Efficacy of the novel calcium antagonist R(+)-semotiadil in limiting the ventricular rate during atrial flutter in isolated guinea pig hearts.

Ca2+ antagonists slow the ventricular rate by blocking conduction in the anterograde direction through the atrioventricular (AV) node. The aim of this study was to investigate the efficacy of the novel Ca2+ antagonist semotiadil compared with verapamil and diltiazem on the filtering capacity of the AV node during simulated atrial flutter in isolated guinea-pig hearts perfused by the method of Langendorff. During sinus rhythm, semotiadil as well as verapamil and diltiazem induced comparable depressant effects on AV-nodal conduction time and, during tachycardia, a comparable enhancement of this effect. The time constant (tau-on) for the drug-specific rate-dependent effect on AV-nodal conduction slowing was longest in the presence of verapamil compared with the long tau-on of semotiadil and the short tau-on of diltiazem. Verapamil and semotiadil exhibited a significantly greater effect than diltiazem on the mean ventricular cycle length (VCLmeun), on the maximal ventricular cycle length (VCLmax) and on the standard deviation of the VCL (SD(VCL)) during atrial flutter. Therefore the kinetics of the rate adaptation of AV-nodal conduction time in the presence of Ca2+ antagonists predicts the filtering capacity of the AV node during atrial flutter. Semotiadil has a verapamil type of action on ventricular cycle length during atrial flutter, whereas the disadvantageous prolongation of maximal VCL as well as the dispersion of VCL with semotiadil was only about half those found with verapamil.

Magnesium abolishes inadequate kinetics of frequency adaptation of the Q-aT interval in the presence of sotalol.

OBJECTIVE: It has been well established that class III antiarrhythmic drugs can also induce ventricular arrhythmias. Marked changes in the QT interval are correlated with an increased dispersion of repolarization which is an important factor for the induction of ventricular arrhythmias. The aim of the present study was to investigate the effects of sotalol alone and in combination with MgSO4 and the Q-aT interval during abrupt changes in heart rate. METHODS: The experiments were performed on isolated guinea-pig hearts perfused by the method of Langendorff. The rate adaptation of the Q-aT interval was estimated after abruptly changing the ventricular pacing rate from 220 to 180 ms and back to 220 ms. RESULTS: In the presence of 10 microM sotalol, at a constant pacing cycle length of 220 ms, the QT interval was prolonged significantly (P < 0.01) from 152 +/- 4 to 166 +/- 3 ms (mean +/- s.e.m., n = 8 in each group). The addition of 3.4 mM MgSO4 caused a slight further prolongation of the QT interval. After abruptly shortening the pacing cycle length from 220 to 180 ms, the Q-aT interval shortened within 2 min by 11.3 +/- 0.5 ms with a time constant (tau) of 77 +/9 beats under control conditions, by 15.4 +/- 0.9 ms (P < 0.05 vs. control with tau = 52 +/- 7 beats (P < 0.05 vs. control) in the presence of sotalol, and by 13.1 +/- 1.2 ms with tau = 158 +/- 13 beats under the combination of sotalol (10 microM) and MgSO4 (3.4 mM). After abrupt shortening of the pacing cycle length the Q-aT interval of the first beat was shortened by 3.3 +/- 0.3 ms under control conditions, by 7.1 +/- 0.2 ms (P < 0.01 vs. control) under sotalol, and by 4.2 +/- 0.2 ms with the combination of sotalol and MgSO4. If the pacing cycle length was abruptly increased from 180 to 220 ms, the effects were comparable to those described above. CONCLUSIONS: Sotalol led to inadequate kinetics of fate adaptation of the Q-aT interval indicated by a high amplitude of Q-aT interval change, especially within the first beat after abrupt change in the pacing rate. MgSO4 abolished this effect of sotalol. These findings suggest that MgSO4 could reduce sotalol-induced inadequate kinetics of rate adaptation and therefore also dispersion of repolarization, which may result in a reduction of sotalol-induced ventricular arrhythmias.

Influence of duration of rapid ventricular pacing on ventricular refractoriness in the presence of propafenone and lidocaine.

Propafenone and lidocaine have a rate dependent negative dromotropic effect on intraventricular conduction. We investigated the use dependent actions of propafenone and lidocaine on intraventricular conduction in isolated guinea pig hearts perfused by the method of Langendorff. Of primary interest was how the number of stimuli of the conditioning train (S1) might influence the ventricular effective refractory period (VERP) when refractoriness is assessed at a high pacing rate. Propafenone (0.3 microM) and lidocaine (50 microM) caused a comparable prolongation of the intraventricular conduction time during sinus rhythm. During ventricular pacing in the presence of propafenone an abrupt decrease of the pacing cycle length (220 to 120 ms) resulted in an initial peak of rate dependent prolongation of the QRS interval that subsequently decreased to a stable steady-state level. Lidocaine also induced a rate dependent increase of the intraventricular conduction time up to a steady-state level. The time constant, characterizing the changes of the intraventricular conduction time after shortening the ventricular pacing cycle length from 220 to 120 ms was significantly (P < 0.01) longer in the presence of propafenone (tau = 31 +/- 4 beats; mean +/- SEM; n = 11) than for lidocaine (tau = 3 +/- 1; n = 10). Both drugs caused the greatest increase of the VERP when the number of conditioning stimuli (S1, interstimulus interval = 120 ms) was in the range of their respective time constant. However, when the number of conditioning stimuli was further increased, VERP progressively diminished. These effects may be explained by a shortening of the action potential during high rates that results in a decreased binding of propafenone to Na+ channels and by the direct shortening of repolarization period by lidocaine (Class IB drug).

Quantification of rate-dependent effects of verapamil, diltiazem, and digoxin on atrioventricular conduction.

The calcium channel blocking agents, verapamil and diltiazem, and the digitalis compound, digoxin, caused drug specific rate-dependent changes of the atrioventricular conduction time (AVCT). The purpose of this study was to investigate this rate adaptation of the AVCT in isolated guinea pig hearts perfused by the method of Langendorff to get an insight in drug-specific binding kinetic to the respective channel. In the presence of 10 nM verapamil, 30 nM diltiazem, or 0.6 nM digoxin, the atrioventricular conduction time was prolonged to a comparable degree during sinus rhythm. The drug-specific time constant, characterizing the rate-dependent adaptation of the AVCT, in the presence of a substance was comparable if evaluated after abruptly changing the heart rate from the pacing cycle length of 240 ms to 180 ms (tau-on) or from 180 to 240 ms (tau-off). The adaptation of the AVCT in the presence of verapamil (tau-on = 178 +/- 45 beats, tau-off = 125 +/- 33 beats, mean +/- SEM) was more pronounced than in the presence of digoxin (tau-on = 144 +/- 24 beats, tau-off = 98 +/- 15 beats) or diltiazem (tau-on = 70 +/- 11 beats, tau-off = 98 +/- 15 beats). In conclusion, the differences in the rate adaptation of the AVCT may be explained by the drug-specific association and dissociation kinetic to the calcium channel, slow in the case of verapamil, and fast in the case of dilitiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.

Effects of AWD 23-111, a new antiarrhythmic substance, on cardiac conduction and refractoriness.

In isolated spontaneously beating guinea pig hearts, the effects of AWD 23-111 (N-(dicyclohexylcarbamoylmethyl)-N-(3-diethylamino-propyl)-4-nit robenzamid -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 microM 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 microM 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 microM 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 microM 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.

Rate-dependent effects of ajmaline and propafenone on atrioventricular conduction.

The aim of the present study was to characterize the time dependence of the depressant effects of ajmaline and propafenone on the Ca(2+)-channel-dependent tissue of the atrioventricular node in isolated guinea pig hearts perfused by the method of Langendorff. Ajmaline at a concentration of 0.03 microM and propafenone at a concentration of 0.3 microM caused a significant and comparable prolongation of the His bundle and atrioventricular conduction time (AVCT). When the pacing cycle length was abruptly shortened from 240 to 180 ms, the mean time constant (tau on) of the rate-dependent AVCT prolongation was comparable for ajmaline and propafenone. In contrast, if the pacing cycle length was abruptly increased from 180 to 240 ms the mean time constant (tau off) for ajmaline was significantly higher than for propafenone. The rate-dependent increase of the atrioventricular effective refractory period was significantly more pronounced in the presence of ajmaline than of propafenone. Ajmaline and propafenone affect the Ca(2+)-channel-dependent tissue of the myocardium. The more pronounced rate-dependent effect of ajmaline on the atrioventricular effective refractory period may be explained by a slower dissociation kinetic from the channel.

Rate-dependent effects of detajmium and propafenone on ventricular conduction and refractoriness in isolated guinea pig hearts.

Detajmium (4--3'-diethylamino-2'-hydroxypropyl--ajmalin) is an Na(+)-channel-blocking drug with an extremely long recovery from use-dependent sodium channel block. The aim of the present study was to investigate the rate-dependent effects of detajmium on the intraventricular conduction of isolated, spontaneously beating, guinea pig hearts in comparison with the effects of propafenone. Detajmium (0.3 microM) and propafenone (0.3 microM) caused comparable prolongations of the intraventricular conduction time during sinus rhythm. The time to steady state of the rate-dependent QRS prolongation during rapid ventricular pacing follows an exponential function of the beat number after an abrupt change of frequency and is characterized by a drug-specific time constant. This time constant was significantly longer for detajmium (tau = 265 +/- 165 beats; mean +/- SEM; n = 6) than for propafenone (tau = 31 +/- 4 beats; n = 11; p < 0.01). In the presence of propafenone, QRS duration peaked initially before decreasing to a steady state. Detajmium, in contrast, progressively broadened the QRS complex. Both substances caused the greatest increase in the ventricular effective refractory period (V-ERP) when the number of conditioning stimuli (interstimulus interval, 120 ms) was in the range of the time constant. However, when the number of conditioning stimuli was further increased, the V-ERP for propafenone diminished progressively. In conclusion, propafenone displayed, in comparison with detajmium, only a transient rate-dependent effect on intraventricular conduction and V-ERP.