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V Elharrar

Publications and source records attributed to V Elharrar.

At least 19 recordsLinked to original sources
PubMed1989

Effect of altered repolarization course induced by antiarrhythmic drugs and constant current pulses on duration of premature action potentials in canine cardiac Purkinje fibers.

The purpose of this study was to elucidate the mechanism of the upward shift of the electrical restitution curve, i.e., the lengthening of premature action potential duration (APDt) expressed as percentage of basic APD, induced by class I antiarrhythmic drugs in dog Purkinje fibers. In this study, six class I antiarrhythmic drugs lengthened APDt at a diastolic interval of 20 ms by 2.5-14.1%. The drugs also decreased the ratio of APD at 50% to APD at 90% of repolarization from 70.8 +/- 1.8% (n = 60) to 47.4-60.8%. The relation between the decrease in the ratio of APD50 to APD90 of the basic AP and lengthening of the normalized APDt was linear (r = 0.92; p less than 0.01). We attributed the lengthening of normalized APDt to the decreased ratio of APD50 to APD90, and applied repolarizing current pulses in short (less than or equal to 2 mm) fibers to simulate the drug-induced decrease in the ratio of APD50 to APD90. The altered repolarization course of basic AP by the current pulse during late plateau and early phase 3 caused APDt lengthening. The relation between the current-induced decrease in the ratio of APD50 to APD90 of the basic AP and the lengthening of normalized APDt was linear (r = 0.91; p less than 0.01). The slope of regression line describing this relation was similar to that in the presence of drugs. These results suggest that lengthening of the normalized APDt by class I antiarrhythmic drugs results from a more rapid repolarization during phase 2 of the preceding basic AP, possibly due to lesser influence of the delayed outward rectifying current. The lengthening of APDt by class I drugs may contribute to their antiarrhythmic action.

Action Potentials↗
PubMed1989

Frequency-dependent and independent effects of tetrodotoxin on Vmax in cardiac fibers.

Superfusion with 3 microM tetrodotoxin (TTX) induced both a use-dependent and a frequency-independent depression of the rate rise of the action potential (Vmax) in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was fast and exponential with a time constant of 225.4 +/- 7.1 ms in dog Purkinje fibers (n = 6). The onset kinetics of the frequency-dependent Vmax block was rapid, i.e. reached steady state after 3.0 +/- 0.3 beats in guinea pig ventricular muscle (n = 6). The rapid use-dependent interactions with sodium channel make TTX similar to antiarrhythmic drugs with fast kinetics i.e. lidocaine, mexiletine, and tocainide, but unlike antiarrhythmic drugs, TTX-induces a large frequency-independent Vmax block at the same concentrations.

Action Potentials↗
PubMed1988

The effects of amiodarone on repolarization and refractoriness of cardiac fibers.

The effects of superfusion (acute) and chronic amiodarone pretreatment on repolarization in dog Purkinje and guinea pig papillary muscle fibers were studied using standard microelectrode techniques. In dog Purkinje fibers superfusion with 5 and 50 micrograms/ml amiodarone shortened action potential duration, slowed restitution of premature action duration, and decreased the range of premature action potential durations. In Purkinje fibers from pretreated dogs action potential duration and range of premature action potential durations did not differ significantly from the corresponding control values but restitution was slowed. In guinea pig papillary muscle superfusion with 20 micrograms/ml amiodarone did not change action potential duration and restitution kinetics but in the muscle fibers from pretreated animals both the action potential duration and the range of premature action potential durations were increased. We concluded that the designation of 'class III action' applied to chronic amiodarone treatment in ventricular but not to chronic treatment in Purkinje fibers, and not to acute treatment in either fibers.

Action Potentials↗
PubMed1988

Recovery from use-dependent block of Vmax and restitution of action potential duration in canine cardiac Purkinje fibers.

The recovery kinetics during diastole of various plateau currents are thought to control the restitution of action potential duration (APD). Based on the assumption that the recovery of the residual plateau Na current parallels that of Vmax, the hypothesis that Na current recovery kinetics influence the restitution of APD was tested. Drugs that reduced Vmax in a use-dependent manner (tetrodotoxin 3 microM, lidocaine 15 microM, mexiletine 20 microM) were compared with interventions that reduced Vmax in a simply tonic fashion [( Na]o 75 mM, [K]o 6.5 mM, disopyramide 30 microM). Microelectrode techniques and programmed stimulation were used to determine in vitro the kinetics of restitution of APD and of time-dependent recovery of Vmax during rest. Tetrodotoxin, lidocaine and mexiletine induced a blockade of Vmax that showed partial or full time-dependent unblocking in accordance with the known use dependence of their blocking action. Dissipation of the time-dependent component of the block in each case followed a single exponential time course, time constants being 163 +/- 12, 115 +/- 12 and 121 +/- 20 ms, respectively. Analysis of the kinetics of the APD restitution curves showed that the time constant of the fast decaying exponential component of restitution (T1) was prolonged by these drugs from 129 +/- 5 in control fibers to 295 +/- 17, 235 +/- 11 and 242 +/- 26 ms for tetrodotoxin, lidocaine and mexiletine, respectively (P less than .05). Low [Na]o and disopyramide reduced Vmax in a simply tonic fashion and did not significantly prolong the T1 component of APD restitution.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1987

Effect of mexiletine, amiodarone and disopyramide on the excitability and refractoriness of canine cardiac fibers: possible relation to antiarrhythmic drug action and classification.

We tested the hypothesis of Campbell that the effect of the sodium channel-blocking antiarrhythmic drugs on postrepolarization refractoriness i.e., relation between action potential duration (APD) and effective refractory period (ERP) is determined by the drug's effect on the recovery from Vmax block. We studied the effects of two antiarrhythmic drugs with fast (mexiletine, amiodarone), and one with slow (disopyramide) kinetics of recovery from Vmax block, at two different basic cycle lengths (BCL), on ERP/APD ratio in cardiac dog Purkinje and ventricular muscle fibers. ERP was measured using stimuli of 2 ms duration and 1.0 to 5.0 times diastolic threshold strength. The three drugs altered the kinetics of recovery from Vmax block in the manner previously reported by us and other investigators. In both fiber types, mexiletine increased and the other two drugs did not change the ERP/APD ratio. We concluded that the magnitude of postrepolarization refractoriness could not be predicted from the kinetics of the Vmax block. Also, the effect of the drug on the ERP/APD ratio could be altered by changes in the stimulus strength and the BCL.

Amiodarone↗
PubMed1985

Use-dependent effects of amiodarone on Vmax in cardiac Purkinje and ventricular muscle fibers.

Superfusion with 5 micrograms/ml amiodarone for 3-4 h induced use-dependent Vmax block in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was exponential with tau of 289 +/- 30 ms in Purkinje (n = 7) and 282 +/- 47 ms in muscle (n = 6) fibers. The onset of frequency-dependent Vmax block was rapid, i.e. reached steady state after 4.2 +/- 0.5 beats (n = 5). The combination of rapid interaction with sodium channel and the reported action potential lengthening make amiodarone unique among Class I antiarrhythmic drugs.

Action Potentials↗
PubMed1985

Effect of antiarrhythmic drugs on the premature action potential duration in canine cardiac Purkinje fibers.

We studied the effect of six class I antiarrhythmic drugs, i.e., quinidine (5 micrograms/ml), disopyramide (10 micrograms/ml), procainamide (30 micrograms/ml), flecainide (4 micrograms/ml), lidocaine (4 micrograms/ml) and mexiletine (4 micrograms/ml), on the durations of the basic action potential (APDb) at a cycle length of 500 ms and on the premature APD (APDt) elicited at progressively increasing diastolic intervals (DI) in canine Purkinje fibers. The difference between APDt elicited at diastolic intervals of 100 msec and the earliest APDt elicited at the onset of effective refractory period was defined as the range of APDt. In control this range was 98 +/- 1.8 ms (n = 59). Disopyramide and procainamide did not change the range significantly but the other four drugs decreased it significantly (P less than .01) as follows: quinidine by 50.2%, lidocaine by 60.2%, mexiletine by 61.6% and flecainide by 61.4%. The following four factors contributed to this decrease in range of APDt: shorter duration of APDb, increased effective refractory period/APD ratio, slower kinetics of APD restitution, and shift of normalized restitution curve toward longer APDt values. The magnitude of the contribution made by each of the above factors varied with different drugs. The greatest contributing factor for quinidine was an increased effective refractory period/APD ratio, for lidocaine a slower restitution and for flecainide and mexiletine the shift of the restitution curve. We concluded that antiarrhythmic drugs belonging to the same class have different effects on the range of premature APD and that these effects cannot be predicted from the effect of the drug on APDb alone.

Action Potentials↗
PubMed1984

Cycle length-dependent action potential duration in canine cardiac Purkinje fibers.

We studied the effects of pharmacologic probes that affect predominantly the Na inward current [tetrodotoxin (TTX), lidocaine], the slow inward current [cobalt, isoproterenol, verapamil], and the potassium currents [tetraethylammonium chloride (TEA), SG-75] on the duration of the action potential (APD) of canine cardiac Purkinje fibers during steady state and restitution. A schema is proposed in which the APD during steady state or restitution is determined by three factors: maximum action potential duration (APDmax), kinetics of restitution, and "memory." The predicted APDmax was 469 +/- 34 (SE) ms (n = 27) in control. It was prolonged (P less than 0.05) by cobalt, verapamil, and TEA and shortened (P less than 0.05) by TTX, lidocaine, isoproterenol, and SG-75. In control, the kinetics of restitution were described by a sum of two exponentials with time constant T1 = 137 +/- 9 ms and T2 = 1,665 +/- 135 ms (n = 27), respectively. T1 was prolonged (P less than 0.05) by TTX, lidocaine, and verapamil but was not changed by other probes. None of the probes studied altered the T2 of restitution or the memory factor, computed at a cycle length of 500 ms from the predicted APDmax and the plateau of restitution. Low temperature (31 degrees C) prolonged APDmax and T1 and reduced the memory. We conclude that each of the proposed three factors is controlled by different mechanisms and that a TTX-sensitive current appears to contribute to the process of restitution of APD.

Action Potentials↗
PubMed1983

Cycle length effect on restitution of action potential duration in dog cardiac fibers.

Electrical restitution of action potential duration (APD) was determined in Purkinje (n = 8) and ventricular muscle (n = 6) fibers at two different basic cycle lengths (BCL, 1,500 and 500 ms). Restitution curves, normalized for the longest APD (the plateau of restitution), fitted the sum of a fast (T1) and a slow (T2) exponential component. The T1 was shorter in ventricular muscle than Purkinje fibers (89 +/- 5 and 143 +/- 9; mean +/- SE, P less than 0.05), whereas the T2 did not differ (1,448 +/- 231 and 1,439 +/- 211). The BCL altered the APD value during the plateau of restitution but did not change the two exponential components. In both fiber types, the relation between APD and BCL during steady state fitted a hyperbolic curve that predicts the achievement of the maximum APD at long BCL. The restitution curves crossed the steady-state curve at two points outlining three different zones of APD intervals: early premature, late premature, and postmature. The APD during restitution was longer than the steady state in the late premature zone and shorter than the steady-state APD in the post-mature and early premature zones. The APD per se, independent of BCL, did not influence the kinetics of restitution in Purkinje fibers.

Action Potentials↗
PubMed1982

Effects of extracellular calcium ions, verapamil, and lanthanum on active and passive properties of canine cardiac purkinje fibers.

The effects of alteration of extracellular calcium ion concentration ([Ca++]o) were studied in isolated false tendons using microelectrode techniques. Several determinants of cellular excitability and conduction velocity were affected by extracellular calcium. Increasing [Ca++]o from 2 to 8 mM resulted in: (1) a progressive decrease in interelectrode conduction velocity (2) a 7-mV shift of the maximum upstroke velocity-membrane potential relation toward less negative potential, (3) an increase in rheobasic current, (4) a 14-mV shift of the voltage threshold for all-or-none depolarization to less negative potentials, (5) a 52% increase in internal longitudinal resistance per unit length, and (6) a 27% decrease in the capacitance filled by the foot of the action potential from 4.90 to 3.56 microF/cm2. Blockade of the slow inward current by Mn++ or verapamil did not alter the [Ca++]o-induced effects on the maximum upstroke velocity-membrane potential relation. Cable properties were determined during alteration of [Ca++]o in the presence of verapamil (3 X 10(-6) and 1 X 10(-5) M) or in the presence of La+++ (0.2 mM). Verapamil increased membrane resistance X unit length but did not affect internal longitudinal resistance per unit length. La+++ had no effects on either membrane resistance X unit length or internal longitudinal resistance per unit length. Verapamil did not block the increase in ri induced by elevation of [Ca++]o. However, no change in ri occurred during an increase of [Ca++]o when La+++ was present. The results suggest that [Ca++]o-induced changes in internal longitudinal resistance may occur by the influx of calcium ions through the Na+/Ca++ exchange mechanism.

Action Potentials↗
PubMed1981

pH-dependent electrophysiological effects of quinidine and lidocaine on canine cardiac purkinje fibers.

We used standard microelectrode techniques to evaluate the effects of lidocaine and quinidine on canine Purkinje fibers at normal pH (7.3) and in the presence of acidosis (pH 6.9). Acidosis alone reduced resting potential, action potential amplitude, and Vmax, while increasing APD90 and conduction time. Lidocaine concentrations of 6 x 10(-6) to 1.5 x 10(-5) M had minimal effect on resting potential, action potential amplitude, and Vmax at pH 7.3. At pH 6.9, the same lidocaine concentrations significantly reduced resting potential (3-10%), action potential amplitude (3-8%) and Vmax (14-22%). Quinidine (6 x 10(-6) to 1.5 x 10(-5) M) reduced resting potential (3-5%), action potential amplitude (4-9%), and Vmax (19-34%) at pH 7.3. At pH 6.9, quinidine produced significantly greater reductions in resting potential (4-15%), action potential amplitude (5-18%), and Vmax (22-49%). These changes were associated with much more quinidine- and lidocaine-induced prolongation of interelectrode conduction time at acidic than at normal pH. Inexcitability occurred at pH 6.9 in four of 14 experiments with 1.5 x 10(-5) M quinidine and in two of 10 with 1.5 x 10(-5) M lidocaine, and was reversed at the same drug concentration by normalizing pH. Acidosis did not alter the Vmax-resting potential relationship in either the absence or presence of antiarrhythmic agents. Furthermore, changes in ionization did not account for the alterations in electrophysiological effects of quinidine and lidocaine produced by acidosis. Our data suggest that extracellular pH changes may modify importantly the effects of antiarrhythmic agents.

Acidosis↗
PubMed1980

Studies with aprindine.

Aprindine is a very effective antiarrhythmic agent with a narrow therapeutic-toxic ratio. It has been used successfully in treating patients who have both supraventricular and ventricular tachyarrhythmias. Aprindine slows conduction in all cardiac fibers and suppresses digitalis-induced after-depolarizations. Voltage-clamp studies indicate that aprindine, in higher doses, suppresses the slow inward current in frog atria. In the dog subjected to coronary artery occlusion, aprindine may be arrhythmogenic, antiarrhythmic, or have no effect on the development of arrhythmias, depending on the temporal relationship between time of administration and time of occlusion.

Agranulocytosis↗
PubMed1980

A computer-controlled stimulator with applications to cardiac electrophysiology.

A computer-controlled stimulator compatible with S-100 microcomputers using an 8080 or Z-80 microprocessor is described. The pusle interval is controlled from 1 to 65,535 ms and the pulse duration from 1 to 255 ms by steps of 1 ms. The pulse amplitude is controlled from 0 to 10.24 V (in constant voltage mode) and from 0 to 1 mA (in constant current mode) by steps of 4 mV and 4 mu A, respectively. The characteristics of the stimuli and their timing can be altered automatically according to programmed protocols that may or may not take into account the response of the biologic preparation. Applications of this stimulator to the study of experimental cardiac electrophysiology are illustrated in vivo and in vitro.

Animals↗
PubMed1979

Electrophysiological effects of ethmozin on canine myocardium.

The electrophysiological effects of ethmozin on canine myocardium were studied in anesthetised open-chest animals and in superfused Purkinje fibres. The drug did not change spontaneous sinus node cycle length and atrioventricular conduction time when selectively injected into the sinus nodal artery and into the posterior septal artery, respectively. Right and left ventricular diastolic excitability threshold and refractory period were increased following the intravenous administration of ethmozin, 4 mg/kg-1. Ethmozin (3 to 5 mg/kg-1 i.v.) markedly increased conduction delay in the ischaemic zone of the left ventricle during acute coronary artery occlusion. This change was associated with the development of ventricular fibrillation in 50% of the dogs. In vitro, ethmozin 1 X 10(-3) and 1 X 10(-2) g.litre-1 shortened Purkinje fibres' action potential duration. At 1 X 10(-2) g.litre-1, ethmozin decreased the rate of rise of phase 0, and slightly reduced action potential amplitude.

Action Potentials↗
PubMed1979

Adrenergaically mediated ventricular fibrillation in probucol-treated dogs: roles of alpha and beta adrenergic receptors.

A high incidence of sudden death due to ventricular fibrillation (VF) has been observed in dogs under chronic treatment with probucol, a new hypocholesterolemic agent. The present study describes the cardiac electrophysiologic properties of probucol-treated dogs and characterizes the electrophysiological response of these animals to manipulation of the autonomic nervous system. There was no significant difference in the spontaneous sinus cycle length, the QT interval, refractory period of the atrium, ventricle or A-V junction between normal and probucol-treated dogs. Epinephrine produced VF with few and sometimes no preceding premature ventricular extrasystoles. Electrical stimulation of the stellate ganglion induced VF in 16/19 dogs whereas stimulation of the right stellate ganglion induced VF in 1/19 dogs. Phenylephrine induced VF in 0/19 dogs, isoproterenol in 5/19 dogs, but phenylephrine + isoproterenol induced VF in 9/11 dogs in which isoproterenol did not produce VF. alpha (phentolamine) or beta (propranolol) blockade prevented initiation of VF by epinephrine, phenylephrine + is isoproterenol, and left stellate stimulation but alpha blockade did not prevent induction of VF by isoproterenol when isoproterenol alone produced VF. In this nonischemic model, we conclude that left stellate stimulation is a far more potent initiator of VF than right stellate stimulation and that induction of VF appears to require both alpha and beta adrenergic receptor stimulation.

Angiotensin II↗
PubMed1979

On-line analysis of intracellular electrophysiological data using a microcomputer system.

Automated analysis of intracellular action potentials from cardiac Purkinje fibers was implemented using a microcomputer system. A dual sampling rate was used during analog-to-digital conversion of action potentials recorded from stimulated fibers. The rapid phase of depolarization was sampled at 42.55 kHz. The repolarization and the diastolic phases were sampled at 1 kHz. The resting potential, action potential amplitude, conduction time, action potential duration measured at 50% and at 90% of repolarization, and the maximum upstroke velocity were obtained on-line. The digital form of the action potential was stored on cassette tape and a table containing the various measurements was assembled during the experiment. In unstimulated fibers, the time interval between consecutive action potentials was measured on-line along with the maximum diastolic potential, the action potential overshoot, and the slope of the diastolic depolarization.

Action Potentials↗
PubMed1979

[Electrophysiologic effect of ethmosine on the dog's myocardium].

The electrophysiologic effects of ethmozin on canine myocardium were studied in anesthetized open-chest animals and in superfused Purkinje fibers. On selective injection into the sinus node artery and the posterior septal artery the drug caused no changes in the sinus node length and atrioventricular conduction, respectively. Intravenous infusion of 4 mg/kg ethmozin led to an increase of right and left ventricular diastolic excitability threshold and refractory period. Intravenous administration of 3--5 mg/kg ethmozin caused marked increase in conduction delay in which the ischemic zone of the left ventricle during acute coronary artery occlusion, which was associated with ventricular fibrillation in 50% of the dogs. In vitro, 1 x 10(-6) g/ml ethmozin shortened the Purkinje fibers' action potential duration whereas a dose of 1 x 10(-5) g/ml reduced the rate of phase 0 rise and slightly reduced the action potential amplitude. Ethmozin in a dose of 1 x 10(-7) g/ml increased transiently the isometric developed tension of false-tendon preparations. Higher concentrations caused marked depression of contractility. These observations suggest depression of the fast current by ethmozin. However, further studies are needed to elucidate its effect on action potential duration and false-tendor contractility.

Action Potentials↗