Cardiac action potential pacemaker cells

In the following, the cardiac action potential is explained (Fig. 1) An action potential is initiated by depolarization of the plasma membrane due to the pacemaker current (If) (carried by K+ and Na+, which can be modulated by acetylcholine and by adenosine) modulated by effects of sympathetic innervation and (3-adrenergic activation of Ca2+-influx as well as by acetylcholine- or adenosine-dependent K+-channels [in sinus nodal and atrioventricular nodal cells] or to dqjolarization of the neighbouring cell. Depolarization opens the fast Na+ channel resulting in a fast depolarization (phase 0 ofthe action potential). These channels then inactivate and can only be activated if the membrane is hyperpolarized... 

Certain cardiac cells are able to initiate and maintain a spontaneous automatic rhythm. Even in the absence of any neural or hormonal input, these cells will automatically generate an action potential. They are usually referred to as pacemaker cells in the myocardium. Pacemaker cells have the ability to depolarize spontaneously because of a rising phase 4 in the cardiac action potential (see Fig. 23-1). As described previously, the resting cell automatically begins to depolarize during phase 4 until the cell reaches threshold and an action potential is initiated. 

In the atrial cells of the frog heart, the pacemaker depolarization begins immediately after the previous action potential, when the potassium conductance of the membrane is very high. Then the potassium conductance gradually drops, and the membrane shows a corresponding depolarization due to a moderately high steady conductance for sodium. The pacemaker depolarization continues until the excited sodium conductance is activated, and rapid regenerative upstroke of the cardiac action potential takes over. 

Skeletal muscle is neurogenic and requires stimulation from the somatic nervous system to initiate contraction. Because no electrical communication takes place between these cells, each muscle fiber is innervated by a branch of an alpha motor neuron. Cardiac muscle, however, is myogenic, or self-excitatory this muscle spontaneously depolarizes to threshold and generates action potentials without external stimulation. The region of the heart with the fastest rate of inherent depolarization initiates the heart beat and determines the heart rhythm. In normal hearts, this "pacemaker region is the sinoatrial node. 

General definitions relating to action potentials are given in Section 9. This section deals specifically with action potentials within the cardiac pacemaker cells and conducting system. 

You will be expected to have an understanding of action potentials in nerves, cardiac pacemaker cells and cardiac conduction pathways. 

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... 

Transmembrane action potential of a sinoatrial node cell. In contrast to other cardiac cells, there is no phase 2 or plateau. The threshold potential (TP) is -40 mV. The maximum diastolic potential (MDP) is achieved as a result of a gradual decline in the potassium conductance (gK+). Spontaneous phase 4 or diastolic depolarization permits the cell to achieve the TR thereby initiating an action potential (g = transmembrane ion conductance). Stimulation of pacemaker cells within the sinoatrial node decreases the time required to achieve the TR whereas vagal stimulation and the release of acetylcholine decrease the slope of diastolic depolarization. Thus, the positive and negative chronotropic actions of sympathetic and parasympathetic nerve stimulation can be attributed to the effects of the respective neurotransmitters on ion conductance in pacemaker cells of the sinuatrial node. gNa+ = Na+ conductance. 

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.

In healthy cardiac cells, the recovery time from inactivation of sodium channels (back to the resting state) is quite rapid, so that the maximum number of channels is available for activation. In contrast, in sick cells, the recovery time is quite slow. In these sick cells, the action potential develops from the opening of fewer sodium channels, so the action potential is a slow sluggish upstroke as opposed to the fast upstroke in a healthy cell. A slow sluggish upstroke results in poor and perhaps no propagation of the action potential. Chronically depolarized or ischemic cells may (1) fail to conduct an action potential and therefore fail to contract or to transmit the action potential to neighboring cells or (2) become an ectopic pacemaker (due to a... 

In the myocardium, automaticity is the ability of the cardiac muscle to depolarize spontaneously (i.e., without external electrical stimulation from the autonomic nervous system). This spontaneous depolarization is due to the plasma membrane within the heart that has reduced permeability to potassium (K+) but still allows passive transfer of calcium ions, allowing a net charge to build. Automaticity is most often demonstrated in the sinoatrial (SA) node, the so-called pacemaker cells. Abnormalities in automaticity result in rhythm changes. The mechanism of automaticity involves the pacemaker channels of the HCN (Hyperpolarization-activated, Cyclic Nucleotide-gated) family14 (e.g., If, "funny" current). These poorly selective cation channels conduct more current as the membrane potential becomes more negative, or hyperpolarized. They conduct both potassium and sodium ions. The activity of these channels in the SA node cells causes the membrane potential to slowly become more positive (depolarized) until, eventually, calcium channels are activated and an action potential is initiated. 

In contrast, conduction velocity is slow in muscle fibers at the SA and AV nodes. Unlike the majority of cardiac muscle cells, these pacemaker cells have an unstable resting potential ( — 60 mV) due to a cell membrane alteration that allows sodium ions to leak into the cell without a concurrent potassium ion efflux. This sodium leakage reduces the membrane potential allowing even more sodium ions to move into the cell. In addition to the inward sodium movement, there is also an inward calcium flow which causes the pacemaker cells to have a more positive resting potential. Finally, the cell produces an action potential at 40 mV. This phenomenon is called spontane-... 

The basic rhythm of heart rate is maintained by a part of the heart known as the pacemaker or sinoatrial (SA) node. This is a group of cardiac muscle cells in the right atrium that depolarize spontaneously. Depolarization of cardiac muscle cells brings about contraction. The pacemaker forms part of a conduction system that transmits electrical activity through the heart by means of action potentials so that contractions are coordinated and the heart can function as an efficient pump. The conduction pathway of electrical activity goes from the SA node to the atrioventricular (AV) node between atria and ventricles, then down the septum between the two ventricles to the apex of the heart and finally round the ventricles themselves. The conduction pathway in the heart is shown in Figure 4.2. 

In the SA node, each normal cardiac impulse is initiated by the spontaneous depolarization of the pacemaker cells (see Chapter 34). When a threshold is reached, an action potential is initiated and conducted through the atrial muscle fibers to the AV node and thence through the Purkinje system to the ventricular muscle. ACh slows the heart rate by decreasing the rate of spontaneous diastolic depolarization (the pacemaker current) and by increasing the repolarizing current at the SA node (a direct effect of fiy subunits of G/G, ) in sum, the membrane potential is more negative and attainment of the threshold potential and the succeeding events in the cardiac cycle are delayed. 

Figure 14-7. Schematic diagram of the effects of ciass iV drugs in a calcium-dependent cardiac cell in the AV node (note that the AP upstroke is due mainly to calcium current). Class IV drugs reduce inward calcium current during the action potential and during phase 4 (wavy lines). As a result, conduction velocity is slowed in the AV node and refractoriness is prolonged. Pacemaker depolarization during phase 4 is slowed as well if caused by excessive calcium current.

Thanks to the studies of Hodgkin Huxley, which culminated in 1952 with the publication of a series of articles, of which the last was of theoretical nature, the physicochemical bases of neuronal excitability giving rise to the action potential were elucidated. Soon after, Huxley (1959) showed how a nerve cell can generate a train of action potentials in a periodic manner (see also Connor, Walter McKown, 1977 Aihara Matsumoto, 1982 Rinzel Ermentrout, 1989). Even if the properties of the ionic channels involved have not yet been fully elucidated, cardiac oscillations originate in a similar manner from the pacemaker properties of the specialized, electrically excitable tissues of the heart (Noble, 1979,1984 Noble Powell, 1987 Noble, DiFrancesco Denyer, 1989 DiFrancesco, 1993). These examples remained the only biological rhythms whose molecular mechanism was known to some extent, until the discovery of biochemical oscillations. 

As with the normal cardiac conducting system and its propagation of impulses through the His Purkinje network, electrostimulation by an artificial cardiac pacemaker depends on the depolarization of a single or a group of myocyte cell membranes which can then act as pacemaker cells. In order for these cells to depolarize, the electric field of the applied artificial pacemaker stimulus must exceed a threshold voltage. This initiates a complex cascade of ionic currents both in and out of the cell membrane referred to as the action potential. The impulse or wave of depolarization then propagates away from the site of stimulation from cell to cell across gap junctions or intercalated disks, which with normal cells provide very low resistance to depolarization. 

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