Summary
In isolated spontaneously beating guinea pig hearts, the effects of AWD 23-111 (N-(dicyclohexylcarbamoylmethyl)-N-(3-diethylamino-propyl)-4-nitrobenzamid-hydrochloride), a new synthetic class III antiarrhythmic agent with sodium antagonistic properties, were investigated on cardiac electrophysiological parameters, that is, conduction and refractoriness. Concentration-dependent prolongation of the atrioventricular, intraventricular, and His bundle conduction times and of sinus node cycle length were present. At 0.3 μM the repolarization period was prolonged significantly. No reverse use-dependent effect on the repolarization period was observed. During rapid pacing (pacing cycle length = 120 ms for the ventricle and 180 ms for the atrium) the rate-dependent intraventricular (QRS) or atrioventricular conduction time (AVCT) prolongation follows an exponential function of the beat number and is characterized by a drug-specific time constant. The time constant for the intraventricular conduction time prolongation in the presence of 0.1 μM AWD 23-111 was very long at 150±29 beats (mean±SEM; n=6), indicating a slow binding kinetic to the sodium channel. At 0.1 μM AWD 23-111, a significant increase in the ventricular effective refractory period was reached when the interstimulus interval (S1-S1) was 120 ms and the number of conditioning stimuli (S1) was higher than the time constant. The time constant for the rate-dependent AVCT prolongation in the presence of 0.3 μM AWD 23-111 was 34±6 beats (n=6). The effective refractory period of the atrioventricular conduction significantly increased with the number of conditioning stimuli (S1), until the number was comparable with the time constant. In conclusion, AWD 23-111 exerts a wide variety of actions on the cardiac conduction system. Its combined effects on the potassium and sodium channels seem to be responsible for the marked rate-dependent effect on ventricular refractoriness and for the lack of a reverse use-dependency on JT prolongation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ha'la O, Nemeth M, Varro' A, Papp JG. Electrophysiologic effects of detajmium on isolated dog cardiac ventricular and purkinje fibers. J Cardiovasc Pharmacol 1994;24:559–565.
Marx D, Poppe H, Bartsch R. Electrophysiological effects of AWD 23–111, a new class III antiarrhythmic agent in conscious dogs after myocardial infarction and incidence of triggered activities in chloralose anesthetized rabbits. Naunyn Schmiedebergs Arch Phrmacol 1995;351:106.
Poppe H, Bartsch R. Electrophysiologic and frequency dependent effects of the new class III antiarrhythmic agent AWD 23–111 on papillary muscle in guinea pig. Naunyn Schmiedebergs Arch Pharmacol 1995;351:107.
Denes P, Wu D, Dhingra R, et al. The effects of cycle length on cardiac refractory periods in man. Circulation 1974;49: 32–41.
Stark G, Kasper K, Schulze-Bauer C, Stark U, Decrinis M, Tritthart HA. How to measure AV-nodal refractorines in the presence of verapamil, amiodarone, digoxin and diltiazem. PACE 1996;19:157–164.
Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990;81:686–690.
Stark G, Stark U, Tritthart HA. Assessment of the conduction of the cardiac impulse by a new epicardiac surface and stimulation technique (SST-ECG) in Langendorff perfused mammalian hearts. J Pharmacol Methods 1989;21:195–209.
Stark G, Stark U, Hofer E, Tritthart HA. Continous ECG measurements of intracardiac activity from the surface of Langendorff-perfused guinea pig hearts. Basic Res Cardiol 1987;82:437–444.
The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321:406–412.
Stark G, Dhein S, Bachernegg M, et al. Frequency-dependent effects of propafenone decrease with duration of ventricular tachycardia in isolated guinea pig hearts. Eur J Pharmacol 1994;252:283–289.
Kidwell GA, Gonzalez MD. Effects of flecainide and D-sotalol on myocardial conduction and refractoriness: Relation to antiarrhythmic and proarhythmic drug effects. J Cardiovasc Pharmacol 1993;21:621–632.
Restivo M, Yin H, Caref EB, et al. Reentrant arrhythmias in the subacute infarction period. The proarrhythmic effect of flecainide acetate on functional reentrant circuits. Circulation 1995;91:1236–1246.
Ohler A, Amos GJ, Wettwer E, Ravens U. Frequency-dependent effects of E-4031, almokalant, dofetilide and tedisamil on action potential duration: No evidence for “reverse use dependent” block. Naunyn Schmiedebergs Arch Pharmacol 1994;349:602–610.
Carmeliet E. Potassium channels in cardiac cells. Cardiovasc Drugs and Therapy 1992;6:305–312.
Stark G, Schulze-Bauer C, Stark U, Kasper K, Decrinis M, Tritthart HA. Comparison of the frequency-dependent effects on the atrioventricular node of verapamil, amiodarone, digoxin, and diltiazem in isolated guinea pig hearts. J Cardiovasc Pharmacol 1995;25:330–335.
Hondeghem LM, Katzung BG. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 1977;472: 373–398.
McDonald TF, Pelzer D, Trautwein W. On the mechanism of slow calcium channel block in heart. Pflügers Arch Pharmacol 1980;385:175–179.
Hondeghem LM, Katzung BG. Antiarrhythmic agents: The modulated receptor mechanism of action of sodium and calcium channel blocking drugs. Ann Rev Pharmacol Toxicol 1984;24:387–396.
Zipes DP. Genesis of cardiac arrhythmias. In: Braunwald E, ed. Heart Disease, 3rd ed. Philadelphia: WB Saunders, 1988;581–620.
Kokubun S, Nishimura M, Noma A, Irisawa H. Membrane currents in the rabbit atrioventricular node cell. Pflügers Arch Pharmacol 1982;393:15–22.
Ruiz-Ceretti E, Zumino AP. Action potential changes under varied [Na+] and [Ca2+] indicating the existence of two inward currents in cells of the rabbit atrioventricular node. Circ Res 1976;39:326–336.
Billette J. Atrioventricular nodal activation during periodic premature stimulation of the atrium. Am J Physiol 1987; 252:163–177.
Siebels J, Cappato R, Rüppel R, Schneider MA, Kuck KH. Preliminary results of the cardiac arrest study Hamburg (CASH). CASH Investigators. Am J Cardiol 1993;72: 109F-113F.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stark, U., Stark, G., Schwarzl, I. et al. Effects of AWD 23-111, a new antiarrhythmic substance, on cardiac conduction and refractoriness. Cardiovasc Drug Ther 10, 531–538 (1996). https://doi.org/10.1007/BF00050993
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00050993