Purkinje fibers, action

FIGURE 17-1. Purkinje fiber action potential showing specific ion flux responsible for the change in membrane potential. 

Procainamide (Class IA antiarrhythmic drug) is an effective agent for ventricular tachycardia. Its mechanism of action involves blockade of the fast Na+ channels responsible for phase 0 in the fast response tissue of the ventricles. Therefore, its effect is most pronounced in the Purkinje fibers. The effects of this drug s activity include a decrease in excitability of myocardial cells and in conduction velocity. Therefore, a decrease in the rate of the phase 0 upstroke and a prolonged repolarization are observed. As a result, duration of the action potential and the associated refractory period is prolonged and the heart rate is reduced. These effects are illustrated by an increase in the duration of the QRS complex. 

It is customary today to classify anti arrhythmic drugs according to their mechanism of action. This is best defined by intracellular recordings that yield monophasic action potentials. In the accompanying figure, the monophasic action potentials of (A) slow response fiber (SA node) and (B) fast Purkinje fiber are shown. For each description that follows, choose the appropriate drug with which the change in character of the monophasic action potential is likely to be associated... 

Cardiac Action Potential In Vitro Purkinje Fibers. Intracellular recording of action potentials from cardiac Purkinje fibers isolated from dog or sheep ventricle. Measurement of maximum rate of depolarization and action potential duration to detect sodium and potassium channel interactions, respectively, according to recommendations in EM A CPMP Points to Consider document, CPMP 986/96 (1998). 

The electrical impulse for contraction (propagated action potential p. 136) originates in pacemaker cells of the sinoatrial node and spreads through the atria, atrioventricular (AV) node, and adjoining parts of the His-Purkinje fiber system to the ventricles (A). Irregularities of heart rhythm can interfere dangerously with cardiac pumping func-tioa... 

Pharmacology Therapeutic concentrations of lidocaine attenuate phase 4 diastolic depolarization, decrease automaticity and cause a decrease or no change in excitability and membrane responsiveness. Action potential duration and effective refractory period (ERP) of Purkinje fibers and ventricular muscle are decreased, while the ratio of ERP to action potential duration is increased. Lidocaine raises ventricular fibrillation threshold. AV nodal conduction time is unchanged or shortened. Lidocaine increases the electrical stimulation threshold of the ventricle during diastole. 

Mechanism - Structurally like lidocaine, mexiletine inhibits the inward sodium current, thus reducing the rate of rise of the action potential. Phase 0. Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in ERP/APD ratio. 

A. Class la Lengthens duration of action potential (t the refractory period in atrial and ventricular muscle, in SA and AV conduction systems, and Purkinje fibers)... 

C. Class Ic Greater sodium current depression (blocks the fast inward Na current in heart muscle and Purkinje fibers, and slows the rate of t of phase 0 of the action potential)... 

A next-level assay is usually an isolated heart/cardiac tissue preparation. The canine Purkinje fiber assay (GLP) measures several action potential parameters, like resting membrane potential, upstroke velocity, action potential duration and shape, but also if a drug acts reverse-use dependently [72]. Based on changes of the action potential shape it is possible to conclude which ion channels are modulated (e.g., L-type calcium channel block would abolish the plateau phase). The papillary muscle assay (e.g., guinea pigs) determines similar parameters [73]. 

Members of class IB have a minimal effect on the rate of depolarization and are characterized by their ability to decrease the duration of action potential and ERP of Purkinje fibers. Members of this class have a minimal effect on conduction velocity in ventricular myocardium and are without apparent effect on refractoriness. 

Class II antiarrhythmic drugs competitively inhibit /3-adrenoceptors and inhibit catecholamine-induced stimulation of cardiac 15-receptors. In addition, some members of the group (e.g., propranolol and acebutolol) cause electrophysiological alterations in Purkinje fibers that resemble those produced by class I antiarrhythmic drugs. The latter actions have been called membrane-stabilizing effects. 

Quinidine also prolongs repolarization in Purkinje fibers and ventricular muscle, increasing the duration of the action potential. As in atrial muscle, quinidine administration results in postrepolarization refractoriness, that is, an extension of refractoriness beyond the recovery of the resting membrane potential. The indirect (anticholinergic) properties of quinidine are not a factor in its actions on ventricular muscle and the His-Purkinje system. 

Disopyramide administration reduces membrane responsiveness in Purkinje fibers and ventricular muscle and reduces the action potential amplitude. Even greater depression may occur in damaged or injured myocardial cells. Action potentials are prolonged after disopyramide administration, and this results in an increase in the ERPs of His-Purkinje and ventricular muscle tissue. Unlike procainamide and quinidine, disopyramide does not produce postrepolarization refractoriness. 

Propranolol decreases Purkinje fiber membrane responsiveness and reduces action potential amplitude. His-Purkinje tissue excitability also is reduced. These changes result in a decrease in His-Purkinje conduction velocity. However, these electrophysiological alterations are observed at propranolol concentrations in excess of those normally used in therapy. The most striking electrophysiological property of propranolol at usual therapeutic concentrations is a depression of catecholamine-stimulated automaticity. 

When I started as a novice in the field of cardiac electrophysiology, the dogma was that gap junctions are specialized membrane structures present in the cardiac and smooth muscle of vertebrates where they serve to propagate the action potential from cell to cell. Purkinje fibers and muscular trabeculae were the preferred cardiac preparations. These multicellular preparations were suitable to perform cable analyses and diffusion studies. At that time, my mentor, Silvio Weidmann, had already accomplished his elegant functional studies. 

The action potential recorded from a cardiac Purkinje fiber is shown in Figure 23-1. At rest, the interior of the cell is negative relative to the cell s exterior. As in other excitable tissues (neurons, skeletal muscle), an action potential occurs when the cell interior suddenly becomes positive (depolarizes), primarily because of sodium ion influx. The cell interior then returns to a negative potential (repolarizes), primarily because of... 

Pharmacokinetics Procainamide [pro kane A mide] is absorbed following oral administration. [Note The intravenous route is rarely used because hypotension occurs if the drug is too rapidly infused.] Procainamide has a relatively short half-life of 2-3 hours. A portion of the drug is acetylated in the liver to N-acetylprocainamide (NAPA), which has little effect on the maximum polarization of Purkinje fibers but prolongs the duration of the action potential. Thus, NAPA has properties of a Class III drug. NAPA is eliminated via the kidney, and dosages of procainamide may need to be adjusted in patients with renal failure. 

Evaluation of Cardiovascular Function Using Action Potential Parameters in Isolated Dog Purkinje Fibers... 

Evaluation of Cardiovascular Function Using Action Potential Parameters in Isolated Purkinje Fibers ICH S7B The Nonclinical Evaluation of the Potential for Delayed Repolarization (QT Interval Prolongation) by Human Pharmaceuticals 2-4 4-6 20,000-25,000... 

CRITICAL ASSESSMENT OF THE METHOD The Purkinje fiber is a non-contractile tissue, which facilitates electrode positioning and stability. In comparison to the papillary muscle or the monophasic action potential in the intact heart, drug-induced effects on the action potential duration are considerably larger. Whereas this is not necessarily a disadvantage, the model has been viewed as possibly being too sensitive for drug-induced effects on repolarization. 

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