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

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.

Acetylcholine lengthens action potentials of sheep cardiac Purkinje fibers

1980 ◽  
Vol 238 (2) ◽  
pp. H237-H243
Author(s):  
S. L. Lipsius ◽  
W. R. Gibbons
Keyword(s):  
Muscarinic Receptors ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Purkinje Fibers ◽  
Diastolic Depolarization ◽  
Cardiac Purkinje Fibers ◽  
Rate Of Increase ◽  
Definite Sequence ◽  
Microelectrode Techniques ◽  
Diastolic Potential

The effect of acetylcholine (ACh) on the electrical activity of sheep cardiac Purkinje fibers was studied using standard microelectrode techniques. Most fibers showed a definite sequence of changes when exposed to ACh. Initially, action potential duration (APD) increased markedly. After about 20 s, the maximum diastolic potential (MDP) started to become more negative and, at the same time, the rate of increase in APD slowed. Once the MDP stabilized at a more negative level, the APD usually resumed its rapid increase. ACh also increased the slope of diastolic depolarization and made the plateau voltage more positive. APD was increased by ACh concentrations as low as 10(-7) M, and it increased with concentrations up to 10(-5) M (the highest concentration tested). ACh-induced increases in APD depended on the stimulation frequency; 2-min exposures to 10(-6) M ACh increased APD by 76.8 +/- 14.7% at 6 min-1 and 17.7 +/- 4.2% at 60 min-1. Atropine blocked all the effects of ACh. Hexamethonium did not prevent the ACh effects. It is concluded that ACh acts via muscarinic receptors. The changes in APD and MDP appear to be separate events, and it is difficult to see how the former effect may be explained by known actions of ACh.

Class III Antiarrhythmic Effects of Dofetilide in Rabbit Atrial Myocardium

1996 ◽  
Vol 1 (3) ◽  
pp. 229-234 ◽  
Author(s):  
Regan T. Pallandi ◽  
Nigel H. Lovell ◽  
Terence J. Campbell
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Interstimulus Interval ◽  
Class Iii ◽  
Atrial Myocardium ◽  
New Class ◽  
Class Iii Antiarrhythmic Agent ◽  
Prolongation Of Action Potential ◽  
Dose Dependent ◽  
Microelectrode Techniques

Background Dofetilide is a new class III antiarrhythmic agent with demonstrated efficacy in ventricular and atrial tachyarrhythmias. We investigated its class HI actions and their modulation by stimulation rate in rabbit atrial myocardium. Methods and Results Standard microelectrode techniques were used to record action potentials from rabbit atrial tissue at varying stimulation rates. Dofetilide produced a dose-dependent prolongation of action potential duration at concentrations from 1 nM to 1 μM at an interstimulus interval of 1000 ms. Action potential duration at 90% repolarization (action potential duration) was prolonged from 116 ± 11.7 ms in control solutions to 148 ± 13.9 ms at 1nM dofetilide and 186 ± 49.3 ms at 1 μM dofetilide ( P < .05 for 1 nM vs control; P < .01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms had no significant effect on action potential duration prolongation by dofetilide. At faster rates than this, and particularly at an interstimulus interval less than 330 ms, a marked “reverse rate dependence” of the class III effect was observed. Specifically, the high therapeutic concentration of 10 nM showed no effect on action potential duration at interstimulus interval of 250 ms or 200 ms, and even at a concentration of 30 nM, the small class III effect was no longer statistically significant at these rates. Conclusion Dofetilide prolongs action potential duration in rabbit atrial myocardium, but this effect is significantly attenuated at stimulation rates above 2 Hz.

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

1989 ◽  
Vol 67 (7) ◽  
pp. 710-721 ◽  
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.

scholarly journals Effect of Formaldehyde and Glutaraldehyde on Electrical Properties of Cardiac Purkinje Fibers

1969 ◽  
Vol 53 (5) ◽  
pp. 530-540 ◽  
Author(s):  
H. A. Fozzard ◽  
G. Dominguez
Keyword(s):  
Action Potential ◽  
Negative Charge ◽  
Input Resistance ◽  
Membrane Resistance ◽  
Rapid Loss ◽  
Purkinje Fibers ◽  
Electrophysiological Properties ◽  
Cardiac Purkinje Fibers ◽  
Length Constant ◽  
Upstroke Velocity

The effects of formaldehyde, glutaraldehyde, 1-fluoro-2,4-dinitrobenzene, and 1,5-difluoro-2,4-dinitrobenzene on the electrophysiological properties of cardiac Purkinje fibers were studied. At concentrations of 2.5 mM the aldehydes produced a transient hyperpolarization, lengthening of the plateau of the action potential, and an increase in action potential overshoot and upstroke velocity. If exposure to aldehyde was continued, the fiber failed to repolarize after an action potential and the membrane potential stabilized at about -30 mv. If exposure was terminated before this, recovery was usually complete. At the time the fibers were hyperpolarized the input resistance was increased without much change in length constant, leading to an increase in both calculated membrane resistance and calculated core resistance. Although it was anticipated that an effect of the aldehydes on the membrane was to increase fixed negative charge, it was difficult to explain all the electrophysiological changes on this basis. The major effects of the fluorobenzene compounds were not the same; they produced a shortening of the action potential and a rapid loss of excitability.

Effects of [K+]o on electrical restitution and activation dynamics during ventricular fibrillation

2000 ◽  
Vol 279 (6) ◽  
pp. H2665-H2672 ◽  
Author(s):  
Marcus L. Koller ◽  
Mark L. Riccio ◽  
Robert F. Gilmour
Keyword(s):  
Ventricular Fibrillation ◽  
Action Potential ◽  
Action Potential Duration ◽  
Maximum Amplitude ◽  
Spatiotemporal Organization ◽  
Activation Dynamics ◽  
Spontaneous Frequency ◽  
Upstroke Velocity

To test whether hyperkalemia suppresses ventricular fibrillation (VF) by reducing the slope of the action potential duration (APD) restitution relation, we determined the effects of the extracellular K+concentration ([K+]o) ([KCl] = 2.7–12 mM) on the restitution of APD and maximum upstroke velocity ( V max) the magnitude of APD alternans and spatiotemporal organization during VF in isolated canine ventricle. As [KCl] was increased incrementally from 2.7 to 12 mM, V max was reduced progressively. Increasing [KCl] from 2.7 to 10 mM decreased the slope of the APD restitution relation at long, but not short, diastolic intervals (DI), decreased the range of DI over which the slope was ≥1, and reduced the maximum amplitude of APD alternans. At [KCl] = 12 mM, the range of DI over which the APD restitution slope was ≥1 increased, and the maximum amplitude of APD alternans increased. For [KCl] = 4–8 mM, the persistence of APD alternans at short DI was associated with maintenance of VF. For [KCl] = 10–12 mM, the spontaneous frequency during VF was reduced, and activation occurred predominantly at longer DI. The lack of APD alternans at longer DI was associated with conversion of VF to a periodic rhythm. These results provide additional evidence for the importance of APD restitution kinetics in the development of VF.

scholarly journals Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit

2021 ◽  
Author(s):  
Sunil Jit R.J. Logantha ◽  
Xue J. Cai ◽  
Joseph Yanni ◽  
Caroline B. Jones ◽  
Robert S. Stephenson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Computed Tomography ◽  
Action Potential ◽  
Action Potential Duration ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Micro Computed Tomography ◽  
Left And Right ◽  
Upstroke Velocity

Background: Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs. Methods: Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. Results: Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P =0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca 2+ -handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca 2+ -channels, and K + -channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P <0.0001), and arrhythmic events in HF. Similar electrical remodeling was seen at the left PF-ventricular junction. In the failing left ventricle, upstroke velocity and amplitude were increased, but action potential duration at 90% repolarization was unaffected. Conclusions: Severe volume- followed by pressure-overload causes rapidly progressing HF with extensive remodeling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodeling may increase the risk of fatal arrhythmias in HF patients.

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