Action potential duration

Glass lA Antiarrhythmic Agents. Class lA antiarrhythmic agents decrease automaticity, ie, depress pacemaker rates, especially ectopic foci rates produce moderate depression of phase 0 depolarization and thus slow conduction in atria, A-V node, His-Purkinje system, and ventricles prolong repolarization, ie, lengthen action potential duration increase refractoriness and depress excitabiHty. These electrophysiological effects are manifested in the ECG by increases in the PR, QRS, and QT intervals. 

Glass IB Antiarrhythmic Agents. Class IB antiarrhythmic agents produce less inhibition of the inward sodium current than Class lA agents. In normal myocardial tissue, phase 0 may be unaffected or minimally depressed. However, in ischemic or infarcted tissue, phase 0 is depressed. Myocardial tissue exposed to Class IB agents exhibits decreased automaticity, shortened action potential duration, ie, shortened repolarization, and shortened refractory period. Excitability of the myocardium is not affected and conduction velocity is increased or not modified. The refractory period is shortened less than its action potential duration, thus the ratio of refractory period to action potential duration is increased by these agents. The net effect is increased refractoriness. The PR and QT intervals of the ECG are shortened and the QRS interval is unchanged (1,2). 

Glass IG Antiarrhythmic Agents. Class IC antiarrhythmic agents have marked local anesthetic effects. They slow the rapid inward sodium current producing marked phase 0 depression and slow conduction. Action potential duration of ventricular muscle is increased, ie, prolonged repolarization, but decreased in the His-Purkinie system by these agents. The effects on the ECG are increased PR interval, marked prolongation of the... 

The Class III antiarrhythmic agents markedly prolong action potential duration and effective refractory period of cardiac tissue. The QT interval of the ECG is markedly prolonged. 

The electrophysiological effects of amiodarone may be a composite of several properties. In addition to prolonging action potential duration and refractory period in ad tissues of the heart, the compound is an effective sodium channel blocker (49), calcium channel blocker (50), and a weak noncompetitive -adrenoceptor blocking agent (51). Amiodarone slows the sinus rate, markedly prolongs the QT interval, and slightly prolongs the QRS duration (1,2). 

I c With only little effect on action potential duration Lorcainide, Flecainide, Propafenone... 

As with the effects of oxidant stress on the calcium channel, part of the change in the steady-state background current could also be attributed to an indirect effect secondary to the elevation of intracellular calcium (Matsuura and Shattock, 1991b). However, oxidant stress also exerted a direct effect on the inward rectifying potassium current (7ki). The combination of an inhibition of 7ki and the activation of a calcium-dependent current are likely to contribute to the prolongation of the action potential duration and the increased susceptibility... 

The behavioral effects of PCP have been associated with excessive release of a wide variety of neurotransmitters in particular, a massive dopamine release may underlie some of the most prominent symptoms of PCP intoxication (Rappolt et al. 1980). Our results readily explain the genesis of such an effect, because activation of presynaptic K channels is one of the primary factors that influences Ca entry into nerve terminals and Ca-dependent transmitter release by limiting action-potential duration and regulating excitabi1ity. 

Neurotoxin that preferentially binds to activated sodium channels and increases the intracellular calcium concentration. It prolongs the action potential duration in the heart. It is obtained from sabadilla seeds (Schoenocaulon officinale). Yellowish-white amorphous powder that retains water and melts at 356°F. It is insoluble in water but slightly soluble in ether. Various salts (solids) have been reported. The nitrate is sparingly soluble in water. 

Elliott, A.C., G.L. Smith, and D.G. Allen. 1989. Simultaneous measurements of action potential duration and intracellular ATP in isolated ferret hearts exposed to cyanide. Circulat. Res. 64 583-591. 

Studies to assess the effects of compound and any known metabolites on ECG and cardiac action potentials are recommended. Changes in action potential duration and other parameters measured are a functional consequence of effects on the ion channels which contribute to the action potential. This in vitro test is considered to provide a reliable risk assessment of the potential for a compound to prolong Q-T interval in humans. 

Continuous intracellular recording of action potentials and on-line analysis of resting membrane potential, maximum rate of depolarization, upstroke amplitude and action potential duration using Notocord HEM data acquisition system. 

In vitro screening of the drug and its metabolites for effects on action-potential duration. 

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 QT interval (measured from the beginning of the Q wave to the end of the T wave of the surface electrocardiogram) reflects the duration of individual action potentials in cardiac myocytes (Figure 3.1) indeed, a prolongation of the action potential duration (APD) of myocytes will result in a prolonged QT interval. 

Cardiac APD is controlled by a fine balance between inward and outward currents in the repolarization phase. Since outward K+ currents, especially the delayed rectifier repolarizing current, IK (which is the sum of two kinetically and pharmacologically distinct types of K+ currents a rapid, 1k and a slow, IKs, component), play an important role during repolarization and in determining the configuration of the action potential, small changes in conductance can significantly alter the effective refractory period, hence the action potential duration. 

Hondeghem, L.M., Carlsson, L. and Duker, G. (2001) Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhyfhmic. Circulation, 103, 2004-2013. 

Hondeghem, L.M. and Hoffmann, P. (2003) Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs importance of triangulation, reverse use dependence, and instability. Journal of Cardiovascular Pharmacology, 41, 14—24. 

Schematic illustration of an integrated risk assessment aimed at assessing the liability for an NCE to prolong the QT interval in man. APD = Action Potential Duration NCE = New Chemical Entity QTCV = Van de Water corrected QT interval duration.

Class III agents increase the refractoriness of cardiac tissue, thus preventing an aberrant impulse from propagating. A selective Class III agent has little or no effect on simple PVC s. At the cellular level, the increased refractoriness is manifest by a delay in the repolarization phase (Phase 3) of the cardiac action potential Figure 2.1), thereby increasing action potential duration. During the action potential cycle a complex series of ionic currents. 

C20 APD95 = concentration of drug which caused a 20% increase in action potential duration at 95% repolarization (APD95). Reported is the log mean average of n determinations with the lowest and highest values given in parentheses. 

High sensitivity of sensory nerves, low sensitivity of motor nerves. Impulse conduction in sensory nerves is inhibited at a concentration lower than that needed for motor fibers. This difference may be due to the higher impulse frequency and longer action potential duration in nociceptive, as opposed to motor, fibers. 

---