Ulrike Stark

Different stereoselective effects of (R)- and (S)-propafenone : clinical pharmacologic, electrophysiologic, and radioligand binding studies

Propafenone is a class 1c antiarrhythmic agent with moderate β‐blocking activity as a result of a structural similarity to β‐adrenoceptor antagonists. In a randomized, double‐blind crossover exercise study, eight healthy volunteers were examined before and 2½ hours after oral administration of 300 mg (R,S)‐, 150 mg (R)‐, and 150 mg (S)‐propafenone hydrochloride. The mean rate pressure product was significantly reduced by (R,S)‐propafenone hydrochloride (− 5.2%; p = 0.045) and half‐dosed (S)‐propafenone hydrochloride (−5.9%; p = 0.013), whereas the (R)‐enantiomer caused no significant changes. There was a significant difference between the effects of (R)‐ and (S)‐propafenone (p = 0.033). In β‐adrenoceptor–binding inhibition experiments with (S)‐(125I)iodocyanopindolol in a sarcolemmaenriched cardiac membrane preparation, the eudismic ratio of (S)‐ over (R)‐propafenone was 54. On the spontaneously beating Langendorff‐perfused guinea pig heart, 3 · 10−6 mol/L of both (R)‐ and (S)‐propafenone resulted in significant changes (p < 0.01) on His bundle conduction (+ 79% ± 27% and + 69% ± 9%), as well as comparable decreases in the maximal rate of pacing with 1:1 conduction of the atrial (−54% ± 10% and −57% ± 8%) and ventricular myocardium (−42% ± 6% and −43% ± 6%), indicating equal effects in sodium channel–dependent antiarrhythmic class 1 activity. Thus (R)‐ and (S)‐propafenone exert different β‐blocking actions but equal effects on the sodium channel–dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of β‐blocking side effects may be attained with optically pure (R)‐propafenone hydrochloride instead of the currently used racemic mixture.

Assessment of the conduction of the cardiac impulse by a new epicardiac surface and stimulation technique (SST-ECG) in Langendorff perfused mammalian hearts.

The assessment of the effects on the conduction of the cardiac impulse and of refractoriness simultaneously from multiple cardiac structures is important to evaluate the mode of action of new compounds, as well as to investigate undesired cardiac side effects. The measurements of intracardiac electrical activities of special structures have required catheter methods or averaging techniques to produce clear deflections of low-level potential wave forms. We have developed an epicardial surface electrocardiogram (S-ECG) recording technique to detect continuously sinus node and His-bundle activities in spontaneously beating Langendorff perfused heart preparations. A bipolar surface stimulation technique electrocardiogram (ST-ECG) could be combined with this S-ECG method to assess the effect of pacing at maximal rate on the refractoriness of the sino-atrial, AV-nodal, and His-bundle conduction, as well as that of the atrial and ventricular myocardium. Epicardial surface electrodes were also used for vector analysis of the signals, which include those of the sinus node and His-bundle potentials, in addition to the usual atrial and ventricular loops. The present results demonstrate that this new epicardial surface ECG recording technique, combined with the described SST-ECG, provided a way to improve or replace more elaborate intracardiac techniques used in isolated hearts or in animal experiments.

Modulation of cardiac impulse generation and conduction by nifedipine and verapamil analyzed by a refined surface ECG technique in Langendorff perfused guinea pig hearts

SummaryUsing a modified Langendorff system, a special ECG recording technique and appropriate placement of two silver wire electrodes, early atrial and His bundle activity can be detected continuously from the surface of intact and spontaneously beating guinea pig hearts. This new method was applied to measure the direct and inhibitory effects of nifedipine and verapamil on impulse generation and conduction in isolated and perfused guinea pig hearts. Depression of sinoatrial conduction was the most prominent effect of nifedipine. In all concentrations applied (10−7 M, 10−6 M, 10−5 M) nifedipine predominantly led to sinoatrial blocks of different degrees. Heart rate decreased slightly in a dosedependent manner. PQ and HV duration remained essentially constant. In the highest concentration of nifedipine (10−5 M), sinus node activity was so depressed that AV dissociation or ventricular rhythm developed. Only in one out of eight experiments with cumulative increase of nifedipine concentrations to 10−5 M was the AV node affected by nifedipine and a second-degree AV block developed (10−6 M).Verapamils inhibitory effects on the rate of impulse initiation in the sinus node were more pronounced than those of nifedipine, but the inhibition of sinoatrial conduction by verapamil was less marked. At 10−6 M verapamil, the incidence of sinoatrial blocks and of ventricular rhythm was similar to the incidence of first degree AV blocks. PQ time (+14%) but also HV time (+12%) were prolonged under the influence of this concentration of verapamil. At the highest concentration of verapamil (10−5 M) applied for 10 min, ventricular rhythm developed in five out of eight experiments, as well as one second and two third-degree AV blocks.The results confirm that the simultaneous measurement of sinus node activity of sinoatrial and atrioventricular conduction and of HV duration is feasible with this ECG technique, to evaluate the inhibitory effects of Ca-antagonists on sinus and AV node activity in the intact heart.

Direct cadiac electorphysiologic effects of sufentanil and vecuronium in isolated guinea‐pig hearts

Sufentanil and vecuronium are commonly used simultaneously in anaesthesia. Bradycardia and asystole have been described immediately after the administration of these two compounds. Therefore, the purpose of the present study was to evaluate the direct cardiac effects of sufentanil and vecuronium in all parts of the cardiac pacemaker and conduction system.

Stereoselective electrophysiological effects of propafenone in Langendorff perfused guinea pig hearts.

SummaryThe present study was focused on the stereoselective electrophysiological effects of (R)-and (S)-propafenone·HCl evaluated in isolated Langendorff perfused guinea pig hearts. Conduction intervals were measured using an ECG-recording method of high resolution. Refractory periods of the different parts of the myocardium were determined by stimulation with premature stimuli, as well as by stimulation with increasing pacing rate (rate-dependent/refractory periods). Drug concentrations of 0.1, 1 and 3 μM were tested. Both compounds induced a dose-dependent increase in AV-nodal, His-bundle, and intraventricular conduction time which reached significance (p<0.01) following 3 μM of either compound. Sinus rate was also dose-dependently and significantly reduced.(R)- and (S)-propafenone·HCl induced a marked prolongation of the rate-dependent refractory period of sino-atrial (by 140±22%, p<0.01 and by 141±14%, p<0.01, respectively) and AV-nodal (by 34±22%, p<0.01 and by 42±15%, p<0.01, respectively) conduction and of the atrial (by 182±21%, p<0.01 and by 195±15%, p<0.01, respectively) and ventricular (by 93±16%, p<0.01 and by 88±16%, p<0.01, respectively) myocardium. The effective refractory periods evaluated by stimulation with premature stimuli were also significantly prolonged under the influence of (R)- and (S)-propafenone·HCl, except the ventricular myocardial refractoriness by (R)-propafenone·HCl (increase to 114±23%, n.s.). Both compounds showed a strong rate-dependence of their effects and, thus, the refractory periods evaluated by stimulation with increasing pacing rate were significantly more prolonged than the refractory periods evaluated by stimulation with premature stimuli. The main difference between the effects of (R)- and (S)-propafenone·HCl on the cardiac electrical activity is the lack of effect of (R)-propafenone·HCl on the ventricular myocardial refratoriness evaluated by stimulation with premature stimuli.

Action of Atp on Ventricular Automaticity

ATP is an effective treatment of supraventricular tachycardia when the atrioventricular (AV) node is part of the reentrant circuit. However, the lower a pace-maker in the pacemaker hierarchy, the more sensitive it is to adenosine. Therefore, we investigated the effects of ATP on ventricular automaticity in in vivo and in vitro conditions. Wide and narrow QRS complex tachycardia in 46 patients was treated with 6, 12, and 18 mg ATP as sequential intravenous (i.v.) bolus. ATP terminated tachycardias in 67%. Bolus infusion ATP caused < or = 6.4-s asystole that was self-limited. Perfusion of isolated spontaneously beating guinea pig heart with 100 microM ATP completely suppressed ventricular automaticity. After ATP-infusion was discontinued, the first ventricular beat was evident after 3.1 +/- 0.9 s and sinus node activity recovered with a time constant of 3.0 +/- 1.1 s. Because sinus node and ventricular automaticity recovered within seconds after ATP infusion was discontinued in vitro, recovery in vivo is also likely to be determined by the short half-life (+1/2) of ATP.

Comparison of acute electrophysiological effects of amiodarone and its metabolite desethylamiodarone in Langendorff perfused guinea pig hearts.

SummaryDuring long-term treatment with amiodarone, slowing of conduction through the atrioventricular node, a prolongation of the QT-interval, and a prolongation of the atrial and ventricular myocardial refractoriness always developed. During short-term treatment, these effects were not found, except for depression of the AV-nodal conduction. This led to the suggestion that the electrophysiological effects of amiodarone during long-term treatment might be partly the result of the accumulation of its metabolite desethylamiodarone. Therefore, we examined the electrophysiological effects of amiodarone and desethylamiodarone on conduction and refractoriness in isolated spontaneously beating guinea pig hearts perfused by the method of Langendorff. Within 1 h of perfusion, desethyl-amiodarone caused a more pronounced prolongation of the AV-nodal, His-bundle, and intraventricular conduction intervals than did amiodarone. Desethylamiodarone, but not amiodarone led to a prolongation of the QT-interval. The refractoriness of sinoatrial-, AV-nodal conduction, and of the atrial myocardium were significantly more prolonged by amiodarone than by desethylamiodarone. Both compounds showed a comparable strong rate-dependent effect on AV-nodal refractoriness. The ventricular refractoriness was similarily prolonged by either compound. These results show that for the class-III effects (i.e., prolongation of repolarization period) observed under chronic treatment of amiodarone the metabolite desethylamiodarone may be responsible. Desethylamiodarone also exerts more pronounced effects on the fast-channel-dependent parts of the conduction system than does amiodarone, a fact indicated by a higher prolongation of His-bundle and intraventricular conduction.

Effects of semotiadil, a novel Ca2+ channel antagonist, on the electrical activity of Langendorff-perfused guinea pig hearts in comparison with diltiazem, amlodipine and nifedipine

Semotiadil, a new Ca2+ antagonist with a high vasoselectivity, in high concentrations depresses AV nodal conduction in a frequency-dependent manner. The aim of the present study was to investigate the effects of semotiadil on intact cardiac conduction and the pacemaker system in comparison with diltiazem, amlodipine and nifedipine. The effects were studied in isolated guinea pig hearts perfused by the method of Langendorff. Both semotiadil and diltiazem decreased markedly the sinus rate in a concentration-dependent manner whereas this was not the case in the presence of amlodipine and nifedipine. Semotiadil (10 microM) markedly prolonged sinus node recovery time and in the presence of diltiazem (10 microM) in 5 out of 7 experiments an intermittent sinus node arrest occurred. Atrioventricular conduction and the effective refractory period of the AV node were most affected by diltiazem and semotiadil. The Ca2+ channel blocking compound semotiadil showed the most pronounced rate-dependent effects on the AV node. In the presence of diltiazem the QT interval became even shorter than in untreated hearts. In contrast, semotiadil did not act on the QT interval. In conclusion, as semotiadil exerts a clear rate-dependent effect on AV nodal conduction with a long time constant, it mimics the electrophysiological behavior of a substance of the verapamil type.

The effects of the propranolol enantiomers on the intracardiac electrophysiological activities of Langendorff perfused hearts

SummaryThe optical isomers of the beta blocking agent propranolol exert beta receptor blocking as well as membrane stabilizing effects. The latter is thought to be responsible for the antiarrhythmic effect of the drug.In this study we quantified the electrophysiological effects of both isomers of propranolol on the conduction and pacemaker system of the heart. The experiments were performed on isolated hearts using a special ECG recording and stimulation technique. To abolish isoproterenols beta adrenergic stimulatory effect on heart rate, 30-times higher concentrations of (+)propranolol were necessary than of (−)propranolol in order to be consistent. Both isomers caused a similar and marked slowing of conduction velocity through the bundle of His and ventricular myocardium. Also, heart rate, as well as atrio-ventricular conduction velocity were significantly slowed by a concentration of 10 μM of either drug, (−)propranolol being slightly more effective. Only in the presence of (−)propranolol did significant changes of atrio-ventricular and His-bundle conduction occur at a concentration of 1 μM. During programed stimulation sinus node recovery time was more prolonged by (−)propranolol than during perfusion with (+)propranolol. The highest rate of pacing with 1∶1 conduction of the sino-atrial conduction, the atrial and ventricular myocardium was significantly depressed to a comparable degree by either isomers of propranolol. These effects appear to be primarily responsible for the antiarrhythmic effects of both isomers. Because of the minor effects of (+)propranolol on sinus- and AV-node activity, as well as on beta adrenergic receptors, this isomer may have potential clinical importance in the treatment of arrhythmias.

Frequency-dependent effects of adenosine and verapamil on atrioventricular conduction of isolated guinea pig hearts.

Frequency-dependent depressant effects of a drug on slow channels in the atrioventricular (AV) node are important in its efficacy against supraventricular tachycardias. Verapamil terminates reentrant supraventricular arrhythmias by depressing conduction through the AV node. Similar effects have been described for adenosine. We compared the use-dependent effects of both drugs on AV nodal conduction in isolated guinea pig hearts perfused by the method of Langendorff. Adenosine 3 μM and verapamil 0.01 μM caused a comparable prolongation of AV conduction time (AVCT) and reduction in sinus rate (SR). The time dependence of drug-induced changes in AV conduction was characterized after the atrial pacing rate was changed abruptly. The basic cycle length was shortened abruptly from 240 to 180 ms. The resulting time constant for adenosine (T = 467 ± 187 beats, mean ± SD) was significantly (p < 0.05) longer than that for verapamil (T = 264 ± 121 beats). At a pacing cycle length of 180 ms, the rate-dependent conduction slowing tended to be more pronounced in the presence of adenosine than of verapamil. Adenosine had more pronounced frequency-dependent effects on AV conduction than did the calcium channel blocker verapamil. This may explain the higher clinical efficacy of adenosine in supraventricular tachycardias in which the AV node forms a part of the reentrant circuit.