Abstract
Quinidine and verapamil are widely used as antiarrhythmic agents and their combination is often used in the treatment of supraventricular tachycardia. This study was undertaken to clarify, whether these drugs exert proarrhythmic effects on the ventricles in therapeutic concentrations and whether possible arrhythmogenic effects might be enhanced by combination. Isolated rabbit hearts perfused according to the Langendorff technique were treated with increasing concentrations of quinidine (0.05 to 3.5 μM) or verapamil (5 to 50 μM) or of their combination (70:1 or 10:1; quinidine:verapamil) corresponding to common low, medium and high free therapeutic concentrations. The epicardial activation process was measured using a computer assisted mapping system for unipolar multichannel recording (256 channels simultaneously).
Both substances prolonged the atrioventricular conduction time PQ. This effect was even more pronounced if the 70:1 combination was administered. The activation pattern was altered by both drugs and their combination to the same extent as became obvious from analysis of local activation vectors and of localisation of breakthroughpoints of epicardial activation for heart beats under control conditions and under drug treatment. The epicardial potential durations were prolonged by quinidine and to the same degree by the combinations, but not by verapamil alone. The total activation time was prolonged under the influence of quinidine and if the 70:1 combination was given. Both substances exerted a negative inotropic effect which was enhanced in an additive manner if both drugs were combined. In parallel the coronary flow was diminished.
From these results it is concluded that (1) in this therapeutic concentration range quinidine possess a greater proarrhythmic risk than verapamil, (2) that both drugs' PQ prolonging effect can be enhanced by combination, (3) that combination does not enhance the proarrhythmic effects but the negative inotropic effects.
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References
Arisi G, Macchi E, Baruffi S, Spaggiari S, Taccardi B (1983) Potential field on the ventricular surface of the exposed dog heart during normal excitation. Circ Res 52:706–715
Buchanan JW, Saito T, Kagiyama Y, Hill JL, Ettes S (1982) The relationship between upstroke velocity and conduction in guinea pig myocardium. Am J Cardiol 49:983 (abstr)
Buchanan JW, Saito T, Gettes LS (1985) The effects of antiarrhythmic drugs, stimulation frequency and potassium induced resting membrane potential changes on conduction velocity and dV/dtmax in guinea pig myocardium. Circ Res 56:696–703
Carlsson L, Alnmgren O, Duker G (1990) QTU-prolongation and torsades de pointes induced by putative class III antiarrhythmic agents in the rabbit: etiology and interventions. J. Cardiovasc Pharmacol 16:276–285
Dhein S, Rutten P, Klaus W (1988) A new method for analysing the geometry and timecourse of epicardial potential spreading. Int J Biomed Comput 23:201–207
Dhein S, Müller A, Klaus W (1989) The potential of epicardial activation mapping in isolated hearts for the assessment of arrhythmogenic and antiarrhythmic drug activity. J. Pharmacol Methods 22:197–206
Dhein S, Müller A, Klaus W (1990) Prearrhythmia: changes preceding arrhythmia, new aspects by epicardial mapping. Basic Res Cardiol 85:285–296
Dhein S, Müller A, Gerwin R, Klaus W (1993) Comparative study on the proarrhythmic effects of some class I antiarrhythmic agents. Circulation 87:617–631
Durrer D, Van der Tweel LH (1954) Spread of activation in the left ventricular wall of the dog. Activation conditions at the epicardial surface. Am Heart J 47:192–203
Echt DS et al (1991) Mortality and morbidity in patients receiving encainide, flecainide or placebo. The cardiac arrhythmia suppression trial. N Engl J Med 324:781–788
El Sherif N (1987) The ventricular premature complex: Mechanisms and significance. An update. In: Mandel J (ed): Cardiac arrhythmias. JB Lippincott, Philadelphia, pp 475–506 Langendorff O (1895) Untersuchungen am Säuberlebenden Säugetierherzen. Archiv ges Physiol 61:291–331
Geddes J, Burgess MJ, Millar K, Abildskov JA (1974) Accelerated repolarization as a factor in reentry. Simulation of the electrophysiology of acute myocardial infraction. Am Heart J 88:61–68
Goodman Gilman A, Goodman LS, Rall TW, Murad F (1985) The pharmacological basis of therapeutics. Macmillan New York, pp 748–873, 1668–1713
Haas H, Raschack M, Fischer U (1971) Kombinationsversuche mit Verapamil und Chinidin. Arzneimittelforsch Drug Res 21: 1392–1399
Habbab MA, El-Sherif N (1990) Drug-induced torsade de pointes: role of early after depolarizations and dispersion of repolarization. Am J Med 89:241–246
Han J, Moe GK (1964) Nonuniform recovery of excitability in ventricular muscle. Circ Res 16:46–60
Haworth RA, Goknurr AB, Berkoff HA (1989) Inhibition of ATP-sensitive potassium channels of adult rat heart cells by antiarrhythmic drugs. Circ Res 65:1157–1160
Hunter PJ, McNaughton PA, Noble D (1975) Analytical models of propagation in excitable cells. Prog Biophys Mol Biol 30:99–144
Kuo CS, Munakata K, Reddy CP, Surawicz B (1983) Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 67: 1356–1367
Langendorff O (1895) Untersuchungen am überlebenden Säugetier-herzen. Archiv ges Physiol 61:291–331
Merx W, Yoon MS, Han J (1977) The role of local disparity in conduction and recovery time on ventricular vulnerability to fibrillation. Am Heart J 94:603–610
Millar CK, Kralios FA, Lux RL (1985) Correlation between refractory periods and activation recovery intervals from electrograms: effects of rate and adrenergic interventions. Circulation 72:1372–1379
Müller A, Klaus W, Dhein S (1991) Heterogeneously distributed sensitivities to potassium as a cause of hypokalemic arrhythmias in isolated rabbit hearts J Cardiovasc Electrophysiol 2:145–155
Nawrath H (1981) Action potential, membrane currents and force of contraction in mammalian heart muscle fibers treated with quinidine. J Pharmacol Exp Ther 216:167–181
Nishimura M, Yamada S, Watanabe Y (1982) Electrophysiologic effects of disopyramide phosphate on the spontaneous action potential and membrane current system. Am J Cardiol 49:921 (abstr)
Podrid PJ (1985) Aggravation of ventricular arrhythmia. A drug induced complication. Drugs 29 (Suppl 4):33–44
Rensma PL, Allessie MA, Lammers WJEP, Bonke FIM, Schalij MJ (1988) Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res 62: 395–410
Smeets JLRM, Allessie MA, Lammers WJEP, Bonke FJM, Hollen J (1986) The wave length of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium. Circ Res 58:96–108
Spach MS, Dolber PC (1986) Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Circ Res 58:356–371
Spach MS, Dolber PC, Heidlage JF (1989) Interaction of inhomogeneties of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initating reentry. Circ Res 65:1612–1631
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Dhein, S., Schott, M., Gottwald, E. et al. Electrocardiological profile and proarrhythmic effects of quinidine, verapamil and their combination: a mapping study. Naunyn-Schmiedeberg's Arch Pharmacol 352, 94–101 (1995). https://doi.org/10.1007/BF00169195
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DOI: https://doi.org/10.1007/BF00169195