Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry.

OBJECTIVE: Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated the hypotheses that: (1) the activation patterns of the initial PVT beats would be consistent with an origin in the ventricular conduction system; and (2) the inhomogeneous prolongation of repolarisation intervals can provide refractory barriers for re-entrant activity. METHODS: Unipolar electrograms were recorded from 127 epicardial (EPI) sites with a sock electrode array as well as from intramural and endocardial sites during PVTs. Electrograms were analysed to generate isochronal maps and measure the spatial distribution of activation-recovery intervals (ARI). RESULTS: Under S (9.9-14.5 mg.l-1), spontaneously terminating PVTs (cycle length of 270 +/- 43 ms, n = 45) (mean +/- s.d.) occurred when a PE bolus (10-50 micrograms.kg-1) was injected. The first beat of the PVTs occurred with a coupling interval of several hundred ms to the preceding idioventricular beat (IDV) without any bridging activity and its earliest EPI breakthrough occurred in areas overlying the terminations of the right or left bundle branch. ARI values measured in IDV (295 +/- 47 ms) were significantly prolonged prior to PVT (462 +/- 92 ms). Prolongation was greater in apical than in basal epicardial areas, and at endocardial than epicardial sites (to > 500 ms). Maximum delays > 200 ms developed in the regions of marked ARI prolongation and, in later beats, circus movement re-entry occurred around refractory barriers, shifting between various regions of the ventricles. CONCLUSION: Thus, PVTs occurring spontaneously under conditions of delayed repolarisation originate from shifting sites in the ventricular conduction system and re-entrant activity shifting between various regions of the ventricle may occur in later beats of the more sustained arrhythmias.

A quantitative description of the E-4031-sensitive repolarization current in rabbit ventricular myocytes.

We have measured the E-4031-sensitive repolarization current (IKr) in single ventricular myocytes isolated from rabbit hearts. The primary goal of this analysis was a description of the IKr kinetic and ion transfer properties. Surprisingly, the maximum time constant of this component was 0.8 s at 33-34 degrees C, which is significantly greater than the value of 0.18 s previously reported under similar conditions in the original measurements of IKr from guinea pig ventricular myocytes. The primary, novel feature of our analysis concerns the relationship of the bell-shaped curve that describes the voltage dependence of the kinetics and the sigmoidal curve that describes the activation of IKr. The midpoint of the latter occurred at approximately +10 mV on the voltage axis, as compared to -30 mV for the point on the voltage axis at which the maximum time constant occurred. Moreover, the voltage dependence of the kinetics was much broader than the steepness of the activation curve would predict. Taken together, these results comprise a gating current paradox that is not resolved by the incorporation of a fast inactivated state in the analysis. The fully activated current-voltage relation for IKr exhibited strong inward-going rectification, so much so that the current was essentially nil at +30 mV, even though the channel opens rapidly in this voltage range. This result is consistent with the lack of effect of E-4031 on the early part of the plateau phase of the action potential. Surprisingly, the reversal potential Of /Kr was ~15 mV positive to the potassium ion equilibrium potential,which indicates that this channel carries inward current during the latter part of the repolarization phase of the action potential.

Frequency and voltage-dependent effects of mono-N-dealkyldisopyramide, the major metabolite of disopyramide, in canine ventricular tissue.

Mono-N-dealkyldisopyramide (MND), the major metabolite of disopyramide, reaches significant concentrations in patients; however, the contribution of MND to the antiarrhythmic or toxic effects of disopyramide is not known. We assessed the kinetics and magnitude of interaction of MND with the sodium channel in canine ventricular tissue superfused in vitro using Vmax as an index of sodium channel block. At a basic cycle length of 1000 msec, MND (4-32 micrograms/ml) produced a concentration-dependent depression of both Vmax and amplitude of the action potential and accelerated all phases of repolarization in Purkinje fibers. To assess rate-dependent block, Purkinje fibers were stimulated with pulse trains at interstimulus intervals of 400 to 2000 msec. MND produced a concentration- and rate-dependent increase in the magnitude of rate-dependent block. There was also a concentration-dependent increase in the kinetics of onset of block (decrease in rate constant). The rate constant increased with faster stimulation rates. Minimal tonic block occurred at clinically relevant concentrations. Recovery from rate-dependent block followed a single exponential time course with time constants of 5.23 +/- 0.90 and 4.88 +/- 0.94 sec for Vmax and activation time, respectively. There was no shift of the normalized Vmax-membrane potential relationship except at the highest concentration, 32 micrograms/ml. At cycle lengths of 250 to 1000 msec, MND (4 micrograms/ml) shortened all phases of repolarization in Purkinje fibers, the greatest shortening occurring at the longest cycle length. Prolongation of effective refractory period occurred only at rapid heart rates. Both action potential duration and effective refractory period were prolonged in ventricular muscle which was independent of rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent advances in understanding the mechanisms of drug-induced torsades de pointes arrhythmias.

QTU prolongation and polymorphic ventricular tachycardia "torsades de pointes" have occurred in association with electrolyte abnormalities and during therapy with class IA and III antiarrhythmic drugs. Several recent studies have suggested that the arrhythmia may be due to bradycardia-dependent early afterdepolarizations and triggered activity. These drugs produce 2 types of triggered activity, each with a different frequency profile. The possible role of each type in arrhythmia generation is discussed. The existing evidence suggest that drug-induced triggered activity may originate in the Purkinje system. Triggered activity can be abolished or prevented by various interventions that are also effective clinically. The results of studies at the cellular level, when compared with recordings of monophasic action potentials in vivo, suggest a role for early afterdepolarizations in torsades de pointes arrhythmias.

Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers.

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. Vmax was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of Vmax depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on Vmax. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on Vmax but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 +/- 535 ms and 15.7 +/- 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when Vmax depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.

Ontogeny of adenosine production and degradation and its implications in neonatal cerebral blood flow regulation.

Adenosine is a neuromodulator and potent vasoactive metabolite involved in various CNS regulatory mechanisms. We have recently shown that the newborn has maturationally related deficiency in adenosine production. The brains of Sprague-Dawley rats studied at ages 1, 7, 21 and 60 days (n = 6-12/group) showed that adenosine and its metabolites (measured by high-pressure liquid chromatography) is deficient in the newborn. Adenosine brain concentration was 0.99 nmol/g brain in newborn rats (day 0-1) and progressively increased postnatally to an adult value of 14.4 nmol/g brain. Inosine, a degradative product of adenosine by deaminase is significantly increased in newborns (mean +/- SEM = 48.3 +/- 14.3 nmol/g brain) relative to the 7-day-old rat (7.4 +/- 1.1 nmol/g brain) and to the adult (17.8 +/- 3.6 nmol/g brain). Thus, newborns have deficient adenosine brain concentration and this is due in part to increased deamination of adenosine. However, adenosine brain production may be augmented by ischemic-hypoxic insult. This was tested in 2 age groups of rats: 7 days old (n = 35) and adults (n = 35). Under nembutal anesthesia, bilateral carotid arteries were exposed and loosely tied, then both carotids were ligated and 5 animals from each group were decapitated and heads immediately frozen in liquid N2 at 5, 15, 30, 60, 120 and 300 s after ligation. Similar animals with carotids exposed but not ligated served as control (time zero). Brains were removed and assayed for adenosine and metabolites using high-pressure liquid chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of the frequency- and voltage-dependent effects of quinidine when administered in combination with tocainide in canine Purkinje fibers.

Frequency- and voltage-dependent modification of drug-induced inhibition of maximal upstroke velocity of the action potential (Vmax) by the combined administration of two class I antiarrhythmic drugs was studied in canine Purkinje fibers, taking depression of upstroke velocity as an indicator of sodium channel blockade. The kinetics of onset of drug-induced Vmax depression and the time course of Vmax recovery were studied after exposure to therapeutic concentrations of tocainide (50 microM) and quinidine (5 microM) both singly and in combination. The rate constant for onset of block during a drive train at a cycle length of 600 msec was 0.95 +/- 0.32 pulses in the presence of tocainide and 5.61 +/- 0.50 pulses in the presence of quinidine. The magnitude of block was three times greater with quinidine than with tocainide. The magnitude of block produced by the combination was no greater than that produced by quinidine alone and may be partly due to abbreviation of action potential duration by tocainide. Onset of block in the presence of the combination was best fitted by a double exponential with rate constants of 0.88 +/- 0.19 and 6.47 +/- 1.36 pulses. Vmax recovery after termination of a rapid train of impulses was delayed by both drugs. Poststimulation recovery from either tocainide- or quinidine-induced block was characterized by a single time constant (1.04 +/- 0.49 and 4.81 +/- 0.76 sec, respectively), while that of the combination was characterized by two time constants (0.43 +/- 0.22 and 5.94 +/- 0.56 sec), presumably corresponding to dissociation of each drug from the sodium channel receptor. The mixture of the two drugs produced a large depression of Vmax of early diastolic premature responses without producing much further depression of Vmax than that produced by quinidine alone at longer coupling intervals. The time constant of recovery from tocainide-induced block was greatly dependent upon membrane potential. After steady-state changes in frequency, the combination produced a greater depression of Vmax at rapid heart rates compared with that produced by quinidine alone, but abbreviated action potential duration more at slower heart rates. Addition of tocainide to fibers equilibrated with quinidine shifted the Vmax-membrane potential relationship to more hyperpolarized potentials, resulting in greater depression of Vmax at more depolarized membrane potentials with little or no additional depression of Vmax at more negative membrane potentials. The results provide a rationale for a possible enhanced antiarrhythmic efficacy of a combination of two class I drugs that have different kinetics of interaction with the sodium channel.

Pharmacologic effects of theophylline in the newborn.

Theophylline is an effective respiratory stimulant for apnea of prematurity. In the newborn, theophylline stimulates the central nervous system, particularly the respiratory center, leading to decreased apnea frequency and increased ventilation. Neonates appear to be more sensitive to the cardiovascular effect of theophylline; tachycardia occurs at plasma concentrations of 13 mg/L. Minimal effects on renal and gastrointestinal function are observed at therapeutic doses. Augmentation in oxygen consumption and alteration in glucose homeostasis may occur, even at therapeutic doses. If used appropriately, the drug is safe and effective for the treatment of neonatal apnea.

Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate.

Overdose with amitriptyline and other tricyclic antidepressants can result in ventricular conduction abnormalities as well as severe ventricular arrhythmias. The arrhythmogenic effects of these compounds may be attributed to their direct local anesthetic actions in blocking sodium channels in cardiac membranes. Thus tricyclic-induced ventricular arrhythmias usually do not respond well to therapy with standard Class I antiarrhythmic drugs that also have the same direct local anesthetic action and may potentiate the adverse effects of tricyclic antidepressants. Cardiac toxicity was produced in dogs by the administration of amitriptyline, both orally and IV. At serum concentrations less than 2,000 ng/mL, sinus tachycardia occurred with widened QRS complexes. At higher concentrations, QRS duration became more markedly prolonged and was followed by ventricular tachyarrhythmias. Occurrence of ventricular tachyarrhythmias was associated with QRS durations of more than 0.11 second. Sodium bicarbonate (18 to 36 mEq) administered IV over either 30 seconds or two minutes rapidly converted ventricular tachycardia to normal sinus rhythm. Conversion was associated with abbreviation of the QRS complex and was accompanied by a rise in both systolic and diastolic pressures. The duration of sodium bicarbonate effect paralleled the duration of the changes in arterial pH and plasma bicarbonate concentrations. In vitro studies in cardiac Purkinje fibers suggested that reversal of amitriptyline-induced cardiac membrane effects by sodium bicarbonate may be attributed not only to alkalinization but also to increased in extracellular sodium concentration, diminishing the local anesthetic action of amitriptyline and resulting in less sodium channel block.(ABSTRACT TRUNCATED AT 250 WORDS)

Furosemide and vitamin E. Two problem drugs in neonatology.

This article focuses on some of the problems encountered with two of the drugs currently given to newborns.

Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate.

Alkalinization with NaHCO3 can effectively reverse ventricular arrhythmias caused by amitriptyline intoxication, but the mechanism is unclear. To test whether alkalinization per se is important or whether increases in extracellular Na concentration also contribute, we exposed Purkinje fibers to 500 ng/ml (1.8 microM) of amitriptyline and then superfused them with three different test solutions, viz. 1) high Na-Tyrode's, 2) high NaHCO3-Tyrode's and 3) high pH-low pCO2-Tyrode's. Amitriptyline significantly depressed action potential amplitude and Vmax without altering resting membrane potential and abbreviated action potential duration at all phases of repolarization. Effects on phase 0 were accompanied by a depression of conduction velocity. All three test solutions produced significant hyperpolarization and improvement in action potential amplitude and Vmax. However, the magnitude of improvement of phase 0 characteristics was significantly greater after high NaHCO3 and resulted in significant improvement of conduction velocity in fibers depressed by amitriptyline. The effects of amitriptyline on phase 0 were rate-dependent. Reversal of this effect by NaHCO3 was equally effective at all rates. Improvement of Vmax was partly related to a shift of the Vmax-membrane potential relationship in the depolarizing direction. NaHCO3 had minimal and variable effects on action potential duration. The results suggest that the beneficial effects of NaHCO3 are related to a reversal of drug effects on phase 0 characteristics and that this effect is due both to alkalinization and to increases in extracellular Na concentration.

Symposium on the management of ventricular dysrhythmias. Concept of reentry versus automaticity.

Arrhythmias can result from abnormal impulse initiation or conduction. Abnormal initiation results from either automaticity or triggered activity. Enhanced automaticity may be due to a normal automatic mechanism (a normal property of the sinus node and specialized conducting fibers) or to an abnormal mechanism such as automaticity in depolarized fibers. Triggered activity is caused by afterdepolarizations that occur either during repolarization (early afterdepolarization) or after repolarization is complete (delayed afterdepolarization). Triggered activity due to delayed afterdepolarizations is dependent on critical heart rates. Overdrive pacing may distinguish between normal and abnormal automaticity. Antiarrhythmic drugs can alter arrhythmias that result from abnormal impulse initiation. To suppress an arrhythmia resulting from abnormal impulse generation, a drug may (1) suppress the abnormal automatic mechanism, i.e., specific effect on ionic current; (2) suppress afterdepolarizations; (3) depress conduction in tissue surrounding automatic focus; or (4) modify refractory period of tissue in and around automatic focus. Abnormal impulse conduction results in reentrant excitation. Conditions necessary for reentry include a combination of unidirectional block and slowed conduction. A reentrant mechanism can be determined by an anatomically defined circuit or solely by the functional properties of the tissue (leading circle mechanism). Circus movement reentry around an anatomic obstacle may respond to antiarrhythmic drugs differently from reentry caused by a leading circle mechanism. Initiation and perpetuation of a reentry mechanism depends on a delicate interplay between conduction velocity and duration of the functional refractory period in the reentry circuit.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental amitriptyline intoxication: electrophysiologic manifestations and management.

Amitriptyline intoxication can result in severe ventricular arrhythmias that may be refractory to medical management. The mechanisms of these arrhythmias are unclear, and their optimal management is problematic. We studied the cardiac effects of amitriptyline infusion in anesthetized and awake dogs. Amitriptyline significantly increased heart rate, QRS duration, and AH and HV intervals. The concentration-response curves for these effects were, however, quite different, with significant changes beginning at a concentration of 1.5 +/- 0.4 mg/L for heart rate, compared with 2.4 +/- 0.4 mg/L for QRS and HV intervals and 3.7 +/- 0.5 mg/L for the AH interval. Ventricular tachyarrhythmias developed after marked QRS widening had occurred, and appeared in all six awake dogs and five of the six anesthetized dogs studied. Sodium bicarbonate was given to seven animals with ventricular tachyarrhythmias, and it rapidly reversed the arrhythmia in all instances. The benefit from sodium bicarbonate could not be attributed to changes in serum potassium or amitriptyline concentrations. It may have been due to alkalinization or changes in serum sodium concentration. These experiments suggest that: (a) amitriptyline intoxication frequently produces ventricular tachyarrhythmias, if high enough drug concentrations are achieved; (b) these arrhythmias are associated with marked slowing of intraventricular conduction; and (c) sodium bicarbonate is effective therapy for amitriptyline-induced ventricular arrhythmia.

Pharmacologic considerations in the therapy of neonatal apnea.

Theophylline and caffeine are both effective stimulants of the central nervous system for the therapy of neonatal apnea. Both drugs are slowly eliminated from the body, and doses should be adjusted to account for this slow elimination. Interconversion of theophylline and caffeine occurs in the newborn infant, with the methylation of theophylline to caffeine as the probable predominant pathway. Caffeine may offer advantages over theophylline: wider therapeutic index, case of administration, less need for therapeutic drug monitoring, less fluctuation in plasma concentrations, and fewer peripheral effects. A major disadvantage of caffeine is in the lack of a readily available commercial preparation. Both drugs exert many pharmacologic actions that require further evaluation in the newborn infant. Long-term effects of these drugs administered during a critical period in the developing human remains an area of concern.

Pharmacokinetics of diuretics and methylxanthines in the neonate.

The elimination of diuretics and methylxanthines is considerably slower in the neonate than in the adult. Dose guidelines, especially during long term maintenance, must be adjusted to account for this slower drug elimination. Pharmacokinetic studies and the requisite pharmacologic evaluation on diuretics such as hydrochlorothiazide, spironolactone, ethacrynic acid and others should be done. Furosemide undergoes biotransformation in the newborn producing an acid metabolite and a glucuronide conjugate. Methylxanthines are effective in the treatment of neonatal apnea. Plasma elimination of theophylline is exceedingly slow, more so with caffeine. Decreased elimination is partly explained by decreased oxidative biotransformation. Caffeine is excreted in the urine of the newborn mainly unchanged (85%) in contrast to the adult where caffeine is a minor portion of urinary excretion (2%). Theophylline is methylated to caffeine and may possibly exert additive pharmacologic effects.

In vitro preparation of infarcted myocardium.

An isolated ventricular endocardial preparation removed from canine hearts one to two days after coronary artery occlusion and superfused in vitro is described. The alteration in electrophysiological characteristics of subendocardial Purkinje fibers surviving in infarcted regions and the relationship of these changes to the generation of ventricular arrhythmias is discussed. The advantages of such preparations for assessing the mechanism of action of antiarrhythmic drugs in post-infarction ventricular arrhythmias is discussed.

Disopyramide phosphate: is it just another quinidine.

We compared the effects of a therapeutic concentration of disopyramide with those of quinidine and lidocaine on the action potential characteristics and on the steady-state relationship between membrane potential and the maximum rate of rise of the action potential in the same normal Purkinje fiber in which constant impalement was maintained for more than 7 h. All the drugs depressed the steady-state upstroke velocity in the following order of magnitude: quinidine greater than disopyramide greater than lidocaine. Both lidocaine and disopyramide shifted the normalized steady-state curve to more negative membrane potentials indicating a greater depression of upstroke velocity at lower membrane potentials. Quinidine did not shift this curve. Lidocaine abbreviated all phases of repolarization while both disopyramide and quinidine shortened the plateau phase and lengthened the terminal phase of the action potential. The results suggest that the actions of disopyramide on upstroke velocity resemble those of lidocaine, while its effects on action potential duration resemble those of quinidine. The actions of this drug are therefore more complex than previously assumed.

The electrophysiological effects of disopyramide phosphate on canine ventricular muscle and Purkinje fibers in normal and low potassium.

We studied the effect of lowering the extracellular potassium concentration ([K+]o) on the electrophysiological actions of disopyramide phosphate, a new antiarrhythmic drug. At low [K+]o, therapeutic concentrations of disopyramide phosphate caused significantly less depression of action potential amplitude and maximum upstroke velocity of both Purkinje fiber and ventricular muscle action potentials. The drug shifted the membrane responsiveness curve along the voltage axis to more negative membrane potentials regardless of [K+]o. However, a greater shift occurred when [K+]o was normal. Disopyramide phosphate prolonged both action potential duration and effective refractory period in all fibers but there was consistently greater prolongation of these parameters at low [K+]o. More importantly, disopyramide phosphate altered repolarization time course of action potentials in such a way that action potentials with dissimilar durations throughout the ventricular conducting system became more equal. The drug was less effective in decreasing this disparity in action potential durations throughout the ventricles in the presence of low [K+]o. These modifications of the electrophysiological actions of disopyramide by low [K+]o suggest that a therapeutic concentration of disopyramide might have less of an antiarrhythmic effect in the presence of hypokalemia.

Effects of disopyramide phosphate on ventricular arrhythmias in experimental myocardial infarction.

A myocardial infarction model in which infarction is the result of an occluding thrombus was used to evaluate the effectiveness of disopyramide phosphate (DP) in abolishing postinfarction ventricular arrhythmis. Two types of ventricular arrhythmias were observed, rapid multifocal arrhythmias. and slow unifocal rhythms. DP, in doses of 5 mg/kg, were effective against slow ventricular tachycardia. The time course of action varied with the type of rhythm present. Conversion of the slow ventricular tachycardia usually occurred within a minute whereas abolition of the rapid ventricular tachycardia took 5 to 10 minutes. Effective arrhythmia control could be maintained by a bolus dose (3 mg/kg) followed by a constant infusion at a rate of 0.2 mg/kg/min. DP had minimal effects on arterial blood pressure at antiarrhythmic doses. The drug had significant hypotensive effects if infused at rates greater than 2 mg/kg/min. However, the hypotensive effect was always transient at doses of 5 mg/kg or less. DP produced significant changes in the lead II electrocardiogram. At doses of 5 mg/kg, the drug significantly increased the P-R and Q-Tc intervals and increased the QRS duration. The drug slowed conduction through all parts of the conducting system to approximately the same degree with perhaps a slightly greater slowing through the atrioventricular node. However, the changes observed were never more than 20%