs. Twenty three subjects aged 18–70 years (44±16 years, mean±SD) who underwent an electrophysiological study Techniques (EPS) and who did not have ischemic heart disease or car- A Franz-combination catheter (EPT Ltd, Sunnyvale, CA, USA) was used to record the monophasic action potential (Received February 28, 2000; revised manuscript received August 24, (MAP). A quadripolar electrode with 2-mm interelectrode 2000; accepted September 19, 2000) space was used for atrial pacing, which was performed The Second Department of Medicine, Nihon University School of using 2-ms rectangular pulses at twice the late diastolic Medicine, Tokyo, Japan threshold. A Franz-combination catheter was introduced A summary of this article was presented at the 12th Meeting of the through the right femoral vein and pushed against the high Japanese Society of Electrocardiology and at the 61st Annual Scientific right atrium to record the atrial MAP with a band pass filter Meeting of Japanese Circulation Society. Mailing address: Hiromi Watanabe, MD, The Second Department of of 0.05–500Hz. MAPs were recorded at a paper speed of Medicine, Nihon University School of Medicine, 30-1 Ohyaguchikami- 200mm/s. MAP duration was measured at 90% repolariza- machi, Itabashi-ku, Tokyo 173-0186, Japan. E-mail: iwatanab@med. tion (MAPD90) and calculated as the average of 5 consecu- nihon-u.ac.jp tive complexes. IACT was measured from the pacing spike

Japanese Circulation Journal Vol.65, January 2001 2 WATANABE H et al.

Fig1. Recording of the right atrial monophasic action potential at a pacing cycle length of 600ms, and AV sequential pacing interval of 100ms. I, II, III, V1: surface ECG leads; CSd, coronary sinus distal potential; RA MAP, right atrial muscle monophasic action potential; RA MAPD90, RA MAP duration at 90% repolarization; IACT, intra-atrial conduction time.

Fig2. Electrophysiological effects of flecainide on atrial muscle (1). ERP, effective refractory period of the right atrium; MAPD, monophasic action potential duration in the right atrium; IACT, intra-atrial conduction time.

Fig3. Electrophysiological effects of flecainide on atrial muscle (2). ∆ERP, change in ERP before and after flecainide; ∆MAPD, change in MAPD before and after flecainide; ∆ERP/MAPD, change in ERP/MAPD before and after flecainide; ∆IACT, change in IACT before and after flecainide. at the high right atrium (St) to the distal coronary sinus administration of flecainide, nifekalant and d,l-sotalol were atrium potential during AV sequential pacing with the AV measured. interval varying from 50 to 150ms (Fig1). (1) With 120beats of AV sequential pacing at a basic Electrophysiological indices before and after intravenous cycle length (BCL) of 600 and 350ms, the right atrial

Japanese Circulation Journal Vol.65, January 2001 Flecainide, Nifekalant and d,l-Sotalol on Human Atrium 3

Fig4. Use-dependent electrophysiological effects of nifekalant on atrial muscle (1).

Fig5. Use-dependent electrophysiological effects of nifekalant on atrial muscle (2).

MAPD90 and IACT were measured between 110 and 120 beats of pacing at which the MAP duration reaches a steady Results state.4 Flecainide Group (2) The right atrial ERP was measured at the site adja- Changes in right atrial ERP, MAPD, ERP/MAPD and cent to where the MAP recordings were obtained. An extra IACT are shown in Figs2 and 3. Flecainide prolonged ERP stimulus was applied during late diastole after 12beats of from 193.0±12.3ms to 233.5±29.1ms at a BCL of 600ms basic drive (BCL 600 and 350ms) with successive decre- (p<0.01) and from 176.0±15.2 ms to 222.5±36.8 ms at a ments of the coupling interval of the extra stimulus by 5ms. BCL of 350 ms (p<0.01). Flecainide prolonged MAPD (3) ERP/MAPD was measured as an index of post repo- from 215.9±17.9ms to 239.1±27.9ms at a BCL of 600ms larization refractoriness. (p<0.05) and from 186.7±20.2 ms to 207.1±15.4 ms at a (4) ∆ERP, MAPD and IACT show the changes in these BCL of 350ms (p<0.01). Although there was no significant parameters following the administration of the drug at each change in the ERP/MAPD ratio at BCL 600ms (0.90±0.07 cycle length. ms to 0.94±0.08 ms), it increased from 0.95±0.14 ms to (5) Drugs were administered intravenously in the follow- 1.07±0.15ms at BCL 350ms (p<0.05). IACT was prolonged ing dose rates: 2mg/kg of flecainide; 0.5mg/kg of saline- at both BCL 600 and 350ms from 125.2±16.5ms to 162.4± dissolved nifekalant followed by a continuous infusion of 24.8ms, and from 132.4±18.6ms to 194.6±35.3ms respec- 0.017 mg·kg–1·min–1; 1.5 mg/kg of saline-dissolved d,l- tively (p<0.01). Changes in ERP (∆ERP) before and after sotalol. flecainide were 30.5±27.4ms at BCL 600ms, and 46.5±29.0 ms at BCL 350 ms, the latter being significantly greater Statistics (p<0.05). Changes in MAPD (∆MAPD) before and after All data are expressed as mean±SD. Student’s paired and flecainide were 23.2±24.3ms at BCL 600ms, and 20.4±13.9 unpaired t test and Wilcoxon signed rank test were used for ms at BCL 350ms with no statistical difference. Changes in data analysis. A p value <0.05 was considered statistically IACT (∆IACT) before and after flecainide were 37.2±17.9 significant. at BCL 600 ms, and 62.1±28.3 ms at BCL 350 ms, the former being significantly greater (p<0.01). Changes in

Japanese Circulation Journal Vol.65, January 2001 4 WATANABE H et al.

Fig6. Use-dependent electrophysiological effects of d,l-sotalol on atrial muscle (1).

Fig7. Use-dependent electrophysiological effects of d,l-sotalol on atrial muscle (2).

ERP/MAPD (∆ERP/MAPD) before and after flecainide ∆ERP/MAPD between BCL 600ms and 350ms (–0.08±0.07 were 0.04±0.10 at a BCL of 600ms, and 0.12±0.15 at a and –0.05±0.14, respectively). BCL of 350ms, which was not statistically different despite the change being much greater at BCL of 350ms than at d,l-Sotalol Group BCL 600ms. Changes in right atrial ERP, MAPD, ERP/MAPD and IACT are shown in Figs6 and 7. d,l-Sotalol prolonged ERP Nifekalant Group from 195.0±21.8ms to 234.0±21.0ms at a BCL of 600ms Changes in right atrial ERP, MAPD, ERP/MAPD and (p<0.05), and from 181.0±16.7ms to 212.0±17.9ms at a IACT are shown in Figs4 and 5. Nifekalant prolonged ERP BCL of 350 (p<0.05). It prolonged MAPD from 218.4± from 213.0±22.8ms to 275.0±28.6ms at a BCL of 600ms 24.8ms to 258.0±25.7ms at a BCL of 600ms (p<0.05), and (p<0.05), and from 195.0±24.0ms to 223.0±15.2ms at a from 194.1±25.6ms to 221.7±23.5ms at a BCL of 350ms BCL of 350 ms (p<0.05). MAPD was prolonged from (p<0.05). d,l-Sotalol did not influence the ERP/MAPD 234.6±28.4ms to 318.0±53.4ms at a BCL of 600ms (p< ratio (from 0.91±0.10 to 0.93±0.10 at a BCL of 600ms, and 0.05); and from 213.2±27.4ms to 256.8±23.7ms at a BCL from 0.97±0.17ms to 0.99±0.19ms at a BCL of 350 ms) of 350 ms (p<0.05). Nifekalant did not influence the nor did it affect IACT at a BCL of 600ms (from 105.3± ERP/MAPD ratio (from 0.91±0.05 to 0.84±0.07 at a BCL 15.3 ms to 109.5±18.7 ms); however, it increased IACT of 600ms; and from 0.92±0.09 to 0.87±0.07 at a BCL of from 105.3±15.3ms to 109.5±18.7ms at a BCL of 350ms 350ms) or IACT (from 109.8±36.1ms to 111.5±35.8ms at (p<0.05). There was no change in ∆ERP between BCL 600 a BCL of 600ms; and from 116.5±37.0ms to 118.0±37.1 ms and 350 ms (39.0±13.9 ms and 31.0±8.9 ms, respec- ms at a BCL of 350ms). ∆ERP at 58.8±7.5ms was greater tively). ∆MAPD at 39.6±20.7ms was greater at a BCL of at a BCL of 600ms compared with 28.0±14.4ms at a BCL 600ms than at a BCL of 350ms (27.6±16.4ms; p<0.05). of 350ms (p<0.05). ∆MAPD at 83.4±38.9ms was greater ∆IACT at 10.0±7.04ms was greater at a BCL of 350ms at a BCL of 600ms compared with 43.6±30.3ms (p=0.05). than at a BCL of 600ms (4.17±6.94 ms; p<0.05). There ∆IACT was not influenced by nifekalant at either BCL 600 was no significant difference in ∆ERP/MAPD between ms or 350ms (1.75±3.59ms at BCL 600ms and 1.50±1.73 BCL 600 and 350ms (–0.08±0.07ms and –0.05±0.14ms, ms at BCL 350ms). There was no significant difference in respectively).

Japanese Circulation Journal Vol.65, January 2001 Flecainide, Nifekalant and d,l-Sotalol on Human Atrium 5

a different result to nifekalant. d,l-Sotalol significantly Discussion prolonged ERP and MAPD, and although it showed signif- Flecainide, a class Ic antiarrhythmic drug, significantly icant reverse use-dependency on MAPD, this was not prolonged the MAPD of the atrial muscle, ERP and IACT apparent with ERP. Shimizu et al reported that the adminis- and the effects were use-dependent. Flecainide has been tration of d,l-sotalol showed reverse use-dependency of shown to block Na+ and K+ channels.5–7 The prolongation ERP in the human ventricle,22 and although Debra et al of ERP and IACT by flecainide has been linked to its reported that d,l-sotalol increases atrial ERP, they did not potent Na+ channel blocking effect,8 which has been conduct a study on its use-dependency.23 The reason why observed in both animal experiments and clinical studies of d,l-sotalol did not show reverse-use-dependency on ERP in the human heart.9,10 Both the conjunction and dissociation the present study is unclear, but might be related to itsβ- of flecainide with the Na+ channel are very slow, so the receptor blocking effect, which might affect post repolariza- use-dependency effect would be expected to occur at a tion refractoriness in the atria at a faster heart rate (BCL slower heart rate compared with other class I antiarrhythmic 350 ms). Shimizu et al have shown that β stimulation drugs. Camm et al reported that the atrial ERP at BCL 500 predominates over that of direct vagal stimulation in the ms was unchanged by flecainide, but that the atrial MAPD human atrium for MAPD and ERP.26 Our results showed of the earliest inducible atrial beat was significantly that IACT at a BCL of 350ms was significantly longer than increased in patients with WPW syndrome.11 Katritsis et al at a BCL of 600ms; that is, use-dependency was noted. also reported that flecainide prolonged atrial ERP during Shimizu et al reported that isoproterenol shortens atrial sinus rhythm, but not during atrial pacing at any heart rate.12 ERP and IACT and Fishmann et al reported thatβ-blockers O’Hara et al13 and Hodess et al14 reported that atrial ERP cause a conduction delay in the atrium.25 Thus, the effect of prolongation was more pronounced when flecainide was d,l-sotalol on IACT is most likely a result of itsβ-receptor administered in dogs with pharmacological autonomic blocking effect. Kanki et al have shown in canine experi- nerve block. Although we did not compare the effects in ments that a pure class Ic antiarrhythmic drug, pilsicainide, the presence or absence of autonomic nerve block, the decreased conduction velocity, did not affect atrial MAPD, sympathetic nerve activity in the present study was expected but did increase the atrial ERP in a use-dependent manner,27 to be low because of the deep sedation induced by adminis- and that nifekalant did not affect conduction velocity, but tration of midazolam and fentanyl. Our data showed a increased the atrial MAPD and ERP in a reverse use-depen- further increase in atrial ERP at a faster heart rate (BCL 350 dent manner.28 Kanki et al have also shown that pilsicainide ms) compared with a slower heart rate (BCL 600ms); that terminated vagally-induced atrial fibrillation in 9/10 dogs is, use-dependent prolongation of ERP in spite of a similar (90%) and nifekalant terminated it in 4/8 dogs (50%).28 increase in atrial MAPD. Therefore, the use-dependent Our results also demonstrated that flecainide prolonged prolongation of atrial ERP in this study might be due to a the ERP and IACT of human atrial muscles in a use-depen- use-dependent increase in post repolarization refractoriness dent manner whereas nifekalant prolonged the MAPD and caused by the potent Na+ channel blocking effect of ERP in a reverse use-dependent manner without affecting flecainide. Nifekalant, a class III antiarrhythmic drug devel- IACT and d,l-sotalol prolonged MAPD in a reverse use- oped in Japan, is comparatively pure because it is a I K+r dependent manner, prolonged ERP to a similar extent at channel blocker (rapid component of delayed rectifier BCL 600 and 350ms and prolonged IACT in a use-depen- K+current) without aβ-receptor blocking effect.15,16 Kamiya dent manner. Thus, it would appear that flecainide more et al found that nifekalant increased atrial and ventricular effectively terminates atrial tachyarrhythmias, and that MAPD and ERP in dogs,17 and the present results, which nifekalant and d,l-sotalol are more effective for preventing showed that nifekalant significantly prolonged the MAPD atrial tachyarrhythmias; however, d,l-sotalol might be more and ERP of human atrium with reverse use-dependency effective than nifekalant for preventing atrial tachyarrhyth- effects, are compatible with their canine heart experiments. mias because its β-receptor blocking effect prevents an The fact that nifekalant did not affect IACT shows that it increased heart rate, which in turn lessens its class III effect. does not have a Na+ channel blocking effect. Although Furthermore, the efficacy of newly developed antiar- class III antiarrhythmic drugs can terminate tachyarrhyth- rhythmic drugs on human atrial tachyarrhythmias might be mia, the effect is relatively weak because of the reverse predicted by conducting similar studies to those reported use-dependency;18 however, Kamiya et al reported that here. nifekalant decreased the inducibility of reentrant ventricular tachycardia by extra-stimuli in 3–5 days after myocardial Study Limitations infarction in dogs because of prolongation of ERP.19 The number of subjects in each drug group was relatively Furthermore, they and Kunimoto et al reported that the small and their clinical backgrounds varied, although all extent of ERP prolongation by nifekalant is greater in atrial the subjects had electrophysiological abnormalities of the muscle compared with ventricular muscle,18,20 which might heart. Thus, our data may not represent the effects of the be effective for terminating and preventing atrial flutter and drugs in the healthy population. fibrillation. However, Hirata et al reported that nifekalant We measured MAPD and ERP at 2 basic cycle lengths increased the vulnerability to atrial fibrillation when the only; that is, 600 and 350ms. However, we have shown that effects of nifekalant on termination and prevention of atrial changes in MAPD and ERP were almost linear between the fibrillation and flutter were studied in a canine model. cycle lengths of 600 and 300ms.29 Thus, we were able to Kunimoto et al also reported that atrial flutter was induced in evaluate the frequency-dependent effects of the drugs using some cases after nifekalant was administered in humans.20,21 2 basic cycle lengths. This results might be because of the increased dispersion of refractoriness by nifekalant; therefore multiple site measure- ment of ERP is needed in human studies. References d,l-Sotalol, a class III agent with aβ-blocking effect, had 1. Hohdeghem LM, Katzung BG: Mechansm of action of antiarrhythmic

Japanese Circulation Journal Vol.65, January 2001 6 WATANABE H et al.

drugs. In: Sperelakis N, editor. Physiology and patho-physiology of 157–163 the heart, 2nd edn. Boston: Kluwer Academic Publishers, 1989: 509– 17. Kamiya J, Ishii M, Yoshihara K, Oyabe A, Banno H, Katakami T: 525 MS-551: Pharmacologial profile of a novel class III anti-arrhythmic 2. Singh BN: Electrophysiologic basis for the antiarrhythmic actions of agent. Drug Dev Res 1993; 30: 37–44 sotalol and comparison with other agents. Am J Cardiol 1993; 72: 18. Shinagawa K, Mitamura H, Sato T, Kanki H, Takatsuki S, Ogawa S: 8A–18A Effect of Na and K channel blockers on the spatial and temporal 3. Hondeghem LM, Snyders DJ: Class III antiarrhythmic agents have a dispersion of atrial refractoriness during atrial fibrillation. Jpn J lot of potential but a long way to go: Reduced effectiveness and Electrocardiol 1998; 18: 433–442 dangers of reverse use dependence. Circulation 1990; 81: 686–690 19. Kamiya J, Ishii M, Katakami T: Antiarrhythmic effects of MS-551, a 4. Franz MR, Swerdlow CD, Lien LB, Schaefer J: Cycle length depen- new class III antiarrhythmic agent, on canine models of ventricular dence of human action potential duration in vivo. J Clin Invest 1988; arrhythmia. Jpn J Pharmacol 1992; 58: 107–115 82: 972–979 20. Kunimoto S, Watanabe I, Kojima T, Kanda A, Kondo K, Takahashi 5. Ikeda N, Singh BN, Davis LD, Hauswirth O: Effects of flecainide on Y, et al: Electrophysiological effect of a novel class III antiarrhythmic the electophysiologic properties of isolated canine and rabbit myocar- agent, MS-551 on human atrium and ventricle. Jpn J Cardiac Pacing dial fibers. J Am Coll Cardiol 1985; 5: 303–310 Electrophysiol 1995; 11: 257–282 6. Page RL, Frame LH, Hoffman BF: Flecainide: Unusual use-depen- 21. Hirata T, Mitsuoka T, Hirata M, GK Kakota, Hano O, Matsumota Y, dent kinetics (abstract). J Am Coll Cardiol 1984; 3: 616 et al: Effect of MS-551 (class III) on electrically induced atrial flutter 7. Kyam DC, Banett EH, Schmid JR: Arrhythmic and electro-physio- and atrial fibrillation in the dog (abstract). Jpn Circ J 1991; 55: 200 logic actions of flecainide and animal models. Am J Cardiol 1984; 22. Shimizu W, Kurita T, Suyama K, Aihara N, Kamakura S, Simomura 53: 22B–25B K: Reverse use dependence of human ventricular repolarization by 8. Bruno LG, Jean-Yves LH, Patrick P, Pierre P, Thomas L, Stephane chronic oral sotalol in monophasic action potential recordings. Am J H, et al: Cellular electro-physiological effects of flecainide on human Cardiol 1996; 77: 1004–1008 atrial fibers. Cardiovasc Res 1990; 24: 232–238 23. Debra SE, Larry EB, William TC, Rolf GS, Donald CH: Prolonga- 9. Wang Z, Fermini B, Nattel S: Effect of flecainide, quinidine, and 4- tion of the human cardiac monophasic action potential by sotalol. Am aminopyridine on transient outward and ultrarapid delayed rectifier J Cardiol 1982; 50: 1082–1086 currents in human atrial myocyte. J Pharmacol Exp Ther 1995; 272: 24. Shimizu A, Yamagata T, Ueyama T, Hayano T, Tatsuno H, Esato M, 184–196 et al: Mechanism of atrial fibrillation - clinical electrophysiological 10. Follmer CH, Colasky TJ: Block of delayed rectifier potassium current, test for atrial vulnerability. Jpn J Electrocardiol 1998; 18: 195–202 Ik, by flecainide and E-4031 in cat ventricular myocyte. Circulation 25. Frishman WH, Sonnenbrick EH: β-adrenergic blocking drugs. In: 1990; 82: 289–293 Schlant RC, Alexander RW, editors. The heart, 8th edn. New York: 11. Camm AJ, Katritsis D, O’Nunain S: Effect of flecainide on atrial McGraw Hill, 1994: 1271–1290 electrophysiology in the Wolff-Parkinson-White syndrome. Am J 26. Shimizu W, Tsuchioka Y, Karakawa S, Nagata K, Mukai J, Yamagata Cardiol 1992; 70: 33A–37A T, et al: Different effect of pharmacological autonomic blockade on 12. Katritsis D, Rowland E, O’Nunain S, Shakespeare CF, Poloniecki J, some electrophysiological properties of the human ventricle and Camm AJ: Effect of flecainide on atrial and ventricular refractoriness atrium. Br Heart J 1994; 71: 34–37 and conduction in patients with normal left ventricle. Eur Heart J 27. Kanki H, Mitamuta H, Takatsuki S, Sato T, Shinagawa K, Sueyoshi K, 1995; 16: 1930–1935 et al: Post repolarization refractoriness as a potent anti-atrial fibrilla- 13. O’Hara G, Villemaire C, Talajic M, Nattel S: Effects of flecainide on tion mechanism of pilsicainide, a pure sodium channel blocker with the rate dependence of atrial refractoriness, atrial repolarization and slow recovery kinetics. Cardiovasc Drugs Ther 1998; 12: 475–482 atrioventricular node conduction in anesthetized dogs. J Am Coll 28. Kanki H, Mitamuta H, Sato T, Shinagawa K, Takatsuki S, Sueyoshi K, Cardiol 1992; 19: 1335–1342 et al: Post repolarization refractoriness as a potent anti-atrial fibrilla- 14. Hodess AB, Follansbee WP, Spear JF, Moore EN: Electro-physiolog- tion mechanism of pilsicainide, a pure sodium channel blocker with ical effects of a new antiarrhythmic agent, flecainide, on the intact slow recovery kinetics. Jpn J Electrocardiol 1998; 18: 315–323 (in canine heart. J Cardiovasc Pharmacol 1979; 1: 427–439 Japanese) 15. Iijima T, Taira N: Electrophysiological action of MS-551, a new anti- 29. Fuyama Y, Watanabe I, Masaki Y, Kojima T, Oshikawa N, et al: arrhythmic agent, on ventricular myocyte (abstract). Folia Pharmacol Frequency-dependent electrophysiological effects of nifekalant on Jpn 1990; 96: 88 human atrium in patients with chronic atrial fibrillation cardioverted 16. Nakaya H, Tohse N, Takeda Y, Kanno M: Effects of MS-551, a new with internal atrial defibrillation. J Arrhythmia 2000; 16: P290 (in class III antiarrhythmic drug, on action potential and membrane Japanese) currents in rabbit ventricular myocyte. Br J Pharmacol 1993; 109:

Japanese Circulation Journal Vol.65, January 2001