Ionic mechanism of PD occurrence in atypical cardiomyocytes. Action potentials of cardiomyocytes. The main types of ion channels heart
October 26, 2017 No comments
According to the traditional concept, the reason for the emergence of cell potentials both at rest and during their activation is primarily the uneven distribution of potassium and sodium ions between the cell contents and the extracellular environment. Recall that the concentration of potassium ions inside cells is 20-40 times higher than their content in the fluid surrounding the cell (note that the excess of positive charges of potassium ions inside the cells is compensated mainly by anions of organic acids), and the sodium concentration in the intercellular fluid is 10- 20 times higher than inside cells.
Such an uneven distribution of ions is provided by the activity of the "sodium-potassium pump", i. E. N a + / K + -ATPase. The emergence of the resting potential is mainly due to the presence of a concentration gradient of potassium ions. This point of view is based on the fact that potassium ions inside the cell are predominantly in a free state, i.e. are not bound with other ions, molecules, therefore they can freely diffuse.
According to the well-known theory of Hodgkin et al., The cell membrane at rest is permeable mainly only for potassium ions. Potassium ions diffuse along concentration gradient through the cell membrane into environment, while anions cannot penetrate the membrane and remain on its inner side.
Due to the fact that potassium ions have a positive charge, and the anions remaining on the inner surface of the membrane are negative, the outer surface of the membrane is charged positively, and the inner one is negatively charged. It is clear that diffusion continues only until an equilibrium is established between the forces of the arising electric field and the forces of diffusion.
The membrane at rest is permeable not only to potassium ions, but also to a small extent to sodium and chlorine ions. The cell membrane potential is the resultant electromotive forces generated by these three diffusion channels. The penetration of sodium from the surrounding fluid into the cell along the concentration gradient leads to some decrease in membrane potential, and then - to their depolarization, i.e. a decrease in polarization (the inner surface of the membranes becomes positive again, and the outer surface becomes negatively charged). Depolarization underlies the formation of the action potential of membranes.
All cells of excitable tissues under the action of various stimuli of sufficient strength are able to pass into a state of excitement. Excitability is the ability of cells to respond quickly to irritation, manifested through a combination of physical, physicochemical processes and functional changes.
An obligatory sign of excitement is a change in the electrical state. cell membrane... In general, the membrane permeability increases (this is one of the common cell responses to various damaging influences) for all ions. As a result, ionic gradients disappear and the potential difference across the membrane decreases to zero. This phenomenon of "lifting" (canceling) polarization is called depolarization.
In this case, the inner surface of the membranes becomes positive again, and the outer surface becomes negatively charged. This redistribution of ions is temporary; after the end of the excitation, the original resting potential is restored again. Depolarization underlies the formation of the action potential of membranes.
When membrane depolarization reaches a certain threshold level or exceeds it, the cell is excited, that is, an action potential appears, which is an excitation wave moving along the membrane in the form of a short-term change in the membrane potential in a small area of the excitable cell. The action potential has standard amplitude and time parameters that do not depend on the strength of the stimulus that caused it (the “all or nothing” rule). The action potentials provide the conduction of excitation along the nerve fibers and initiate the processes of contraction of muscle cells.
Action potentials arise as a result of excess, compared with rest, diffusion of sodium ions from the surrounding fluid into the cell. The period during which the permeability of the membrane for sodium ions increases when the cell is excited is very short-term (0.5-1.0 ms); this is followed by an increase in the membrane permeability for potassium ions and, consequently, an increase in the diffusion of these ions from the cell to the outside.
An increase in the potassium ion flux directed from the cell to the outside leads to a decrease in the membrane potential, which in turn causes a decrease in the membrane permeability for sodium ions. Thus, the second stage of excitation is characterized by the fact that the flow of potassium ions from the cell to the outside increases, and the counter flow of sodium ions decreases. This continues until the ENT, until the restoration of the potential for rest. Thereafter, the permeability to potassium ions also decreases to its original value.
The outer surface of the membrane, due to the positively charged potassium ions released into the medium, again acquires a positive potential with respect to the inner one. This process of returning the membrane potential to its original level, i.e. resting potential level is called repolarization.
The repolarization process is always longer than the depolarization process and is represented on the action potential curve (see below) in the form of a flatter descending branch. Thus, membrane repolarization occurs not as a result of the reverse movement of sodium ions, but as a result of the release of an equivalent amount of potassium ions from the cell.
In some cases, the membrane permeability for sodium and potassium ions remains elevated after the end of excitation. This leads to the fact that the so-called trace potentials, which are characterized by a small amplitude and a relatively long duration, are recorded on the action potential curve.
Under the action of subthreshold stimuli, the membrane permeability to sodium increases insignificantly and depolarization does not reach a critical value. Membrane depolarization is less critical level called local potential, which can be represented in the form of "electrotonic potential", or "local response".
Local potentials are not capable of spreading over considerable distances, but attenuate near the place of their origin. These potentials do not obey the “all or nothing” rule - their amplitude and duration are proportional to the intensity and duration of the irritating stimulus.
With repeated action of subthreshold stimuli, local potentials can add up, reach a critical value and cause the appearance of propagating action potentials. Thus, local potentials can precede the emergence of action potentials. This is especially clearly observed in the cells of the cardiac conduction system, where slow diastolic depolarization, which develops spontaneously, causes the appearance of action potentials.
It should be noted that the transmembrane movement of sodium and potassium ions is not the only mechanism for generating an action potential. Its formation also involves transmembrane diffusion currents of chlorine and calcium ions.
Outlined above general information Membrane potentials are equally attributed to both atypical cardiomyocytes, which form the conducting system of the heart, and to contractile cardiomyocytes - the direct executors of the pumping function of the heart. Changes in the membrane charge underlie the generation of electrical impulses - signals necessary to coordinate the functioning of contractile cardiomyocytes of the atria and ventricles throughout the cardiac cycle and the pumping function of the heart as a whole.
Specialized cells - "pacemakers" of the sinus node have the ability to spontaneously (without external influence) generate impulses, that is, action potentials. This property, called automatism, is based on the process of slow diastolic depolarization, which consists in a gradual decrease in the membrane potential to a threshold (critical) level, from which rapid membrane depolarization begins, i.e., phase 0 of the action potential.
Spontaneous diastolic depolarization is provided by ionic mechanisms, among which the traditionally nonspecific flow of Na + ions into the cell occupies a special position. However, according to modern studies, this current accounts for only about 20% of the activity of transmembrane ion movement.
Currently great importance has the so-called. delayed (delayed) current of K + ions leaving the cells. It has been established that the suppression (delay) of this current provides up to 80% of the automatism of the pacemakers of the sinus node, and the increase in the current K + slows down or completely stops the pacemaker activity. A significant contribution to the attainment of the threshold potential is made by the current of Ca ++ ions into the cell, the activation of which turned out to be necessary to reach the threshold potential. In this regard, it is appropriate to draw attention to the fact that clinicians are well aware of how sensitive the sinus rhythm is to blockers of Ca ++ channels (L-type) of the cell membrane, for example, to verapamil, or to beta-blockers, for example, to propranolol. capable of influencing these channels through catecholamines.
In the aspect of electrophysiological analysis of the pumping function of the heart, the interval between systoles is equal to the length of time during which the resting membrane potential in the cells of the sinus node shifts to the level of the threshold excitation potential.
Three mechanisms affect the duration of this interval and therefore the heart rate. The first in the most important of them is the rate (steepness of rise) of diastolic depolarization. With its increase, the threshold potential of excitation is reached faster, which determines the increase in the frequency of sinus rhythm. The opposite change, that is, a slowdown in spontaneous diastolic depolarization, leads to a decrease in sinus rhythm.
The second mechanism that affects the level of automatism of the sinus node is a change in the resting membrane potential of its cells (maximum diastolic potential). With an increase in this potential (in absolute values), that is, with hyperpolarization of the cell membrane (for example, under the influence of acetylcholine), it takes more time to reach the threshold excitation potential, if, of course, the rate of diastolic depolarization remains unchanged. The consequence of this shift will be a decrease in the number of heartbeats per unit of time.
The third mechanism is changes in the threshold excitation potential, a shift of which towards zero lengthens the path of diastolic depolarization and contributes to a decrease in sinus rhythm. The approach of the threshold potential to the resting potential is accompanied by an increase in the sinus rhythm. Various combinations of the three main electro-physiological mechanisms that regulate the automatism of the sinus node are also possible.
Phases and basic ionic mechanisms of the formation of the transmembrane action potential
The following phases of TMPD are distinguished:
Phase 0 - depolarization phase; characterized by rapid (within 0.01 s) recharging of the cell membrane: its inner surface becomes positively, and the outer surface becomes negatively charged.
Phase 1 - phase of initial rapid repolarization; is manifested by a slight initial decrease in TMPD from +20 to 0 mV or slightly lower.
Phase 2 - plateau phase; relatively long period (about 0.2 s), during which the TMPD value is maintained at the same level
Phase 3 - phase of final rapid repolarization; during this period, the initial membrane polarization is restored: its outer surface becomes positively charged, and its inner surface becomes negatively charged (-90 mV).
Phase 4 - diastole phase; the value of TMPD of the contractile cell remains approximately at the level of -90 mV, the initial transmembrane gradients of K +, Na +, Ca2 + and CG ions are restored (not without the participation of Na + / K + -Hacoca).
Different phases of TMPD are characterized by unequal excitability of the muscle fiber.
At the beginning of TMPD (phase 0,1,2), the cells are not completely excitable (absolute refractory period). During rapid terminal repolarization (phase 3), excitability is partially restored (relative refractory period). During diastole (phase 4), refractoriness is absent and the myocardial fiber completely restores its excitability. Changes in the excitability of the cardiomyocyte during the formation of the transmembrane action potential are reflected in the ECG complex.
Under natural conditions, myocardial cells are constantly in a state of rhythmic activity. During diastole, the resting membrane potential of myocardial cells is stable - minus 90 mV, its value is higher than in pacemaker cells. In the cells of the working myocardium (atria, ventricles), the membrane potential, in the intervals between the following PDs, is maintained at a more or less constant level.
The action potential in myocardial cells arises under the influence of excitation of pacemaker cells, which reaches cardiomyocytes, causing depolarization of their membranes (Figure 3).
The action potential of the cells of the working myocardium consists of a phase of rapid depolarization (phase 0), an initial rapid repolarization (phase 1), passing into a phase of slow repolarization (plateau phase, or phase 2) and a phase of rapid final repolarization (phase 3) and a resting phase - (Phase 4).
The phase of rapid depolarization is created by the activation of fast voltage-gated sodium channels, which provide a sharp increase in the permeability of the membrane for sodium ions, which leads to the emergence of a fast incoming sodium current. The membrane potential decreases from minus 90 mV to plus 30 mV, i.e. during the peak, the sign of the membrane potential changes. The amplitude of the action potential of the cells of the working myocardium is 120 mV.
When the membrane potential of plus 30 mV is reached, fast sodium channels are inactivated. Depolarization of the membrane causes the activation of slow sodium-calcium channels. The flow of Ca 2+ ions into the cell through these channels leads to the development of a PD plateau (phase 2). During the plateau period, the cell goes into a state of absolute refractoriness.
Then potassium channels are activated. The flow of K + ions leaving the cell ensures rapid repolarization of the membrane (phase 3), during which slow sodium-calcium channels are closed, which accelerates the repolarization process.
Repolarization of the membrane causes gradual closure of potassium channels and reactivation of sodium channels. As a result, the excitability of the myocardial cell is restored - this is the period of the so-called relative refractoriness.
Final repolarization in myocardial cells is due to a gradual decrease in membrane permeability for calcium and an increase in potassium permeability. As a result, the incoming calcium current decreases and the outgoing potassium current increases, which ensures a rapid restoration of the resting membrane potential (phase 4).
The ability of myocardial cells during a person's life to be in a state of continuous rhythmic activity is ensured by the effective operation of the ion pumps of these cells. During diastole, Na + ions are removed from the cell, and K + ions return to the cell. Ca 2+ ions that have penetrated the cytoplasm are absorbed by the endoplasmic reticulum.
Deterioration of myocardial blood supply (ischemia) leads to depletion of ATP and creatine phosphate reserves in myocardial cells, as a result, the work of pumps is disrupted, as a result of which the electrical and mechanical activity of myocardial cells decreases.
The action potential and myocardial contraction coincide in time. The entry of calcium from the external environment into the cell creates conditions for the regulation of the force of myocardial contraction.
Removal of calcium from the intercellular space leads to dissociation of the processes of excitation and contraction of the myocardium. In this case, the action potentials are recorded almost unchanged, but myocardial contraction does not occur. Substances that block calcium entry during action potential generation have a similar effect. Substances that inhibit calcium current, reduce the duration of the plateau phase and action potential and reduce the ability of the myocardium to contract.
With an increase in the calcium content in the intercellular environment and with the introduction of substances that increase the entry of calcium ions into the cell, the force of heart contractions increases.
The relationships between the phases of myocardial AP and the magnitude of its excitability are shown in Figure 5.
Due to depolarization, the membrane of cardiomyocytes becomes absolutely refractory. The period of absolute refractoriness lasts 0.27 s. During this period, the cell membrane becomes immune to the action of other stimuli. The presence of a prolonged refractory phase prevents the development of continuous shortening (tetanus) of the heart muscle, which would lead to the impossibility of the heart's pumping function.
The refractory phase is somewhat shorter than the duration of the AP of the ventricular myocardium, which lasts about 0.3 s.
The duration of atrial AP is 0.1 s, the same is the duration of atrial systole.
The period of absolute refractoriness is replaced by a period of relative refractoriness, during which the heart muscle can respond by contraction only to very strong stimuli. It lasts 0.03 s.
After a period of relative refractoriness, a short period of supernormal excitability sets in, when the heart muscle can respond by contraction to subthreshold stimuli.
It is determined mainly by the transmembrane concentration gradient of K + ions and in most cardiomyocytes (except for the sinus node and AV node) it ranges from minus 80 to minus 90 mV. When excited, cations enter the cardiomyocytes, and their temporary depolarization occurs - the action potential.
The ionic mechanisms of the action potential in working cardiomyocytes and in the cells of the sinus node and AV node are different, therefore the shape of the action potential is also different (Fig. 230.1).
At the action potential of the cardiomyocytes of the His-Purkinje system and the working myocardium of the ventricles, five phases are distinguished (Fig. 230.2). The phase of rapid depolarization (phase 0) is due to the entry of Na + ions through the so-called fast sodium channels. Then, after a short phase of early rapid repolarization (phase 1), a phase of slow depolarization, or plateau, begins (phase 2). It is due to the simultaneous entry of Ca2 + ions through slow calcium channels and the exit of K + ions. The phase of late rapid repolarization (phase 3) is due to the predominant release of K + ions. Finally, phase 4 is the resting potential.
Bradyarrhythmias can be caused either by a decrease in the frequency of occurrence of action potentials, or by a violation of their conduction.
The ability of some heart cells to spontaneously generate action potentials is called automatism. This ability is possessed by the cells of the sinus node, the atrial conduction system, the AV node and the His-Purkinje system. Automatism is due to the fact that after the end of the action potential (that is, in phase 4), instead of the resting potential, the so-called spontaneous (slow) diastolic depolarization is observed. Its cause is the entrance of Na + and Ca2 + ions. When, as a result of spontaneous diastolic depolarization, the membrane potential reaches a threshold, an action potential arises.
Conductivity, that is, the speed and reliability of the excitation, depends, in particular, on the characteristics of the action potential itself: the lower its slope and amplitude (in phase 0), the lower the speed and reliability of the conduction.
In many diseases and under the influence of a number of drugs, the rate of depolarization in phase 0 decreases. In addition, conductivity also depends on the passive properties of cardiomyocyte membranes (intracellular and intercellular resistance). So, the rate of conduction of excitation in the longitudinal direction (that is, along the fibers of the myocardium) is higher than in the transverse (anisotropic conduction).
During the action potential, the excitability of cardiomyocytes is sharply reduced - up to complete non-excitability. This property is called refractoriness. During the period of absolute refractoriness, no stimulus is able to excite the cell. During the period of relative refractoriness, excitement arises, but only in response to suprathreshold stimuli; the speed of the excitation is reduced. The period of relative refractoriness continues until the full recovery of excitability. An effective refractory period is also distinguished, in which excitement can arise, but is not carried out outside the cell.
DetailsAllocate two types of action potential(PD): quick(myocytes of the atria and ventricles (0.3-1 m / s), Purkinje fibers (1-4)) and slow(SA-1st order pacemaker (0.02), AV-2nd order pacemaker (0.1)).
The main types of ion channels in the heart are:
1) Fast sodium channels(blocking with tetrodotoxin) - cells of the atrial myocardium, working ventricular myocardium, Purkinje fibers, atrioventricular node (low density).
2) Calcium channels L type(antagonists verapamil and diltiazem reduce the plateau, reduce the force of cardiac contraction) - cells of the atrial myocardium, working ventricular myocardium, Purkinje fibers, cells of the sinatrial and atrioventricular nodes of automation.
3) Potassium channels
a) Abnormal straightening(rapid repolarization): cells of the atrial myocardium, working ventricular myocardium, Purkinje fibers
b) Delayed straightening(plateau) cells of the myocardium of the atria, working myocardium of the ventricles, Purkinje fibers, cells of the sinatrial and atrioventricular nodes of automation
v) forming I-current, the transient outgoing current of Purkinje fibers.
4) "Pacemaker" channels forming I f - incoming current, activated by hyperpolarization, are found in the cells of the sinus and atrioventricular nodes, as well as in the cells of Purkinje fibers.
5) Ligand-dependent channels
a) acetylcholine-sensitive potassium channels are found in the cells of the sinatrial and atrioventricular nodes of automation, the cells of the atrial myocardium
b) ATP-sensitive potassium channels are characteristic of the cells of the working myocardium of the atria and ventricles
c) calcium-activated nonspecific channels are found in the cells of the working myocardium of the ventricles and Purkinje fibers.
Action potential phases.
A feature of the action potential in the heart muscle has a pronounced plateau phase, due to which the action potential has such a long duration.
1): The "plateau" phase of the action potential. (feature of the excitation process):
AP of the myocardium in the ventricles of the heart lasts 300-350 msec (in the skeletal muscle 3-5 msec) and has an additional "plateau" phase.
PD starts with rapid depolarization of the cell membrane(from - 90 mV to +30 mV), because fast Na-channels open and sodium enters the cell. Due to the inversion of the membrane potential (+30 mV), fast Na-channels are inactivated and the sodium current is stopped.
By this time, slow Ca-channels are activated and calcium enters the cell. Due to the calcium current, depolarization continues for 300 msec and (in contrast to skeletal muscle) a "plateau" phase is formed. Then the slow Ca channels are inactivated. Rapid repolarization occurs due to the release of potassium (K +) ions from the cell through numerous potassium channels.
2) Long refractory period (a feature of the excitation process):
As long as the "plateau" phase continues, sodium channels remain inactivated. Inactivation of fast Na-channels makes the cell non-excitable ( phase of absolute refractoriness which lasts about 300 msec).
3) Tetanus in the heart muscle is impossible (a feature of the contraction process):
The duration of the absolute refractory period in the myocardium (300 msec) coincides with duration of reduction(ventricular systole 300 msec), therefore, during systole, the myocardium is not excitable, does not respond to any additional stimuli; summation of muscle contractions in the heart in the form of tetanus is impossible! The myocardium is the only muscle in the body that always contracts only in a single contraction mode (after contraction, relaxation always follows!).
