The Action Potential

The action potential consists primarily of two sequential events an inward surge of positive charge largely due to the inward movement of Na into the cell followed by an outward surge of positive charges largely 

FIGURE 3. Plot of resting potential against external K and Na+ concentration ratio at different values of B. Ordinate represents which is equal to -constant. Abscissa represents ]ex/[Na+which is ([K ]e,/[Na+ ]e, For experiments carried out in the 

In 1953, Ling extended his theoretical model of the living cell to include a two-dimensional replica of the three-dimensional cell body at the cell surface. The /S- and y-carboxyl groups at the cell surface like many other P- and y-carboxyl groups existing throughout the ceU substance in resting cells, prefer over Na . It is the selective preference of these sur- 

Theoretical calculations presented briefly in 1960 and in full in 1962 39) provided a basis for the postulation of the AI hypothesis that the j8- and y-carboxyl groups at the cell surface and elsewhere may alter their electron charge density by allosteric interaction at a distant site, e.g., by the detatchment or adsorption of a cardinal adsorbent, Ca As a result, the electron density of the anionic carboxyl groups increases with a consequent rise of the c value. The c value is the underlying parameter that determines the pKa of acidic groups. 

A molecular interpretation of the action potential in terms of the AI hypothesis is as follows  

This equation is similar to the Nemst equation except that it simultaneously takes into account the contributions of all three permeant ions. It indicates that the membrane potential is governed by tw o factors (1) the ionic concentrations, which determine the equilibrium potentials for the ions, and, (2) their relative permeabilities, which determine the relative importance of a particular ion in governing where lies. For many cells, including most neurons and immune cells, this equation can be simplified the chloride term can be dropped altogether because the contribution of chloride to the resting membrane potential is insignificant. In this case, the Goldman equation becomes  

Because it is easier to measure relative ion permeabilities than the absolute permeabilities, this equation can be rewritten in a slightly different form  

Because the steady-state membrane potential Lies between the equilibrium potentials for Na+ and K , there is a constant movement of out from the cell and Na into the cell. To ensure that this does not lead to a progressive decline in the concentration gradients across the membrane, all cells have a Na-K pump, which uses the hydrolyses of ATP to simultaneously pump K+ into the cell and push Na out. The constant fluxes of and Na constitute electrical currents across the cell membrane, and at steady-state, these currents cancel each other out so that the net membrane current is zero. 

The key to understanding the origin of the action potential lies in the factors that influence the membrane potential of the cell as exemplified by the Goldman relationship. Recall that the membrane potential of the cell lies somewhere between E and E. At rest, because the relative permeability of the membrane is much higher for K+ than Na+, the 

The Sequence of Activation and Inactivation of Na and Channels During an Action Potential 

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Conductivity. Conductivity is an electrical property of excitable tissue which ensures that if one area of a membrane is excited to full activity, that area excites adjacent areas. Conduction of an impulse varies direcdy with the rate of development of phase 0 and the ampHtude of the action potential. Phase 0 is faster, and ampHtude of the action potential is greater, the more negative the transmembrane potential at the time of initiation of the impulse. Conduction velocity is faster when phase 0 is fast. 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Fleca.inide, Elecainide acetate, a fluorobenzamide, is a derivative of procainamide, and has been reported to be efficacious in suppressing both supraventricular and ventricular arrhythmias (26—29). The dmg is generally reserved for patients with serious and life-threatening ventricular arrhythmias. Elecainide depresses phase 0 depolarization of the action potential, slows conduction throughout the heart, and significantly prolongs repolarization (30). The latter effect indicates flecainide may possess some Class III antiarrhythmic-type properties (31). 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

A cell may produce early afterdepolarizations that are depolarization during incomplete repolarization. This is possible if the action potential is considerably prolonged. This is the typical mechanism for elicitation of Torsade de Pointes arrhythmia, a typical complication of class III antiarrhythmics and many other drugs. 

Quinidine, the classical class IA drug, binds to the open state oftheNa+ channel, and prolongs the action potential by block of the delayed rectifier-. In higher concentrations, L-type Ca2+ channels are inhibited. Quinidine exerts antimuscarinic effects, thereby accelerating AV-nodal... 

Antiarrhythmic drugs are antagonists of the fast Na+ channel, which slow the propagation of the cardiac action potential. Class I drugs suppress the fast upstroke of the action potential. 

Class HI antiarrhythmic drugs are drugs which act as K+ channel antagonists and result in action potential prolongation without effect on the upstroke of the action potential. 

Long nerve-cell process transmitting the action potential and ending as the synapse. 

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. 

Excitation-contraction coupling (EC coupling) is the mechanism underlying transformation of the electrical event (action potential) in the sarcolemma into the mechanical event (muscle contraction) which happens all over the muscle. In other words, it is the mechanism governing the way in which the action potential induces the increase in the cytoplasmic Ca2+ which enables the activation of myofibrils. 

Clarkson CW, Hondeghem LM (1985) Mechanism for bupivacaine depression of cardiac conduction fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62 396-405... 

QT syndrome and as a side effect of the action potential prolonging drugs. 

T-tubule is a transverse invagination of the plasma membrane, which occurs at the specified sites characteristic to animal species and organs, i.e. at the Z-line in cardiac ventricle muscle and non-mammalian vertebrate skeletal muscle and at the A-I junction in mammalian skeletal muscle. It is absent in all avian cardiac cells, all cardiac conduction cells, many mammalian atrial cells and most smooth muscle cells. T-tubule serves as an inward conduit for the action potential. 

Action potentials, self-propagating. Action potentials of smooth muscle differ from the typical nerve action potential in at least three ways. First, the depolarization phases of nearly all smooth muscle action potentials are due to an increase in calcium rather than sodium conductance. Consequently, the rates of rise of smooth action potentials are slow, and the durations are long relative to most neural action potentials. Second, smooth muscle action potentials arise from membrane that is autonomously active and tonically modulated by autonomic neurotransmitters. Therefore, conduction velocities and action potential shapes are labile. Finally, smooth muscle action potentials spread along bundles of myocytes which are interconnected in three dimensions. Therefore the actual spatial patterns of spreading of the action potential vary. 

Voluntary muscle contraction is initiated in the brain-eliciting action potentials which are transmitted via motor nerves to the neuromuscular junction where acetylcholine is released causing a depolarization of the muscle cell membrane. An action potential is formed which is spread over the surface membrane and into the transverse (T) tubular system. The action potential in the T-tubular system triggers Ca " release from the sarcoplasmic reticulum (SR) into the myoplasm where Ca " binds to troponin C and activates actin. This results in crossbridge formation between actin and myosin and muscle contraction. 

As described above, the propagation of the action potential is sensitive to Na -K changes over the membranes. These changes are most pronounced during continu-... 

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