Effect of 4-Aminopyridine on Action Potential Parameters in Isolated Dog Purkinje Fibers

Coronary flow and transmembrane potentials of Purkinje and muscle fibers in reperfused infarcts and infarcts caused by permanent coronary occlusion were compared. Purkinje fibers in permanently occluded infarcts at 24 h had markedly reduced resting potentials. Action potential amplitudes, and Vmax were reduced and duration markedly prolonged. In reperfused infarcts, changes in Purkinje fiber transmembrane potentials were not as marked. Action potential duration in 3-day-old permanently occluded infarcts were longer than at 24 h, but in reperfused infarcts durations had returned to normal. Premature impulses conducted more rapidly in the reperfused infarct Purkinje system than in the permanently occluded. Other transmembrane potential parameters of Purkinje fibers in 3-day-old and 9- to 10-day-old reperfused and permanently occluded infarcts were not significantly different from each other. The ventricular muscle cells that survived in reperfused infarcts at all times also had reduced resting potentials and action potentials with decreased amplitudes, reduced Vmax, and prolonged durations. Almost no muscle cells survived in permanently occluded infarcts. Therefore, reperfusion salvages subendocardial fibers and prevents some but not all of the electrophysiological abnormalities.

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Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.254.6.h1157 ◽

1988 ◽

Vol 254 (6) ◽

pp. H1157-H1166 ◽

Cited By ~ 6

Author(s):

J. A. Wasserstrom ◽

J. J. Salata

Keyword(s):

Action Potential ◽

Action Potentials ◽

Ventricular Myocytes ◽

Ionic Currents ◽

Detectable Effect ◽

Na Channel ◽

Na Current ◽

Voltage Range ◽

Purkinje Fibers ◽

Ventricular Cells

We studied the effects of tetrodotoxin (TTX) and lidocaine on transmembrane action potentials and ionic currents in dog isolated ventricular myocytes. TTX (0.1-1 x 10(-5) M) and lidocaine (0.5-2 x 10(-5) M) decreased action potential duration, but only TTX decreased the maximum rate of depolarization (Vmax). Both TTX (1-2 x 10(-5) M) and lidocaine (2-5 x 10(-5) M) blocked a slowly inactivating toward current in the plateau voltage range. The voltage- and time-dependent characteristics of this current are virtually identical to those described in Purkinje fibers for the slowly inactivating inward Na+ current. In addition, TTX abolished the outward shift in net current at plateau potentials caused by lidocaine alone. Lidocaine had no detectable effect on the slow inward Ca2+ current and the inward K+ current rectifier, Ia. Our results indicate that 1) there is a slowly inactivating inward Na+ current in ventricular cells similar in time, voltage, and TTX sensitivity to that described in Purkinje fibers; 2) both TTX and lidocaine shorten ventricular action potentials by reducing this slowly inactivating Na+ current; 3) lidocaine has no additional actions on other ionic currents that contribute to its ability to abbreviate ventricular action potentials; and 4) although both agents shorten the action potential by the same mechanism, only TTX reduces Vmax. This last point suggests that TTX produces tonic block of Na+ current, whereas lidocaine may produce state-dependent Na+ channel block, namely, blockade of Na+ current only after Na+ channels have already been opened (inactivated-state block).

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Shortening of the action potential and reduction of pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac purkinje fibers. An effect on Na or K currents?

Circulation Research ◽

10.1161/01.res.50.2.257 ◽

1982 ◽

Vol 50 (2) ◽

pp. 257-272 ◽

Cited By ~ 116

Author(s):

E Carmeliet ◽

T Saikawa

Keyword(s):

Action Potential ◽

Pacemaker Activity ◽

Purkinje Fibers ◽

Cardiac Purkinje Fibers ◽

K Currents

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Persistence of the electrophysiologic effects of mexiletine in canine Purkinje fibers alters the response to subsequent hypoxia

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-330 ◽

1987 ◽

Vol 65 (10) ◽

pp. 2104-2109

Author(s):

Neil D. Berman ◽

Richard I. Ogilvie ◽

James E. Loukides

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Free Solution ◽

Purkinje Fibers ◽

Subsequent Exposure ◽

Hydrochloride Solution ◽

Drug Free ◽

Microelectrode Techniques ◽

Upstroke Velocity ◽

Normal Formula

The persistence of cellular electropharmacologic effects of mexiletine on canine Purkinje fibers was studied utilizing standard microelectrode techniques and two different protocols. In the first, the tissue was exposed to hypoxic perfusion before and 30 min after perfusion with one of the following: mexiletine hydrochloride 6.25 μM solution, mexiletine hydrochloride 12.5 μM solution, or drug-free Tyrode's solution. With the higher concentration of mexiletine, depression of the maximal upstroke velocity [Formula: see text] persisted 30 min after drug washout and subsequent exposure to hypoxia did not result in the anticipated shortening of action potential duration but did prevent the restoration of normal [Formula: see text]. After perfusion with the lower concentration of mexiletine, [Formula: see text] was not depressed and hypoxic action potential duration shortening was not prevented. In the second protocol, Purkinje fibers were perfused with 12.5 μM mexiletine hydrochloride solution and then exposed to hypoxia after 15, 30,45, or 60 min of perfusion with drug-free solution. Depression of maximal upstroke velocity and shortening of action potential duration persisted during washout, returning to control values by 45 min, although mexiletine was not detectable in the tissue bath after 10 min of washout. Hypoxia initiated at 15 or 30 min of washout failed to produce the anticipated shortening of action potential duration. At 45 and 60 min, action potential duration was shortened by hypoxia. We concluded that mexiletine depression of [Formula: see text] and shortening of action potential duration may persist in the absence of drug. Further shortening of action potential duration in response to hypoxia is prevented during this period. The persistence of [Formula: see text] depression is prolonged by hypoxia.

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A re-examination of late outward plateau currents of cardiac Purkinje fibers

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1985.249.1.h108 ◽

1985 ◽

Vol 249 (1) ◽

pp. H108-H121

Author(s):

J. M. Jaeger ◽

W. R. Gibbons

Keyword(s):

Action Potential ◽

Voltage Clamp ◽

Critical Role ◽

Membrane Current ◽

Purkinje Fiber ◽

Purkinje Fibers ◽

Outward Currents ◽

Cardiac Purkinje Fibers

Two outward currents, IX1 and IX2, are thought to be activated by depolarization of the Purkinje fiber. One of these, IX1, is presently believed to play a critical role in repolarization of the action potential. The IX currents were originally analyzed in voltage-clamp experiments in sheep Purkinje fibers. These experiments were designed to minimize interference by other currents, and it was assumed that changes of the net current were produced entirely by the IX currents. We have tried to repeat the original experiments and the analysis that led to acceptance of the existence and roles of the IX currents, without success. Moreover, tests of how membrane current should behave if the IX current hypothesis is correct did not give satisfactory results. Our data suggest the original conclusions about IX1 and IX2 may need substantial revision.

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Slow inward current may produce many results attributed to IX1 in cardiac Purkinje fibers

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1985.249.1.h122 ◽

1985 ◽

Vol 249 (1) ◽

pp. H122-H132

Author(s):

J. M. Jaeger ◽

W. R. Gibbons

Keyword(s):

Action Potential ◽

Outward Current ◽

Purkinje Fiber ◽

Slow Inward Current ◽

Channel Blockers ◽

Inward Current ◽

Purkinje Fibers ◽

Cardiac Purkinje Fibers ◽

Current Voltage ◽

Current Voltage Relation

We have tried to answer two fundamental questions concerning the outward current IX1 of cardiac Purkinje fibers. 1) Is it possible that current changes identified as arising from IX1 in voltage-clamp experiments are actually manifestations of changes in the slow inward current (Isi); and 2) is IX1 in fact required to produce the electrical phenomena attributed to it? Isi behavior and the role of IX1 were explored using computer simulation. The Isi model produced current changes during depolarizations and hyperpolarizations from depolarized resting potentials like those attributed to IX1. It also produced a component of "tail currents" that behaved like IX1. If these current changes were analyzed, assuming that an outward current is responsible, the resulting kinetics and current voltage relation would be very similar to the kinetics and current voltage relation reported for IX1. Using the McAllister, Noble, and Tsien formulation of the Purkinje fiber action potential, we found that IX1 is not essential for repolarization of the reconstructed action potential nor is it needed to reproduce interval duration effects and the effects of applied current in that model. Data suggesting that calcium channel blockers reduce IX1 and that catecholamines increase IX1 may be explained as arising from changes in Isi. Thus many manifestations of IX1 can be explained as arising from unanticipated behavior of Isi, and IX1 does not necessarily play a key role in generating Purkinje fiber electrical activity.

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Electrical uncoupling and impulse propagation in isolated sheep Purkinje fibers

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.1.h179 ◽

1989 ◽

Vol 257 (1) ◽

pp. H179-H189 ◽

Cited By ~ 6

Author(s):

J. Jalife ◽

S. Sicouri ◽

M. Delmar ◽

D. C. Michaels

Keyword(s):

Action Potential ◽

Electrical Coupling ◽

Conduction Delay ◽

Heart Cells ◽

Hypertonic Solution ◽

Purkinje Fibers ◽

One Dimensional ◽

Action Potential Propagation ◽

Electrical Uncoupling ◽

Impulse Propagation

Alterations in electrical coupling may have a major role in the development of cardiac rhythm and conduction disturbances. We have used microelectrodes and linear Purkinje fibers to analyze the relative importance of cell-to-cell coupling on action potential propagation and to study the changes in the relationship between conduction velocity (theta) and upstroke velocity (Vmax) induced by three agents (heptanol, hypertonic solution, and ouabain) known to alter gap junction resistance. Heptanol superfusion (1.5–3.0 mM) reversibly led to a major decrease in theta and ultimately to block at a time when Vmax had been reduced by approximately 38%. Conduction delay was closely correlated with an increase in intracellular resistance (Ri), calculated as the sum of myoplasmic and junctional resistances, assuming a one-dimensional cable model. Qualitatively similar results were obtained by superfusion with 0.1–0.5 mM ouabain or hypertonic Tyrode solution (up to 600 mM sucrose added) instead of heptanol. In contrast, when the Vmax vs. theta relationship was studied by changing the KCl from 4 to 20 mM, decreases in Vmax correlated well with changes in theta. No significant effects on Ri were observed during KCl superfusion. Finally, we developed a computer model of action potential propagation along a one-dimensional strand of 90 electrically coupled heart cells. By changing systematically the degree of electrical coupling or the maximum sodium conductance in the model and by studying the effects of these changes on propagation and Vmax, we obtained strong evidence supporting the validity of our experimental results. The overall data provide testable predictions regarding the role of electrical uncoupling on abnormal impulse propagation.

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

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-115 ◽

1989 ◽

Vol 67 (7) ◽

pp. 710-721 ◽

Cited By ~ 2

Author(s):

Matthew A. Flemming ◽

Betty I. Sasyniuk

Keyword(s):

Potassium Channels ◽

Action Potential ◽

Sodium Channel ◽

Action Potential Duration ◽

Refractory Period ◽

Drug Effect ◽

Effective Refractory Period ◽

Slow Inactivation ◽

Purkinje Fibers ◽

Rate Dependent

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. [Formula: see text] was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of [Formula: see text] depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on [Formula: see text]. 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 [Formula: see text] 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 [Formula: see text] 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.Key words: action potential duration, effective refractory period, upstroke velocity, conduction, rate of sodium channel unblocking.

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