Mechanism of Inactivation in Voltage-Gated Na(+) Channels.

Voltage-gated Na(+) channels (VGSCs) initiate action potentials thereby giving rise to rapid transmission of electrical signals along cell membranes and between cells. Depolarization of the cell membrane causes VGSCs to open but also gives rise to a nonconducting state termed inactivation. Inactivation of VGSCs serves a critical physiologic function as it determines the extent of excitability of neurons and of muscle cells. Depending on the time course of development and removal of inactivation both "fast-" and "slow"-inactivated states have been described. Evidence from mutagenesis studies suggests that fast inactivation is produced by a block of the internal vestibule by a tethered inactivation particle that has been mapped to the internal linker between domains III and IV. The motion of this linker may be regulated by parts of the internal C-terminus. The molecular mechanism of slow inactivation is less clear. However, aside from a high number of mutagenesis studies, the recent availability of 3D structures of crystallized prokaryotic VGSCs offers insights into the molecular motions associated with slow inactivation. One possible scenario is that slow movements of the voltage sensors are transmitted to the external vestibule giving rise to a conformational change of this region. This molecular rearrangement is transmitted to the S6 segments giving rise to collapse of the internal vestibule.

Sodium current properties of primary skeletal myocytes and cardiomyocytes derived from different mouse strains.

The mouse has become the preferred animal for genetic manipulations. Because of the diverse genetic backgrounds of various mouse strains, these can manifest strikingly different characteristics. Here, we studied the functional properties of currents through voltage-gated sodium channels in primary cultures of skeletal myocytes and cardiomyocytes derived from the three commonly used mouse strains BL6, 129/Sv, and FVB, by using the whole-cell patch-clamp technique. We found strain-specific sodium current function in skeletal myocytes, which could partly be explained by differences in sodium channel isoform expression. In addition, we found significant effects of cell source (neonatal or adult animal-derived) and variation of the differentiation time period. In contrast to skeletal myocytes, sodium current function in cardiomyocytes was similar in all strains. Our findings are relevant for the design and proper interpretation of electrophysiological studies, which use excitable cells in primary culture as a model system.

[Acute effects on the health of children after accidental exposure to epichlorohydrine]. / Akute gesundheitliche Effekte bei Kindern nach einer akzidentellen Freisetzung von Epichlorhydrin.

PURPOSE: In September 2002, two freight trains collided at Bad Muender, Germany. The inhabitants were potentially exposed to combustion products and to the human carcinogen epichlorohydrine (ECH). We aimed to describe the geographical distribution of and potential risk factors for acute symptoms among children residing in Bad Muender. METHODS: The parents of a random sample of children were invited to answer a mail-in questionnaire (response rate 63%). The main outcome measures were self-reported acute symptoms potentially associated with combustion products (e. g., irritation of the eyes, nose, or throat) and stress-related unspecific symptoms (e. g., gastrointestinal complaints, sleep problems, headaches). The main location during the first 26 hours after the train accident served as exposure proxy measure. In addition, potential predictors for the symptoms under study were assessed. RESULTS: The prevalence of symptoms associated with combustion products was 5.9%. Unspecific symptoms were reported for 6.3% of the children. Main location and prevalence of symptoms were not significantly associated. Physician-diagnosed asthma and nasal allergies were the main predictors of symptoms. CONCLUSION: The prevalence of acute symptoms was relatively high in a random sample of children living close to the incident. However, associations between exposure to the accident and symptoms could not be established conclusively.

The Kleine-Levin syndrome - effects of treatment with lithium -.

Kleine-Levin syndrome (KLS) is a rare disorder which affects mainly adolescents. Periods of extreme somnolence alternate with megaphagia, psychomental changes and behavioural symptoms. The cause and pathogenesis of KLS remains unknown. Several treatments have been tried and recently lithium has been proposed for a prophylactic use in single cases. In view of the rarity of KLS, long-term results of lithium therapy have not been described yet. We report the clinical course of five adolescents with KLS who were treated with lithium. All patients showed significant EEG and polysomnographic changes during the episodes and had normal results in the interval. All patients had relapses while being treated with lithium. But episodes of hypersomnia under lithium therapy were shorter and monosymptomatic with lack of behavioural symptoms. Statistical modelling showed that the risk for a relapsing episode under maintenance of lithium drops per months of therapy from 100 % to 93 %, and furthermore that the maintenance of lithium shortens the mean duration of episodes to 19 %. No severe side effects were observed. In conclusion, in KLS with a high frequency of episodes and severe behavioural changes lithium may become a treatment option.

The selectivity filter of the voltage-gated sodium channel is involved in channel activation.

Amino acids located in the outer vestibule of the voltage-gated Na+ channel determine the permeation properties of the channel. Recently, residues lining the outer pore have also been implicated in channel gating. The domain (D) IV P-loop residue alanine 1529 forms a part of the putative selectivity filter of the adult rat skeletal muscle (mu1) Na+ channel. Here we report that replacement of alanine 1529 by aspartic acid enhances entry to an ultra-slow inactivated state. Ultra-slow inactivation is characterized by recovery time constants on the order of approximately 100 s from prolonged depolarizations and by the fact that entry to this state can be reduced by binding to the pore of a mutant mu-conotoxin GIIIA, suggesting that ultra-slow inactivation may reflect a structural rearrangement of the outer vestibule. The voltage dependence of ultra-slow inactivation in DIV-A1529D is U-shaped, with a local maximum near -60 mV, whereas activation is maximal only above -20 mV. Furthermore, a train of brief depolarizations produces more ultra-slow inactivation than a single maintained depolarization of the same duration. These data suggest that ultra-slow inactivation emanates from "partially activated" closed states and that the P-loop in DIV may undergo a conformational change during channel activation, which is accentuated by DIV-A1529D.

Fulminant course in a case of diffuse myelinoclastic encephalitis-- a case report.

We report on a 10-year old previously healthy boy who exhibited a fulminant and nearly monophasic clinical course of demyelinating encephalitis with relapsing intracranial hypertension syndrome. Histologic examination of a diagnostic brain biopsy revealed an inflammatory demyelinating process with perivascular T lymphocytic infiltration and axonal damage reminiscent of multiple sclerosis-like lesions. In the brain, the DNA of human Herpes virus 6 (HHV6) was detectable. Eleven months after the initial symptoms and on maintainance with oral steroids, MRI showed demyelination of both hemispheres as well as demyelination of the brain stem and Wallerian degeneration. The boy exhibited a severe neurologic defect syndrome. The clinical and radiological course is unusual because of the asymmetric progression of the encephalitis and the extensive confluent lesions without demarcated border or enhancement of the rim after injection of gadolinium. The clinical course showed no definite steroid response. The pathogenetic relevance of HHV6 remains elusive. Although single patients with HHV6-associated encephalomyelitis have been reported, HHV6 DNA is occasionally detected in brains of healthy individuals.

Temporary response of localized intracranial mast cell sarcoma to combination chemotherapy.

Cerebral involvement of systemic mastocytosis and intracranial sarcoma of myelogenic origin are well known entities. An 8-year-old girl with an isolated cerebral mast cell tumor is presented. Specific histopathologic stains were used to confirm the diagnosis detecting immunophenotype and proliferative activity. Treatment with irradiation, intrathecal cytarabine, and interferon-alpha2b did not induce regression whereas polychemotherapy did. Systemic combination chemotherapy led to marked transient tumor regression in this proliferating mast cell sarcoma in an unusual intracranial location.

Ultra-slow inactivation in mu1 Na+ channels is produced by a structural rearrangement of the outer vestibule.

While studying the adult rat skeletal muscle Na+ channel outer vestibule, we found that certain mutations of the lysine residue in the domain III P region at amino acid position 1237 of the alpha subunit, which is essential for the Na+ selectivity of the channel, produced substantial changes in the inactivation process. When skeletal muscle alpha subunits (micro1) with K1237 mutated to either serine (K1237S) or glutamic acid (K1237E) were expressed in Xenopus oocytes and depolarized for several minutes, the channels entered a state of inactivation from which recovery was very slow, i.e., the time constants of entry into and exit from this state were in the order of approximately 100 s. We refer to this process as "ultra-slow inactivation". By contrast, wild-type channels and channels with the charge-preserving mutation K1237R largely recovered within approximately 60 s, with only 20-30% of the current showing ultra-slow recovery. Coexpression of the rat brain beta1 subunit along with the K1237E alpha subunit tended to accelerate the faster components of recovery from inactivation, as has been reported previously of native channels, but had no effect on the mutation-induced ultra-slow inactivation. This implied that ultra-slow inactivation was a distinct process different from normal inactivation. Binding to the pore of a partially blocking peptide reduced the number of channels entering the ultra-slow inactivation state, possibly by interference with a structural rearrangement of the outer vestibule. Thus, ultra-slow inactivation, favored by charge-altering mutations at site 1237 in micro1 Na+ channels, may be analogous to C-type inactivation in Shaker K+ channels.

A mu-conotoxin-insensitive Na+ channel mutant: possible localization of a binding site at the outer vestibule.

We describe a mutation in the outer vestibule region of the adult rat skeletal muscle voltage-gated Na+ channel (microliter) that dramatically alters binding of mu-conotoxin GIIIA (mu-CTX). Mutating the glutamate at position 758 to glutamine (E758Q) decreased mu-CTX binding affinity by 48-fold. Because the mutant channel showed both low tetrodotoxin (TTX) and mu-CTX affinities, these results suggested that mu-CTX bound to the outer vestibule and implied that the TTX- and mu-CTX-binding sites partially overlapped in this region. The mutation decreased the association rate of the toxin with little effect on the dissociation rate, suggesting that Glu-758 could be involved in electrostatic guidance of mu-CTX to its binding site. We propose a mechanism for mu-CTX block of the Na+ channel based on the analogy with saxitoxin (STX) and TTX, on the requirement of mu-CTX to have an arginine in position 13 to occlude the channel, and on this experimental result suggesting that mu-CTX binds in the outer vestibule. In this model, the guanidinium group of Arg-13 of the toxin interacts with two carboxyls known to be important for selectivity (Asp-400 and Glu-755), with the association rate of the toxin increased by interaction with Glu-758 of the channel.

Frequency-dependent effects of amitriptyline and maprotiline on conduction in the guinea pig His-Purkinje-system in vivo.

In the Cardiac Arrhythmia Suppression Trial antiarrhythmic drug therapy with slow kinetic sodium channel blockers (class Ic antiarrhythmic drugs) was associated with excess mortality, presumably due to drug induced proarrhythmia. It has been suggested that the degree of rate-dependent conduction slowing produced by agents that have sodium channel blocking properties may be related to the proarrhythmic propensity of these agents. In the present study, rate-dependent conduction slowing by the antidepressants amitriptyline and maprotiline was investigated in anesthetized guinea pigs. After electrical ablation of the sinus node the left atrium was stimulated at cycle lengths between 200 ms and 500 ms. His bundle electrograms were registered by means of an epicardial electrode. Drugs were administered by i.v. infusion of 0.2 mg kg-1 min-1 for 30 min followed by 0.1 mg kg-1 min-1 for up to 30 min. Both drugs produced substantial rate-dependent conduction slowing within the His-Purkinje-system. The relationship between pacing rate and conduction slowing was well fitted by linear regression. The steepness of the regression line was significantly greater for amitriptyline than for maprotiline (slope factors: 9.10 x 10(-4) +/- 7.85 x 10(-5), n = 6, vs. 6.29 x 10(-4) +/- 2.97 x 10(-5), n = 6, P < 0.001), indicating that conduction slowing by amitriptyline exhibits a greater degree of rate-dependence than conduction slowing by maprotiline.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effect of dofetilide on ventricular repolarization during steady state and during restitution in vivo.

Class III antiarrhythmic drugs alter the relation between cycle length and the QT interval. However, the relation between cycle length and the QT interval varies, whether determined for single test stimuli ("restitution") or for sustained rhythm ("steady state"). In anesthetized guinea pigs (n = 6), we assessed QT prolongation by the selective class III antiarrhythmic agent dofetilide (10 micrograms/kg intravenously) by atrial pacing during steady state and during restitution. Spontaneous sinus rhythm was abolished by electrical ablation of the sinus node area. Dofetilide prolonged QT intervals at all cycle lengths (CL), and the changes were more pronounced at long than at short CL. This reverse rate-dependent effect was significantly greater during steady state than during restitution. Thus, at a cycle length of 200 ms, the difference between QT interval during steady state and QT interval during restitution was -10.0 +/- 1.7 ms at baseline and -11.1 +/- 3.5 ms after dofetilide (p = 0.8). At a CL of 500 ms, the respective values were 11.7 +/- 1.3 and 19.1 +/- 1.9 ms (p = 0.01). Dofetilide produces substantially more reverse rate-dependent increase in QT duration during steady state than during restitution. Clinically, these findings indicate that excessive drug-induced QT prolongation by dofetilide is more likely to develop during prolonged periods of bradycardia than after single long coupled extra-beats. Such excessive QT prolongation may in turn predispose to torsade de pointes arrhythmias.

Prolongation of the QT interval by dofetilide modulates rate-dependent effects of mexiletine on intraventricular conduction.

Prolongation of action potential duration during treatment with agents that possess class I antiarrhythmic activity may result in a clinically relevant increase in Na+ channel block. In order to test this hypothesis in vivo, the effect of QT prolongation on intraventricular conduction was assessed during administration of mexiletine. Epicardial His bundle recordings were made in anesthetized guinea pigs. After abolition of spontaneous sinus node activity by application of high-frequency current to the sinus node area, the hearts were paced via the left atrium. Administration of the class III antiarrhythmic agent dofetilide (10 micrograms/kg i.v.; n = 6) significantly prolonged QT intervals without a significant effect on HV intervals. Infusion of mexiletine (bolus 2 mg/kg + 0.18 mg/kg per min i.v.; n = 6) produced significant increases in HV intervals at cycle lengths of 200 and 300 ms. Subsequent addition of dofetilide (20 micrograms/kg i.v.) to mexiletine induced similar increases in QT intervals as single treatment with 10 micrograms/kg dofetilide and significantly enhanced the rate-dependent conduction slowing. Upon abruptly decreasing the pacing cycle length from 500 ms to 300 ms, conduction slowing developed with a rate constant of 1.0 +/- 0.2 beat-1 after mexiletine and with a rate constant of 1.1 +/- 0.2 beat-1 after subsequent addition of dofetilide (P = n.s.). After rapid stimulation at a cycle length of 250 ms the conduction slowing produced by mexiletine recovered with a time constant of 174 +/- 24 ms. No further change of this recovery time constant was observed after subsequent addition of dofetilide to mexiletine (160 +/- 19 ms, P = n.s.). Thus action potential duration, as reflected by the QT interval, is an important modulator of the magnitude Na+ channel block in vivo. The kinetic parameters of Na+ channel block produced by mexiletine, however, remain unchanged by prolongation of action potential duration after addition of dofetilide.

[Joubert syndrome combined with unilateral facial paralysis: a rare variant of Joubert syndrome]. / Joubert-Syndrom in Kombination mit einseitiger Facialisparese: Eine seltene Variante des Joubert-Syndroms.

We report the case of a mature newborn infant, which aroused attention 8 hours after birth due to an unexplainable paroxysmal tachypnea together with subsequently prolonged apnea. The combination of tachypnea, athetoid movement patterns, apraxia of the tongue, nystagmus and dysplasia of the cerebellum with dilation of the 4th ventricle, led to the diagnosis of Joubert-Syndrome. The child also showed a variation of a connatal unilateral facial nerve palsy, which has not previously been described in connection with a Joubert-Syndrome.

Effect of ajmaline on sustained ventricular tachycardia induced by programmed electrical stimulation in conscious dogs after myocardial infarction.

As yet the antiarrhythmic efficacy of ajmaline with regard to suppressing the induction of sustained ventricular tachycardia after myocardial infarction has not been determined. Therefore, programmed electrical stimulation was performed in 8 conscious, chronically instrumented mongrel dogs 8-20 days after a 4-hour occlusion of the left anterior descending coronary artery. At baseline all animals responded with sustained ventricular tachycardia. Thereafter, ajmaline was administered at two consecutive i.v. doses: a bolus of 0.7 mg kg-1 followed by infusion of 2 mg kg-1 h-1 and infusion of 4 mg kg-1 h-1. The induction of sustained ventricular tachycardia was prevented in 2/8 animals by 2 mg kg-1 h-1 ajmaline and in 1/8 animals by 4 mg kg-1 h-1 ajmaline. During sinus rhythm only 4 mg kg-1 h-1 ajmaline significantly increased QRS-duration and intraventricular activation times, but during rapid right ventricular pacing (cycle length = 330 ms) both doses of ajmaline increased QRS duration and intraventricular conduction times. 4 mg kg-1 h-1 ajmaline also increased the cycle length of induced sustained ventricular tachycardia. In 3 animals induction of sustained ventricular tachycardia during infusion of 4 mg kg-1 h-1 ajmaline was achieved by introduction of less extrastimuli than at baseline. Furthermore the coupling intervals of extrastimuli that induced sustained ventricular tachycardia were substantially prolonged by this dose. Inhomogeneity of conduction between left ventricular normal zone and left ventricular infarct zone was significantly increased by 4 mg kg-1 h-1 ajmaline during rapid right ventricular pacing, but not during sinus rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of rate-dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo.

1. The effects of the class I antiarrhythmic agent, tocainide, on intraventricular conduction were assessed in guinea-pigs, anaesthetized with pentobarbitone sodium 60 mg kg-1, i.p. 2. After electrical ablation of the sinus node, heart rate was controlled by atrial pacing. His bundle electrograms were recorded by means of an epicardial bipolar electrode. 3. During continuous stimulation, comparison of HV intervals measured at a cycle length of 475 ms, with HV intervals measured at a cycle length of 250 ms yielded the following results: 25.26 +/- 0.64 ms versus 25.02 +/- 0.70 ms (NS), at baseline, 26.65 +/- 0.80 ms versus 29.88 +/- 1.13 ms (P < 0.001) after i.v. administration of 30 mg kg-1 tocainide, and 28.04 +/- 0.64 ms versus 36.24 +/- 1.31 ms (P < 0.001), after addition of 20 mg kg-1 tocainide. Thus, tocainide caused HV intervals to increase in a strictly rate-dependent fashion. 4. In order to characterize the rate-dependent class I activity of tocainide in terms of its binding kinetics to sodium channels, fractional sodium channel block was estimated from drug induced reductions of intraventricular conduction velocity (delta theta). On abruptly changing the drive cycle length from 500 ms to 250 ms, delta theta reached a new steady state with rate constants of 1.23 +/- 0.09 beat-1 and 1.28 +/- 0.09 beat-1, after administration of 30 mg kg-1 and addition of 20 mg kg-1 tocainide, respectively. At a basic drive cycle length of 250 ms delta theta recovered with time constants of 250.29 +/- 23.32 ms and 183.04 +/- 8.03 ms after administration of 30 mg kg-1 and addition of 20 mg kg-1 tocainide, respectively.5. The experimentally determined kinetic parameters were implemented into a mathematical model that assumes drug binding to sodium channels in terms of a periodical two-state process. Rate-dependent reductions in conduction velocity during continuous stimulation after administration of tocainide were closely approximated by steady state reductions in sodium channel availability as calculated on the basis of the aforementioned model.6. In agreement with previously published in vitro studies, our data, obtained in vivo, confirm the classification of tocainide as a class I antiarrhythmic agent with fast onset and offset kinetics. The kinetic parameters obtained in vivo can be used in order to predict steady state reductions in conduction velocity at a wide range of frequencies.

Mode of QT correction for heart rate: implications for the detection of inhomogeneous repolarization after myocardial infarction.

In 22 conscious, chronically instrumented dogs, the relationship between R-R interval and QT interval was better explained by linear regression than by nonlinear regression according to Bazett's formula. The correction formula QTL = QT-0.1*(RR-1000), which is based on the assumption of a linear relationship between QT and R-R interval, was then compared with Bazett's formula regarding its capability to detect inhomogeneous repolarization 5 to 7 days after temporary occlusion of the left anterior descending coronary artery. This comparison was performed only in those dogs exhibiting changes in QRS duration of less than 5 msec in response to myocardial infarction (n = 12). In these animals, myocardial infarction resulted in a significant dispersion of repolarization between the left ventricular normal zone and the infarct zone and a shift to the right of strength-interval curves of the infarct zone with respect to the normal zone, indicating local dispersion of refractoriness. As opposed to QTc (Bazett's formula), QTL was significantly (p = 0.04) prolonged after occlusion. Hence the adequacy of QT correction contributes significantly to the detection of inhomogeneous ventricular recovery after acute myocardial infarction.

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs.

The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 micrograms/kg/min (i.v.). During 80 micrograms/kg/min lidocaine (mean plasma level 3.5 micrograms/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 micrograms/kg/min and 4 of 8 to 120 micrograms/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p less than 0.05), 67.7 ms (p less than 0.05), 70.0 ms (p less than 0.01) respectively. In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting.

Epicardial His bundle recordings in the guinea pig in vivo.

In small animals, His bundle activity is commonly registered using intracavitary electrodes in Langendorff-perfused hearts. The present study evaluates the feasibility of epicardial registration of His bundle activity in 30 guinea pigs in vivo, anesthetized with 60 mg/kg sodium pentobarbital i.p. Following median sternotomy, a bipolar electrode, mounted on a flexible stand, was placed into the aortic-right atrial groove. His bundle activity was easily detected in all animals. Mean PA, AH, and HV intervals were 16.7 +/- 1.4 msec (range: 6.0-34.0 ms), 36.4 +/- 1.5 ms (range: 22.0-54.0 msec) and 14.4 +/- 0.4 msec (range: 9.0-20 msec), respectively. Administration of verapamil and vagal stimulation induced significant prolongations of AH intervals without affecting HV intervals; lidocaine prolonged both AH and HV intervals. Both at baseline and following drug administration there was excellent agreement between the AH and HV intervals assessed from simultaneously registered epicardial and endocardial His bundle electrograms (n = 12). The presented model provides reproducible values for atrioventricular (AV) nodal and His-to-ventricular conduction intervals in the guinea-pig in vivo and will, thus, be a valuable tool in electrophysiologic drug evaluation.

Efficacy of verapamil against ventricular arrhythmias induced by programmed electrical stimulation in the late myocardial infarction phase in dogs.

The aim of the present study was to investigate the antiarrhythmic potential of verapamil in the late myocardial infarction period in conscious dogs. Verapamil was administered in cumulative doses (0.3 + 0.3 mg kg-1). The drug significantly lowered systolic and diastolic blood pressure after both doses. ECG signals showed short-lasting significant decrease in RR and QT intervals together with an increase in QTc interval. The parameters of the atrioventricular conduction system (PQ interval, 2:1 AV-conduction point) were significantly prolonged over the entire observation period. Ventricular effective refractory periods remained unaltered. In contrast to results obtained during acute ischaemia and in the first week thereafter, the present study demonstrates that verapamil moderately increases intraventricular conduction time 14 days after acute myocardial infarction. Verapamil prevented the induction of arrhythmias by programmed electrical stimulation (PES) in only 11% of all induction attempts. The lack of lengthening of refractory periods in the presence of a prolongation of intraventricular conduction time may be responsible for the poor antiarrhythmic efficacy. We conclude that verapamil is only of negligible value for the management of PES-induced ventricular arrhythmias in the late myocardial infarction period.