Repolarization phase, cardiac action potential

Cardiac IKi is the major K+ current responsible for stabilizing the resting membranepotential and shaping the late phase of repolarization of the action potential in cardiac myocytes. The name should not be confused with that of an Intermediate conductance calcium-activated K+ channel, which sometimes is also called IK1. 

Kvl.5 In human atria, the Kvl.5 presents the ultrarapid delayed rectifier that contributes to the repolarization in the early phase of cardiac action potential. Selective blockers of Kvl.5 channels could be potentially beneficial in the treatment of atrial fibrillation because blocking Kvl. 5 could delay repolarization and prolong refractoriness selectively in cardiac myocytes. Examples for Kvl.5 blockers include AVE0118, S9947, and analogs of diphenyl phosphine oxide (DPO). 

The ventricular cardiac action potential is characterized by five phases and is shaped by the complex interplay of a variety of Na+, Ca2+ and K+ currents (Figure 4.2). The distinct voltage-dependent properties of hERG channels [19,20] govern the time course of Ikt and the manner in which it contributes to the outward K+ current during the repolarization phase of the cardiac action potential. The opening and closing of... 

Figure 4.2 Cartoon representation of an ECC trace and ventricular cardiac action potential, (a) A representation of an ECC trace with its five typical deflections (PQRST) arising from the spread of electrical activitythrough the heart. The QRS wave denotes the ventricular depolarization, while the T wave represents ventricular repolarization. The QT interval therefore estimates the duration of a ventricular action potential, (b) Schematic of the five phases of a ventricular action potential. Phase 0 is the rapid depolarization phase due to a large influx of Na+ ions (Ina). Phase 1 occurs with the inactivation of Na+ channels and the onset of transient outward (repolarizing) currents (/to)...

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. 

Figure 3-2 Contribution of main ion currents (and respective genes) to time course of membrane potential changes constituting the cardiac action potential. Horizontal gray bars indicate the voltage range ion current participation in the different depolarization/repolarization phases.

The cardiac action potential can be divided into five phases, numbered 0-4. These phases result from the subsequent or parallel activity of ion channels (Figure 3.2) and/or transporters. Initially, the cell is polarized to near the electrochemical potential for potassium ions because of high K+ conductance at rest. A rapid depolarization is initiated by the activation of the fast inward Na+ current (phase 0). This depolarization is followed by a brief partial repolarization mainly resulting from the activation of the transient outward current (/t0) and the inactivation... 

The morphology of an action potential is dictated by the flow of ions across the cell membrane (Figure 2a). An inward flow of sodium and calcium ions has a depolarizing influence on the membrane potential, while an outward flow of potassium has a repolarizing effect. The upstroke of the cardiac action potential (phase 0) is due to an inward flux of sodium ions and the plateau phase (phase 2) is maintained... 

It is established that Ca + and K+ are involved in maintenance and termination of the plateau phase of the cardiac action potential. Furthermore, intracellular calcium concentration controls membrane K+ permeability via the various conductance components for K+ (gK], gK2, glx) (69) It is also established that action potential duration and myocardial tension development are integrally related (13). In view of previous observations and explanations for the excitation-contraction coupling process and the effects of calcium inhibitory compounds upon the cardiac action potential of ventricular muscle and Purkinje fibers, one possible explanation for the effects observed in ventricular muscle preparations is that low concentrations of calcium inhibitory compounds reduce the amount of intracellular free calcium in the vicinity of the K+ channel, thereby changing the channel s configuration resulting in a reduction in gK+ and delayed repolarization of the ventricular muscle action potential. 

Electrical activity in the heart can be picked up by electrodes placed on the skin and recorded as the familiar electrocardiogram (ECG). The ECG is a record of the sum of all action potentials in the heart as it contracts. Action potentials are generated by depolarization followed by repolarization of the cardiac muscle cell membrane. Depolarization is initiated by an influx of sodium ions into the cardiac muscle cells, followed by an influx of calcium ions. Repolarization is brought about by efflux of potassium ions. The phases of a cardiac action potential are shown in Eigure 4.3 where the depolarization is the change in resting membrane potential of cardiac muscle cells from —90 mV to 4-20 mV. This is due to influx of sodium ions followed by influx of calcium ions. Contraction of the myocardium follows depolarization. The refractory period is the time interval when a second contraction cannot occur and repolarization is the recovery of the resting potential due to efflux of potassium ions. After this the cycle repeats itself. 

ERP includes both the action potential duration and the time for membrane repolarization and stimulus to threshold. Mexiletine, by blocking fast sodium channels, blunts the amplitude of the cardiac action potential (phase 0 is decreased). The decrease in sodium influx and decrease in phase 0 amplitude results in a lower membrane potential as the action potential enters phase 2 and 3. This results in the membrane potential, at the end of phase 0. being closer to the membrane potential for potassium and calcium, so the influx of these ions is of shorter duration, resulting in a decrease in the length of phase 1 and 2 and a steeper slope of phase 3 repolarization. Phase 4, however, is lengthened, and the rate of rise decreased, with the decrease in the rate of sodium influx. Thus, the cardiac membrane remains relatively refractory. even after repolarization, and the ratio of the ERP to the action potential duration increases. 

Ibutilide increases the transport of sodium into the cardiac myocyte during the plateau phase of the cardiac action potential. The net effect of the drug is a prolongation of the action potential, and a decrease in membrane excitability, as repolarization is decreased. 

Digitalis glycosides cause an influx of extracellular calcium and an accumulation of extracellular potassium. The increased levels of extracellular potassium decrease the rate of repolarization of the cardiac cell. Thus, as levels of the drug approach the toxic range, accumulated extracellular potassium causes a lengthening of phase 3 of the cardiac action potential and an increase in the length of time between depolarizations. Thus, bradycardia is seen. 

A. Type la agents depress the fast sodium-dependent channel, slowing phase zero of the cardiac action potential. At high concentrations, this results in reduced myocardial contractility and excitability, and severe depression of cardiac conduction velocity. Repolarization is also delayed, resulting in a prolonged QT interval that may be associated with polymorphic ventricular tachycardia (torsade de pointes see Figure 1-7, p 15). 

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. 

Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated and ECG). Sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje cells display pacemaker activity (phase 4 depolarization). The ECG is the body surface manifestation of the depolarization and repolarization waves of the heart. The P wave is generated by atrial depolarization, the QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. Thus, the PR interval is a measure of conduction time from atrium to ventricle, and the QRS duration indicates the time required for all of the ventricular cells to be activated (ie, the intraventricular conduction time). The QT interval reflects the duration of the ventricular action potential.

Most calcium channels become activated and inactivated in what appears to be the same way as sodium channels, but in the case of the most common type of cardiac calcium channel (the "L" type), the transitions occur more slowly and at more positive potentials. The action potential plateau (phases 1 and 2) reflects the turning off of most of the sodium current, the waxing and waning of calcium current, and the slow development of a repolarizing potassium current. 

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