Action potentials, pacemaking

The p adrenoceptor antagonists (beta blockers) are class II antiarrhythmic agents. They prolong phase 4 of the cardiac action potential (pacemaker potential), slowing the heart rate. There are three subtypes of P adrenoceptors Pi, P2 and P3. Stimulation of Pi adrenoceptors in the heart increases the force and rate of cardiac contraction, as well as increasing automaticity of the pacemaker sites and conduction through the AV node. The P2... 

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. 

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... 

A pacemaker potential involves gradual depolarization of the cell membrane to threshold. The subsequent generation of an action potential causes smooth muscle contraction. This type of spontaneous depolarization is referred to as a "pacemaker potential" because it creates a regular rhythm of contraction. 

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. 

Parasympathetic stimulation causes a decrease in heart rate. Acetylcholine, which stimulates muscarinic receptors, increases the permeability to potassium. Enhanced K+ ion efflux has a twofold effect. First, the cells become hyperpolarized and therefore the membrane potential is farther away from threshold. Second, the rate of pacemaker depolarization is decreased because the outward movement of K+ ions opposes the effect of the inward movement of Na+ and Ca++ ions. The result of these two effects of potassium efflux is that it takes longer for the SA node to reach threshold and generate an action potential. If the heart beat is generated more slowly, then fewer beats per minute are elicited. 

Injured axons may develop spontaneous and repetitive firing known as ectopic activity. Injured primary afferents develop spontaneous action potential discharges that occur uncoupled from receptor stimulation in the periphery (Fig. 57-5). These ectopic discharges can be evoked by protons, cytokines or mechanical stimulation of the injured nerve. Another source of ectopic activity are pacemaker currents produced in the plasma membrane... 

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. 

For cardiac action potentials and pacemaker potentials see Section 7. 

Cardiostimulation. By stimulating Pi-receptors, hence activation of ade-nylatcyclase (Ad-cyclase) and cAMP production, catecholamines augment all heart functions, including systolic force (positive inotropism), velocity of shortening (p. clinotropism), sinoatrial rate (p. chronotropism), conduction velocity (p. dromotropism), and excitability (p. bathmotropism). In pacemaker fibers, diastolic depolarization is hastened, so that the firing threshold for the action potential is reached sooner (positive chronotropic effect, B). The cardiostim-ulant effect of p-sympathomimetics such as epinephrine is exploited in the treatment of cardiac arrest Use of p-sympathomimetics in heart failure carries the risk of cardiac arrhythmias. 

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... 

The initiation of an epileptic attack involves "pacemaker" cells these differ from other nerve cells in their unstable resting membrane potential, i.e a depolarizing membrane current persists after the action potential terminates. 

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.

By blocking sodium channels, procainamide slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG. The drug also prolongs the action potential duration by nonspecific blockade of potassium channels. The drug may be somewhat less effective than quinidine (see below) in suppressing abnormal ectopic pacemaker activity but more effective in blocking sodium channels in depolarized cells. 

Procainamide INa (primary) and IKr (secondary) blockade Slows conduction velocity and pacemaker rate prolongs action potential duration and dissociates from INa channel with intermediate kinetics direct depressant effects on sinoatrial (SA) and atrioventricular (AV) nodes Most atrial and ventricular arrhythmias drug of second choice for most sustained ventricular arrhythmias associated with acute myocardial infarction Oral, IV, IM eliminated by hepatic metabolism to /V-acetylprocainamide (NAPA see text) and renal elimination NAPA implicated in torsade de pointes in patients with renal failure Toxicity Hypotension long-term therapy produces reversible lupus-related symptoms... 

Recently, both hirsutine (85) and dihydrocorynantheine (86) were found to be active when the effects of these compounds on the action potentials of sino-atrial node, atrium and ventricle tissues were studied with standard microelectrode techniques [65]. In sino-atrial node preparations, both compounds concentration-dependently increased cycle length, decreased the slope of the pacemaker depolarization, decreased the maximum rate of rise and prolonged action potential duration. Thus, it was for the first time shown that hirsutine and dihydrocorynantheine have direct inhibitory effects on the cardiac pacemaker. In atrial and ventricular preparations, both compounds concentration-dependently decreased the maximum rate of rise and prolonged action potential duration. Although stereochemically different, these two alkaloids exhibited no difference in their effects on various myocardial action potential parameters. Dihydrocorynantheine also displays potent a-adrenoceptor blocking activity, while hirsutine is inactive [66]. Experiments with ion channels indicate that the mechanisms for these two phenomena probably differ. The direct effects of hirsutine and dihydrocorynantheine on the action potential of cardiac muscle through inhibition of multiple ion channels may explain the negative chronotropic and antiarrhythmic activities of these two alkaloids. 

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