Abstract
The cellular electrophysiological effects of dridocainide (EGIS-3966), a novel class I antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje fibres and papillary muscle preparations obtained from humans and guinea-pigs. In each preparation, dridocainide (0.6–2 μmol/l) decreased the maximum velocity of action potential upstroke (Vmax) in a frequency-dependent manner, although marked differences were observed in its effects in Purkinje fibre and ventricular muscle preparations. In canine Purkinje fibres, action potential duration measured at 50% and 90% of repolarization was decreased, while action potential duration measured at 10% of repolarization was increased by dridocainide. In addition, the plateau of the action potential was depressed by the drug. These changes in action potential configuration were not observed in guinea pig or human papillary muscles. The offset kinetics of the dridocainide-induced V max block were different in Purkinje fibres and in ventricular muscle: the slow time constant of recovery of V max was estimated to be 2.5 s in dog Purkinje fibre and 5–6 s in human and guinea-pig papillary muscle. In guinea-pig papillary muscle, the rate of onset of the V max block was 0.15 and 0.2 per action potential in the presence of 0.6 and 2 μmol/l dridocainide, respectively. Dridocainide also decreased the force of contraction in this preparation. On the basis of the present results, dridocainide appears to posess mixed class LC and LA properties, with LC predominance in human and guinea-pig ventricular muscle. Present results also indicate that results of conventional classification of class I drugs may depend on the parameters chosen, as well as on the preparation selected.
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References
Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C (1979) The steadystate TTX-sensitive (“window”) sodium current in cardiac Purkinje fibers. Pflügers Arch 379:137–142
Bigger JT, Mandel WJ (1970) Effect of lidocaine on the electrophysiological properties of ventricular muscle and Purkinje fibers. J Clin Invest 49:62–77
Campbell TJ (1983a) Resting and rate-dependent depression of maximum rate of depolarization (V max) in guinea-pig ventricular action potentials by mexiletine, disopyramide and encainide. J Cardiovasc Pharmacol 5:291–296
Campbell TJ (1983b) Kinetics of onset of rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res 17:344–352
Campbell TJ (1983c) Importance of physico-chemical properties in determining the kinetics of the effects of class I antiarrhythmic drugs on maximum rate of depolarization in guinea-pig ventricle. Br J Pharmacol 80:33–40
Carmeliet E (1987) Slow inactivation of the sodium current in rabbit cardiac Purkinje fibers. Pflügers Arch 408:18–26
Cohen I, Attwell D, Strichartz G (1981) The dependence of the maximum rate of rise of the action potential upstroke on membrane properties. Proc R Soc Lond B 214:85–98
Colatsky TJ (1982) Mechanism of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. Cite Res 50:17–27
Courtney KR (1980) Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium. J Mol Cell Cardiol 12:1273–1286
Grant AO, Trantham JL, Brown KK, Strauss HC (1982) pH-dependent effects of quinidine on the kinetics of dV/dt max in guinea-pig ventricular myocardium. Circ Res 50:210–217
Harrison DC (1985) Is there a rational basis for the modified classification of antiarrhythmic drugs? In: Morganroth J, Moore EN (eds) Cardiac arrhythmias: new therapeutic drugs and devices. Nijhoff, Boston, pp 36–48
Hegedüs M, Petôcz L, Szemerédi K (1994) Verification of the effects of EGIS-3966, a potential antiarrhythmic compound. LIXth Meeting of the Hungarian Physiological Society, Budapest, 10–13 July 1994, P2
Hegedüs M, Petôcz L, Budai Z, Mezei T (1995) Antiarrhythmic activity of oximethers. Acta Physiol Hung (in press)
Heistracher P (1971) Mechanism of action of antifibrillatory drugs. Naunyn-Schmiedberg's Arch Pharmacol 269:199–212
Hille B (1977) Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69:497–515
Hiraoka M, Kawano S (1987) Calcium-sensitive and insensitive transient outward current in rabbit ventricular myocytes. J Physiol (Lond) 410:187–212
Hondeghem LM, Katzung BG (1977) Time and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472:373–398
Hondeghem LM, Katzung BG (1984) Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Anna. Rev Pharmacol Toxicol 24:387–423
Ikeda N, Singh BN, Davis LD, Hauswirth O (1985) Effects of flecainide on the electrophysiological properties of isolated canine and rabbit myocardial fibers. J Am Coll Cardiol 5:303–310
Imaizumi Y, Giles WR (1987) Quinidine-induced inhibition of transient outward current in cardiac muscle. Am J Physiol 253:H704-H708
Kus T, Sasyniuk BI (1978) The electrophysiological effects of disopyramide on canine ventricular muscle and Purkinje fibers in normal and low potassium. Can J Physiol Pharmacol 56:139–149
Nánási PP, Knilans TK, Richards IS, Varró A, Lathrop DA (1992) Biphasic effect of tetraethylammonium on canine Purkinje fiber action potential configuration. Gen Pharmacol 23:733–738
Nattel S, Zeng F-D (1984) Frequency-dependent effects of antiarrhythmic drugs on action potential duration and refractoriness of canine cardiac Purkinje fibers. J Pharmacol Exp Ther 229:283–291
Nawrath H (1981) Action potential, membrane currents and force of contraction in mammalian heart muscle fibers treated with quinidine. J Pharmacol Exp Ther 216:176–182
Petôcz L, Budai Z, Mezei T, Hegedüs M (1990) Cyclic oximether derivatives with mainly antiarrhythmic activity. XIth International Symposium on Medical Chemistry, Jerusalem, 2–7 September 1990, p 56
Rosen MR, Merker C, Gelband H, Hoffman BF (1973) Effects of procaine amide on the electrophysiological properties of the canine ventricular conducting system. J Pharmacol Exp Ther 185:438–446
Scanley BE, Fozzard HA (1987) Low conductance sodium channels in canine cardiac Purkinje cells. Biophys J 52:489–495
Sokal RR, Rohlf FJ (1969) Estimation and hypothesis testing. In: Emerson R, Kennedy D, Park RB (eds) Biometry, a series of books in biology. Freeman San Francisco, pp 127–171
Tritthart H, Fleckenstein B, Fleckenstein A (1971) Some fundamental actions of antiarrhythmic drugs on the excitability and contractility of single myocardial fibers. Naunyn-Schmiedberg's Arch Pharmacol 269:212–219
Varró A, Elharrar V, Surawicz B (1985) Effect of antiarrhythmic drugs on the premature action potential duration in canine cardiac Purkinje fibers. J Pharmacol Exp Ther 233:304–311
Varró A, Nakaya Y, Elharrar V, Surawicz B (1986) Effect of antiarrhythmic drugs on the cycle length-dependent action potential duration in dog Purkinje and ventricular muscle fibers. J Cardiovasc Pharmacol 8:178–185
Varró A, Knilans TK, Nánási PP, Rabloczky G, Lathrop DA (1990) Concentration- and rate-dependent electrophysiological effects of restacorin on isolated canine Purkinje fibres. Naunyn-Schmiedberg's Arch Pharmacol 342:691–697
Vaughan Williams EM (1975) Classification of antidysrhythmic drugs. Pharmacol Ther [B]. 1:115–138
Vaughan Williams EM (1984) Subgroups of class I antiarrhythmic drugs. Eur Heart J 5:96–98
Wang CM, Parker CH (1980) Reassessment of electrophysiological effects of the antiarrhythmic agent quinidine in canine Purkinje fibers. Life Sci 27:663–670
Weidmann S (1955) The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J Physiol (Lond) 127:213–224
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Pankucsi, C., Nánási, P.P., Hegedüs, M. et al. Electrophysiological effects of dridocainide on isolated canine, guinea-pig and human cardiac tissues. Naunyn-Schmiedeberg's Arch Pharmacol 352, 520–528 (1995). https://doi.org/10.1007/BF00169386
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DOI: https://doi.org/10.1007/BF00169386