Effects Of Propafenone Research Articles

Propafenone: A New Anti arrhythmic for Treatment of Chronic Ventricular Arrhythmias

Propafenone is a new anti arrhythmic agent with primarily membrane‐stabilizing action. Three U.S. controlled double‐blind cross‐over studies demonstrated the efficacy of propafenone in suppressing ventricular premature complexes (VPCs), including repetitive forms: 67–83% of patients had greater than 80% reduction of VPCs, 62% achieved greater than 90% reduction of couplets and 80%–100% achieved 200% abolition of ventricular tachycardia runs. Other studies showed that propafenone is effective in controlling ventricular arrhythmias refractory to conventional anti arrhythmic agents. Propafenone is at least as effective as these agents. Long‐term sustained efficacy of propafenone was shown in some preliminary studies. Because of the variation in individual response to the drug, therapy should be individualized for each patient. Propafenone is well tolerated: side effects of propafenone are few and involve mostly the cardiac conduction system. Propafenone would be a significant addition to the anti arrhythmic armamentarium.

Short- and long-term effects of propafenone in ventricular arrhythmias

The effectiveness of short- (15 days) and long- (12 months) term propafenone treatment was assessed in 53 patients presenting with more than 30 premature ventricular complexes per hour as detected by 24-hour ambulatory Holter monitoring. Thirty-nine patients had no apparent concomitant heart disease while 14 had chronic coronary artery disease. The effects of propafenone were analysed by ambulatory Holter monitoring after 15 days and at 3, 6 and 12 months. The initial dose was 150 mg four times daily and was increased up to 300 mg four times daily when necessary. Favourable short-term effects were obtained in 39 patients (73.6%). After 12 months, 17 patients (32.1%) were still on propafenone treatment with good results. Treatment was discontinued on account of low compliance in 28.3%. This was because treatment was ineffective even at high doses in 15.2%, because of severe side effects in 13.2%, because of proarrhythmic effects in 5.6% and for other causes in 5.6%.

Propafenone in the Conscious Dog with Chronic Atrioventricular Block

The chronotropic effects of propafenone were studied in the conscious dog with chronic atrioventricular block. Propafenone at 0.5-4 mg/kg, i.e., at plasma levels within the assumed therapeutic range, dose relatedly raises atrial rate. This effect falls off and bradycardia is even observed at 0.5 and 1 mg/kg once plasma levels have dropped below 330 +/- 31 ng/ml. After atropine, propafenone (2 mg/kg) lowers atrial rate, after propranolol it raises it, and after pindolol it does not modify it. Propafenone dose relatedly raises ventricular rate, although again this effect subsequently reverses at 4 mg/kg. After atropine, propranolol, and pindolol, propafenone (2 mg/kg) instead of initially raising ventricular rate lowers it lastingly. It initially lowers mean blood pressure according to dose. At 2 mg/kg neither this effect nor the plasma levels are modified by the antagonists. The beta-blocking potency is 1/40th that of propranolol as determined against isoproterenol-induced cardioacceleration. These results show that the atrial cardioacceleration due to propafenone results from direct and reflex vagolytic action and that the bradycardia at low plasma levels (buffered by the vagolytic effect at high levels) seems due to its membrane-stabilizing action. They also show that the initial ventricular cardioacceleration is a reflex response to its hypotensive effect, whereas the ventricular bradycardia at high doses is attributable to its membrane-stabilizing action and its albeit weak beta-blocking action.

Electrophysiological effects of propafenone in untreated and propafenone-pretreated guinea-pig atrial and ventricular muscle fibres.

The electrophysiological effects of propafenone (10(-7) to 10(-4) M) were studied on guinea-pig isolated atrial and ventricular muscle fibres obtained from untreated animals and animals pretreated with propafenone, 3 and 10 mg kg-1, for 28 days. In untreated atria propafenone produced a dose-dependent decrease in the rate and maximum following frequency, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline. In untreated atrial and ventricular muscle fibres propafenone depressed action potential amplitude and Vmax, reduced the resting membrane potential and prolonged the action potential duration (APD) and the effective refractory period, lengthening the effective refractory period relative to APD. Propafenone depressed the amplitude and Vmax and shortened the duration of the slow action potentials induced by isoprenaline and caffeine in K-depolarized papillary muscles. Pretreatment with propafenone reduced atrial rate, but did not modify the action potential characteristics compared to the values obtained in untreated atria. Further addition of propafenone produced similar but more marked changes in untreated atria. In ventricular muscle fibres pretreated with 3 mg kg-1, action potential characteristics before and after further addition of propafenone were similar to those obtained in untreated fibres. However, muscles pretreated with 10 mg kg-1 exhibited a significant prolongation of the APD compared to that in untreated muscles or those pretreated with 3 mg kg-1; further addition of propafenone shortened the APD even when this parameter was of similar value to those observed in the other two series of experiments. It is concluded that even though the effects of propafenone are similar to those of quinidine (class I antiarrhythmic), it also exhibited class II and class IV actions. In pretreated animals a prolongation of the APD (class III action) could also be involved in the antiarrhythmic effects of the drug.

Electrophysiological effects of propafenone on isolated guinea-pig ventricular muscle and sheep purkinje fibres

The electrophysiological effects of propafenone on transmembrane potentials were studied in sheep Purkinje fibres and guinea-pig ventricular muscle. In both preparations propafenone decreased the amplitude and Vmax of the action potential and shifted the resting membrane potential to less negative values. In Purkinje fibres, propafenone also slowed the conduction velocity and shortened the action potential duration whereas in ventricular muscle it had no effect on action potential duration. Propafenone also suppressed: the normal automatic mechanism in Purkinje fibres as well as the automaticity induced by BaCl2 and isoprenaline in ventricular muscle fibres with high resting membrane potential (between -75 mV and -85 mV), the abnormal automatic mechanisms, including the slow action potentials induced by BaCl2 and isoprenaline in ventricular muscle and Purkinje fibres depolarized above -55 mV, respectively, and the delayed after-depolarizations induced by ouabain in Purkinje fibres and ventricular muscle. The possible mechanisms responsible for the cardiac effects of propafenone and the therapeutic implications of these electrophysiological effects are discussed.

A method for evaluating different modes of action of an antiarrhythmic drug in man. The effects of propafenone on sinus nodal functions

In vitro experiments have shown that the antiarrhythmic effects of propafenone are due to a direct depressant action and to a beta-blocking activity. In this study a method was used to evaluate the direct effect and the autonomically mediated actions of an antiarrhythmic agent in a clinical setting. An electrophysiological study was performed twice, at an interval of 24 hr, in 17 patients (age: 52±17 years) with normal resting and intrinsic heart rate. In the first study the overall effect of intravenous propafenone (1.5–2 mg/kg) was evaluated by comparing the sinus node parameters obtained during the basal state and after drug administration. In the second study the direct depressant effect of the drug was evaluated by comparing the electrophysiological variables obtained following autonomic blockade (propranolol 0.2 mg/kg and atropine 0.04 mg/kg) and after propafenone. In the first study there was no significant change in the sinus cycle length and corrected sinus node recovery time and only a small (9.1%) increase in sinuatrial conduction time, whereas in the second study these variables increased significantly. The degree of increase in sinus cycle length and corrected sinus node recovery time was significantly higher in the second study than in the first one. These data suggest that: (1) propafenone has direct depressant effect on sinus automaticity but this effect is counteracted by autonomically mediated actions (most likely of vagolytic type); (2) the beta-blocking effect of the drug demonstrated in isolated atria is not seen in a clinical setting.

Effect of propafenone in patients with stable ventricular arrhythmias

Thirty patients with clinically significant ventricular ectopy were treated with propafenone, a new potent antiarrhythmic agent with membrane stabilizing action. Patients had a minimum mean of greater than 30 ventricular premature beats per hour documented by continuous 48-hour ambulatory ECG recording. Twenty-five patients qualified as responders, defined as greater than 85% reduction of ventricular ectopy compared to baseline, and completed a double-blind placebo-crossover phase. Significant reduction in single ventricular ectopy per hour, paired ventricular ectopy per hour, and ventricular tachycardia beats per hour were observed. Almost total abolition of ventricular tachycardia and paired ventricular ectopy was achieved. Side effects were minimal and well tolerated. A significant prolongation of the PR interval occurred. QRS prolongation and prolongation of the corrected QT interval was observed in some patients, with new left bundle branch block developing in two patients. Long-term efficacy and safety studies will be necessary to determine the ultimate role of this new agent in the selection of antiarrhythmic therapy, but these inital results are encouraging.

Electrophysiologic effects of propafenone on canine ischemic cardiac cells

The electrophysiologic effects of propafenone were studied by conventional microelectrode techniques in ischemic myocardial and Purkinje fibers from 1-day-old myocardial infarction in the dog. Propafenone reduced the amplitude and rate of rise of normal myocardial and Purkinje action potentials and had little effect on the resting potential. In the control state, both ischemic myocardial and Purkinje fibers had reduced resting potential, action potential amplitude and upstroke velocity. These fibers were more susceptible to the depressant effects of propafenone than normal fibers. Ischemic myocardial fibers were particularly sensitive to the actions of propafenone that resulted in marked depression of action potential characteristics, with little effect on resting potential. These changes resulted in cycle length-dependent conduction disorders in ischemic epicardial preparations. However, in ischemic endocardial preparations in which triggered activity could be initiated, propafenone reversibly suppressed the triggered activity. Termination of the triggered activity was preceded by slowing of the rate, which was attributed to a decrease in the rate of rise of the delayed afterdepolarizations. This activity terminated when the delayed afterdepolarization failed to attain threshold potential. This study suggests that propafenone has a membraneanesthetic effect, with the abnormal fast channel in ischemic cells being more sensitive; propafenone depresses delayed afterdepolarizations in ischemic Purkinje fibers; and the actions of propafenone could result in an antiarrhythmic effect in vivo on both reentrant ventricular rhythms in ischemic myocardium and triggered rhythms in ischemic Purkinje fibers.

Effect of propafenone on the membrane currents of rabbit sino-atrial node cells.

The effects of propafenone (1-50 micrograms/ml) on the membrane potential and currents of the rabbit sino-atrial node were studied using the voltage clamp technique. Propafenone decreased the heart rate, amplitude of the action potential and maximum rate of depolarization. It also depolarized the maximum diastolic potential and the resting potential and prolonged the action potential duration dose dependently. On the current systems of the sino-atrial node, propafenone reduced the outward current (ik), the inward current activated by hyperpolarization (ih) and the slow inward current (is) dose dependently. The decrease in is and ik by propafenone was due to the reductions in their conductance, not to the changes in the voltage dependence of the inactivation of is or activation of ik. The decrease in ik might be the ionic mechanism of the negative chronotropic effect of propafenone.

Electrophysiologic and hemodynamic effects of propafenone, a new antiarrhythmic agent, on the anesthetized, closed-chest dog: Comparative study with lidocaine

The relative hemodynamic and electrophysiologic effects of a new antiarrhythmic drug, propafenone, and lidocaine were evaluated in eight closed-chest, anesthetized dogs. Propafenone (4 mg/kg intravenously) significantly ( p < 0.05) lowered aortic and pulmonary systolic pressures and caused a rise in heart rate ( p < 0.05). Cardiac output decreased from 4.5 ± 1 to 3.8 ± 0.7 L/min ( p < 0.05) during atrial pacing at 400 msec cycle length. Propafenone had no effect on pulmonary and aortic diastolic pressures. Lidocaine (5 mg/kg intravenously) caused a significant ( p < 0.05) decrease in aortic systolic pressure and a rise in heart rate. Lidocaine had no significant effect on the other measured hemodynamic parameters. Propafenone, unlike lidocaine, significantly ( p < 0.05) increased atrioventricular nodal functional refractory period and right ventricular endocardial (apex) cathodal (0.5 ± 0.1 mA to 1.9 ± 0.3 mA) and bipolar (1.4 ± 0.3 to 2.2 ± 0.4 mA) diastolic excitability threshold. Propafenone, unlike lidocaine, also caused a significant ( p = 0.05) intraatrial conduction delay; however, neither drug caused conduction slowing in the His-Purkinje system. Both drugs had no effect on sinus nodal recovery time and on the effective refractory period of the right ventricular endocardium (apex). Mean plasma propafenone levels during hemodynamic and electrophysiologic measurement ranged between 3.2 ± 1.8 μg/ml and 1.7 ± 1.1 μg/ml. All of the propafenone-induced effects were reversible within 90 minutes. We conclude that propafenone differs from lidocaine in its atrial, AV nodal, and ventricular electrophysiologic properties, and thus these may explain propafenone's greater efficacy over lidocaine against both certain atrial and ventricular arrhythmias. Propafenone's negative inotropic effects, however, should necessitate caution in its use.

The multiple modes of action of propafenone.

Previous studies of widely different concentrations of propafenone in various species have reported that in addition to having class 1 antiarrhythmic action, the drug was a beta adrenoceptor blocker and a calcium antagonist. High concentration shortened action potential duration in animal experiments, but Q-T interval was reported as being lengthened in man. It was thought desirable to study the effects of propafenone over a range of concentrations equivalent to those used clinically in various cardiac tissues of a single species, the rabbit. It was concluded that although the primary action of propafenone was on fast inward current, the drug being categorised as of group 1c, its potency as a beta blocker was sufficient for the effect to be of clinical significance. Its potency as a calcium antagonist was relatively weak. Action potential duration and effective refractory period were lengthened in both atrium and ventricle, the effects being long-lasting and persisting on wash-out of the drug when other measurements had returned to control values.

Double-blind placebo-controlled evaluation of propafenone in suppressing ventricular ectopic activity

The effectiveness of oral propafenone in treating ventricular premature complexes (VPCs) was assessed with a single-blind dose-ranging trial followed by a double-blind, randomized, crossover comparison of propafenone and placebo. Patients subsequently were treated with propafenone for up to 24 months. During dose ranging, the average of individual percent suppressions was 83% at the largest dose (300 mg/8 hours). During the double-blind trial, the effectiveness of propafenone was confirmed, with 7 of 12 patients achieving greater than or equal to 80% reduction in VPCs (p less than 0.05 versus double-blind placebo study). Propafenone was also effective in controlling couplets and nonsustained ventricular tachycardia. Seven patients were treated with propafenone for 24 months, during which effectiveness continued, with mean suppression ranging from 67 to 79% (p less than 0.05 versus initial single-blind placebo). Propafenone prolonged PR and QRS intervals by 16 and 18%, respectively; these prolongations continued during long-term therapy. Propafenone increased serum digoxin levels in 5 of 5 patients (mean increase 83%). Cardiovascular side effects included congestive heart failure (1 patient) and conduction abnormalities (3 patients). Thus, propafenone was effective in the treatment of total and repetitive VPCs. Side effects were few, but congestive heart failure, conduction disturbances and increases in serum digoxin were observed.

A controlled trial of propafenone for treatment of frequent and repetitive ventricular premature complexes

The effectiveness of oral propafenone was evaluated for the treatment of ventricular premature complexes (VPCs) in 12 patients, using a singleblind, dose-ranging trial followed by a double-blind comparison with placebo, and then an open-label, long-term protocol. During dose ranging, 8 of 12 patients achieved ≥ 80 % suppression of total VPCs (mean 83%) (p < 0.01 vs single-blind placebo). Paired VPCs were suppressed ≥ 90 % and ventricular tachycardia was eliminated in 11 of the 12 patients (p < 0.01). The effectiveness of propafenone for treatment of VPCs was confirmed during the double-blind trial (p < 0.05 vs double-blind placebo) and during treatment for 6 months (p < 0.05 vs initial single-blind placebo). Propafenone prolonged the PR interval by 16% (p < 0.01 vs single-blind placebo) and the QRS interval by 18 % (p < 0.001). Left ventricular systolic performance decreased as assessed by 2-dimensional echocardiography (p < 0.01 vs single-blind placebo). Propafenone increased serum digoxin levels in 5 of 5 patients (mean increase of 83 %). Side effects included exacerbation of congestive heart failure (1 patient) and conduction abnormalities (2 patients). Thus, propafenone is effective for treatment of total and repetitive VPCs. Although generally well tolerated, the drug reduces left ventricular systolic function and atrioventricular conduction and increases serum digoxin levels.

Effect of propafenone in the wolff-parkinson-white syndrome: Electrophysiologic findings and long-term follow-up

The electrophysiologic and long-term efficacy of propafenone, a relatively new antiarrhythmic agent, was assessed in 47 patients with accessory pathways. In 23 patients (group I), the electrophysiologic effects were assessed initially. In 19 patients in this group and in 24 additional patients (group II), long-term therapy with oral propafenone was initiated. The mean age of the patients was 38 years in group I and 41 years in group II. The duration of a history of tachycardia in both groups was 12 years (mean); 14 patients previously had had attacks of syncope. During the electrophysiologic study in group I, propafenone did not change the spontaneous sinus rate. Corrected sinus node recovery time as well as the AH interval, HV time, QRS duration and effective refractory periods of the atria and ventricles was significantly prolonged. The effective refractory period of the accessory pathway increased from 238 to 322 ms (p less than 0.02). The 1:1 conduction capacity of the accessory pathway decreased from 231 to 176 beats/min (mean; p less than 0.01). Complete block in the anterograde direction occurred in 6 patients. The shortest RR interval during atrial fibrillation increased from 232 to 303 ms (p less than 0.05). The retrograde refractory period of the accessory pathway was prolonged from 245 to 295 ms (p less than 0.01). Complete or 2:1 retrograde block during basic drive occurred in 3 patients and 1 patient, respectively. In 6 of 15 patients, propafenone made sustained supraventricular tachycardia (SVT) either no longer inducible or nonsustained. The cycle length of induced SVT increased from 324 to 395 ms (p less than 0.01). During long-term administration (follow-up duration 2 to 3 years), 17 of 43 patients did not report any episode of symptomatic tachycardia. In another 18 patients, tachycardia was rare, slower and self-terminating. In only 3 patients, the frequency and severity of attacks had not changed. One patient with dilated cardiomyopathy died suddenly. Side effects necessitating discontinuation of medication were observed in only 2 patients. The remaining side effects, if present, were tolerated, and dosage dependent. In conclusion, propafenone is an effective and well-tolerated antiarrhythmic agent in the long-term management of patients with the Wolff-Parkinson-White syndrome.

Effect of propafenone on left ventricular ejection fraction

The effects of orally administered propafenone on ejection fraction (EF) determined by radionuclide angiography were studied in 2 groups of patients receiving different dosing regimens. Fourteen group A patients had no clinical evidence of left ventricular (LV) dysfunction and were not receiving digoxin therapy. In this group a mean daily dosage of 879 mg resulted in a decrease in resting LVEF from 52 +/- 9% to 48 +/- 11% (p less than 0.05). Eight group B patients had clinical radionuclide evidence of LV dysfunction and were receiving digoxin therapy. In this group, a daily dosage of propafenone of 600 mg/day resulted in no significant change in LVEF. No clinically significant effects on cardiac compensation were evident in either group. These data suggest a negative inotropic effect that is either related to propafenone dosage or at least partially attenuated by digoxin therapy. Further studies are necessary to define precisely the effects of propafenone on LV function.

Block of sodium currents by antiarrhythmic agents: Analysis of the electrophysiologic effects of propafenone in heart muscle

Antiarrhythmic efficacy may result from the ability of class I drugs to depress cardiac sodium currents (INa). Drug interaction with sodium channels could underlie INa blockade and can be defined in terms of the law of mass action which is modulated by many experimental conditions. As exemplified by propafenone, INa blockade occurs in 2 forms: tonic and phasic inhibition. Steady-state phasic (or use-dependent) INa blockade is determined by the interstimulus interval and reflects a labile equilibrium between drug occupancy of and dissociation from a channel-associated binding site. The drug-specific kinetics of the latter process together with the duration of the diastole determine the accumulation of blocked, that is, nonconductive, channels. Several lines of evidence suggest that tonic and phasic INa blockade are not 2 different manifestations of the same molecular event. Decreasing resting potential or reducing extracellular Na+ concentration strongly accentuates tonic blockade, whereas phasic blockade is comparatively less affected by these interventions. Consistent with this special susceptibility are individual concentration-response relations characterized by different apparent dissociation constants and Hill (nH) coefficients. Cardiac sodium channels presumably possess less drug affinity under resting conditions. Their binding of drugs no longer seems to be an allosteric process during repetitive stimulation, but could be characterized by 1:1 stoichiometry.

Beta-blocking and electrophysiological effects of propafenone in volunteers.

The chemical structure of propafenone (P) and certain experimental findings suggest that this antiarrhythmic compound could possess beta-blocking properties. To evaluate the clinical relevance of the latter cardiovascular effects of P during exercise were studied. After oral administration of P 150 and 300 mg in solution, six healthy volunteers were subjected to graded exercise. These doses of P, which are usually effective against arrhythmias, decreased exercise-induced tachycardia, whereas the systolic blood pressure was lowered but only at rest, and the diastolic pressure was slightly raised. However, taking into account dose ratio, and the intensity and duration of the reduction in exercise tachycardia, this effect of P was only about 5% at its maximum compared to propranolol and similar active beta-blocking compounds. The reduction in heart rate produced by P was not correlated with the plasma level nor did it show dose dependency, in contrast to beta-blocking agents, and also in contrast to its electrophysiological effects on the PQ interval.

Electrophysiological effects of propafenone studied with programmed electrical stimulation of the heart in patients with recurrent paroxysmal supraventricular tachycardia.

Propafenone is an antiarrhythmic which possesses the properties of a class I agent. Its electrophysiological effects were studied with programmed electrical stimulation of the heart in 12 patients suffering from recurrent episodes of reentrant supraventricular tachycardia (atrioventricular nodal tachycardia:five cases; circus movement tachycardia involving an accessory pathway: six cases; atrial flutter and fibrillation with the Wolff-Parkinson- White syndrome: one case). Propafenone was perfused intravenously at a dose of 2 mg/kg over W min. It lengthened the transnodal conduction time, the H V interval, the VA conduction time (over the A V node) and the refractory period of right atrial muscle. The effects of the drug on accessory pathways used in the anterograde direction were measurable in four cases. Complete blockade along the bypass was seen in one instance and prolongation of the effective refractory period in the other three. In the retrograde direction, four patients out of six showed prolongation of the refractory period of the accessory pathway, after drug injection. Perfused intravenously during episodes of tachycardia, the drug interrupted the rhythm disorder in 10 out of 11 cases, but on three occasions, this was achieved by spontaneous ventricular premature beats which were not present prior to initiation of treatment. Tachycardia could still be initiated in six patients after propafenone (five out of six with circus movement tachycardia, one out of five with AV nodal tachycardia). The effects of chronic oral propafenone administration (300 mg t.d.s.) were assessed in five patients; they were similar to those observed after acute intravenous injection. Propafenone is a promising drug for the treatment of A V nodal tachycardia and might be useful for protection against high ventricular rates in patients with the preexcitation syndrome.

Effects of propafenone on TEA-induced action potentials in vascular smooth muscle of canine coronary arteries.

The Ca++-dependent, TEA-induced action potential is blocked by propafenone in a dose-dependent manner. Such results suggests that in coronary arterial smooth muscle one mechanism of action of propafenone is to inhibit Ca++ inward current.

Inhibition of Vmax of the action potential by propafenone and its voltage-, time- and pH-dependence in mammalian ventricular myocardium.

In microelectrode experiments on isolated papillary muscles of guinea-pigs, the effect of propafenone (1×10−5 mol/l–1×10−4 mol/l) on the fast Na+ action potential was analyzed. Propafenone caused, without changing the resting potential, a concentration dependent decrease of $$\dot V_{\max } $$ . At continuous stimulation with a rate of 12/min, complete inhibition of $$\dot V_{\max } $$ appeared in response to 1×10−4 mol/l. Transformation of the concentration-response curve into the Hill form revealed a Hill coefficient of 1.8. Some minor changes of the action potential configuration occurred consisting of a plateau shift to less positive potentials and of an abbreviation of action potential duration. Propafenone did not alter the linear dependence of $$\dot V_{\max } $$ on the logarithm of external Na+ concentration. Propafenone shifted the curve relating $$\dot V_{\max } $$ to membrane potential (h ∞-curve) to more negative potentials suggesting an interference with the inactivation process of the fast Na+ system. This effect developed on the quiescent, non-stimulated preparation and leads to the occurrence of a resting-state block being, consequently, potential dependent. Repetitive stimulation enhanced the propafenone-induced inhibition indicating a use-dependent block. During a train of 5–7 (at 12/min) or 15–20 (at 120/min) action potentials, a continuous decline of $$\dot V_{\max } $$ occurred until a new steady-state was attained. The interstimulus interval determined strength and kinetics of development (τdevelopment) of the use-dependent block. It was 22% and 8.4s, respectively at 5000 ms, but 70% and 1.8 s, respectively, at 500 ms. A slight intensification could also be induced by a decrease of membrane potential whilst pH or temperature changes remained ineffective. After cessation of continuous stimulation, the use-dependent block disappeared with a time constant of 15.5 s. Neither an increase of pH from 7.4 to 8.4 nor a decrease to 6.4 had any influence on the action of propafenone (pK a=9.0). Resting-state and usedependent block were of an identical amount regardless of the pH in the medium.