What happens during depolarization. Physiology of excitable tissues

All nervous activity functions successfully due to the alternation of phases of rest and excitability. Failures in the polarization system disrupt the electrical conductivity of the fibers. But besides nerve fibers, there are other excitable tissues - endocrine and muscle.

But we will consider the features of conductive tissues, and using the example of the process of excitation of organic cells, we will talk about the significance of the critical level of depolarization. The physiology of nervous activity is closely related to the levels of electrical charge inside and outside the nerve cell.

If one electrode is connected to the outer shell of the axon, and the other to its inner part, then a potential difference is visible. The electrical activity of nerve pathways is based on this difference.

What is resting potential and action potential?

All cells of the nervous system are polarized, that is, they have different electrical charges inside and outside a special membrane. A nerve cell always has its own lipoprotein membrane, which has the function of a bioelectrical insulator. Thanks to the membranes, a resting potential is created in the cell, which is necessary for subsequent activation.

The resting potential is maintained by ion transport. The release of potassium ions and the entry of chlorine increases the resting membrane potential.

The action potential accumulates in the depolarization phase, that is, the rise in electrical charge.

Action potential phases. Physiology

So, depolarization in physiology is a decrease in membrane potential. Depolarization is the basis for the occurrence of excitability, that is, the action potential for a nerve cell. When a critical level of depolarization is reached, no stimulus, even a strong one, is capable of causing reactions in nerve cells. There is a lot of sodium inside the axon.

This stage is immediately followed by a phase of relative excitability. A response is already possible, but only to a strong stimulus signal. Relative excitability slowly moves into the exaltation phase. What is exaltation? This is the peak of tissue excitability.

All this time, sodium activation channels are closed. And their opening will occur only when discharged. Repolarization is needed to restore the negative charge inside the fiber.

What does critical level of depolarization (CLD) mean?

So, excitability, in physiology, is the ability of a cell or tissue to respond to a stimulus and generate some kind of impulse. As we found out, cells need a certain charge - polarization - to work. The increase in charge from minus to plus is called depolarization.

After depolarization there is always repolarization. The charge inside after the excitation phase must again become negative so that the cell can prepare for the next reaction.

When the voltmeter readings are fixed at 80 - rest. It occurs after the end of repolarization, and if the device shows a positive value (greater than 0), it means that the phase reverse to repolarization is approaching the maximum level - the critical level of depolarization.

How are impulses transmitted from nerve cells to muscles?

Electrical impulses generated when the membrane is excited are transmitted along nerve fibers at high speed. The speed of the signal is explained by the structure of the axon. The axon is partially enveloped by a sheath. And between the areas with myelin there are nodes of Ranvier.

Thanks to this arrangement of the nerve fiber, a positive charge alternates with a negative one, and the depolarizing current spreads almost simultaneously along the entire length of the axon. The contraction signal reaches the muscle in a split second. An indicator such as the critical level of membrane depolarization means the point at which the peak action potential is achieved. After muscle contraction along the entire axon, repolarization begins.

What happens during depolarization?

What does such an indicator as the critical level of depolarization mean? In physiology, this means that the nerve cells are already ready to work. The proper functioning of the entire organ depends on the normal, timely change of phases of the action potential.

The critical level (CLL) is approximately 40-50 Mv. At this time, the electric field around the membrane decreases. directly depends on how many sodium channels in the cell are open. The cell at this time is not yet ready to respond, but collects electrical potential. This period is called absolute refractoriness. The phase lasts only 0.004 s in nerve cells, and in cardiomyocytes - 0.004 s.

After passing a critical level of depolarization, superexcitability occurs. Nerve cells can respond even to the action of a subthreshold stimulus, that is, a relatively weak influence of the environment.

Functions of sodium and potassium channels

So, an important participant in the processes of depolarization and repolarization is the protein ion channel. Let's figure out what this concept means. Ion channels are protein macromolecules located inside the plasma membrane. When they are open, inorganic ions can pass through them. Protein channels have a filter. Only sodium passes through the sodium duct, and only this element passes through the potassium duct.

These electrically controlled channels have two gates: one is activation and has the property of allowing ions to pass through, the other is inactivation. At a time when the resting membrane potential is -90 mV, the gate is closed, but when depolarization begins, sodium channels slowly open. An increase in potential leads to a sharp closure of the duct valves.

A factor that influences the activation of channels is the excitability of the cell membrane. Under the influence of electrical excitability, 2 types of ion receptors are triggered:

the action of ligand receptors is triggered - for chemo-dependent channels;
an electrical signal is supplied for electrically controlled channels.

When a critical level of depolarization of the cell membrane is reached, the receptors give a signal that all sodium channels need to be closed, and potassium channels begin to open.

Sodium-potassium pump

The processes of transfer of excitation impulses occur everywhere due to electrical polarization, carried out due to the movement of sodium and potassium ions. The movement of elements occurs based on the principle of ions - 3 Na + inward and 2 K + outward. This metabolic mechanism is called the sodium-potassium pump.

Depolarization of cardiomyocytes. Phases of heart contraction

Cardiac contraction cycles are also associated with electrical depolarization of conduction pathways. The contraction signal always comes from SA cells located in the right atrium and spreads along the Hiss pathway to the bundle of Thorel and Bachmann to the left atrium. The right and left branches of the Hiss bundle transmit the signal to the ventricles of the heart.

Nerve cells depolarize faster and transmit the signal due to the presence of but muscle tissue also gradually depolarizes. That is, their charge turns from negative to positive. This phase of the cardiac cycle is called diastole. All cells here are interconnected and act as one complex, since the work of the heart must be coordinated as much as possible.

When a critical level of depolarization of the walls of the right and left ventricles occurs, a release of energy is generated - the heart contracts. Then all cells repolarize and prepare for a new contraction.

Depression Verigo

In 1889, a phenomenon in physiology called Verigo's Catholic depression was described. The critical level of depolarization is the level of depolarization at which all sodium channels are already inactivated, and potassium channels work instead. If the degree of current increases even more, then the excitability of the nerve fiber decreases significantly. And the critical level of depolarization under the influence of stimuli goes off scale.

During Verigo's depression, the rate of conduction of excitation decreases and, finally, completely subsides. The cell begins to adapt by changing its functional characteristics.

Adaptation mechanism

It happens that under certain conditions the depolarizing current does not switch for a long time. This is characteristic of sensory fibers. A gradual, long-term increase in such current above the norm of 50 mV leads to an increase in the frequency of electronic pulses.

In response to such signals, the conductance of the potassium membrane increases. Slower channels are activated. As a result, the nervous tissue becomes capable of repeated responses. This is called nerve fiber adaptation.

During adaptation, instead of a large number of short signals, cells begin to accumulate and release a single strong potential. And the intervals between two reactions increase.

The electrical impulse that travels through the heart and triggers each contraction cycle is called an action potential; it represents a wave of short-term depolarization, during which the intracellular potential in each cell in turn becomes positive for a short time and then returns to its original negative level. Changes in the normal cardiac action potential have a characteristic progression over time, which for convenience is divided into the following phases: phase 0 - initial rapid depolarization of the membrane; phase 1 - rapid but incomplete repolarization; phase 2 - plateau, or prolonged depolarization, characteristic of the action potential of cardiac cells; phase 3 - final fast repolarization; phase 4 - diastole period.

During an action potential, the intracellular potential becomes positive, as the excited membrane temporarily becomes more permeable to Na + (compared to K +) , therefore, the membrane potential for some time approaches in value the equilibrium potential of sodium ions (E Na) - E N a can be determined using the Nernst relation; at extracellular and intracellular concentrations of Na + 150 and 10 mM, respectively, it will be:

However, the increased permeability to Na + persists only for a short time, so that the membrane potential does not reach E Na and returns to the resting level after the end of the action potential.

The above changes in permeability, causing the development of the depolarization phase of the action potential, arise due to the opening and closing of special membrane channels, or pores, through which sodium ions easily pass. Gating is believed to regulate the opening and closing of individual channels, which can exist in at least three conformations - open, closed and inactivated. One gate corresponding to the activation variable m in the Hodgkin-Huxley description, sodium ion currents in the membrane of the squid giant axon move rapidly to open a channel when the membrane is suddenly depolarized by a stimulus. Other gates corresponding to the inactivation variable h in the Hodgkin-Huxley description, they move more slowly during depolarization, and their function is to close the channel (Fig. 3.3). Both the steady-state distribution of gates within the channel system and the rate of their transition from one position to another depend on the level of membrane potential. Therefore, the terms time-dependent and voltage-dependent are used to describe membrane Na + conductance.

If the resting membrane is suddenly depolarized to a positive potential (for example, in a voltage-clamp experiment), the activation gate will quickly change its position to open the sodium channels, and then the inactivation gate will slowly close them (Figure 3.3). The word slow here means that inactivation takes a few milliseconds, whereas activation occurs in a fraction of a millisecond. The gates remain in these positions until the membrane potential changes again, and for all gates to return to their original resting state, the membrane must be completely repolarized to a high negative potential level. If the membrane is repolarized only to a low level of negative potential, then some inactivation gates will remain closed and the maximum number of available sodium channels that can open upon subsequent depolarization will be reduced. (The electrical activity of cardiac cells in which sodium channels are completely inactivated will be discussed below.) Complete repolarization of the membrane at the end of a normal action potential ensures that all gates return to their original state and are therefore ready for the next action potential.

Rice. 3.3. Schematic representation of membrane channels for inward ion flows at the resting potential, as well as during activation and inactivation.

On the left is the sequence of channel states at a normal resting potential of -90 mV. At rest, the inactivation gates of both the Na + channel (h) and the slow Ca 2+ /Na + channel (f) are open. During activation upon excitation of the cell, the t-gate of the Na + channel opens and the incoming flow of Na + ions depolarizes the cell, which leads to an increase in the action potential (graph below). The h-gate then closes, thus inactivating Na+ conduction. As the action potential rises, the membrane potential exceeds the more positive threshold of the slow channel potential; their activation gate (d) opens and Ca 2+ and Na + ions enter the cell, causing the development of the plateau phase of the action potential. Gate f, which inactivates Ca 2+ /Na + channels, closes much more slowly than gate h, which inactivates Na channels. The central fragment shows the behavior of the channel when the resting potential decreases to less than -60 mV. Most Na channel inactivation gates remain closed as long as the membrane is depolarized; The incoming flow of Na + that occurs when the cell is stimulated is too small to cause the development of an action potential. However, the inactivation gate (f) of the slow channels does not close and, as shown in the fragment on the right, if the cell is sufficiently excited to open the slow channels and allow slowly incoming ion flows to pass, a slow development of an action potential is possible in response.

Rice. 3.4. Threshold potential for cardiac cell excitation.

On the left is the action potential occurring at the resting potential level of -90 mV; this occurs when the cell is excited by an incoming impulse or some subthreshold stimulus that quickly lowers the membrane potential to values below the threshold level of -65 mV. On the right are the effects of two subthreshold and threshold stimuli. Subthreshold stimuli (a and b) do not reduce the membrane potential to the threshold level; therefore, no action potential occurs. The threshold stimulus (c) reduces the membrane potential exactly to the threshold level, at which an action potential then occurs.

The rapid depolarization at the onset of an action potential is caused by a powerful influx of sodium ions entering the cell (corresponding to their electrochemical potential gradient) through open sodium channels. However, first of all, sodium channels must be effectively opened, which requires rapid depolarization of a sufficiently large area of the membrane to the required level, called the threshold potential (Fig. 3.4). Experimentally, this can be achieved by passing current through the membrane from an external source and using an extracellular or intracellular stimulating electrode. Under natural conditions, the same purpose is served by local currents flowing through the membrane immediately before the propagating action potential. At the threshold potential, a sufficient number of sodium channels are open, which provides the necessary amplitude of the incoming sodium current and, consequently, further depolarization of the membrane; in turn, depolarization causes more channels to open, resulting in an increase in the incoming flow of ions, so that the depolarization process becomes regenerative. The rate of regenerative depolarization (or action potential rise) depends on the strength of the incoming sodium current, which in turn is determined by factors such as the magnitude of the Na + electrochemical potential gradient and the number of available (or non-inactivated) sodium channels. In Purkinje fibers, the maximum rate of depolarization during the development of an action potential, denoted as dV / dt max or V max, reaches approximately 500 V / s, and if this rate were maintained throughout the depolarization phase from -90 mV to +30 mV, then the change a potential of 120 mV would take about 0.25 ms. The maximum depolarization rate of the fibers of the working ventricular myocardium is approximately 200 V/s, and that of the atrial muscle fibers is from 100 to 200 V/s. (The depolarization phase of the action potential in the cells of the sinus and atrioventricular nodes differs significantly from that just described and will be discussed separately; see below.)

Action potentials with such a high rate of rise (often called fast responses) travel rapidly throughout the heart. The speed of action potential propagation (as well as Vmax) in cells with the same membrane permeability and axial resistance characteristics is determined mainly by the amplitude of the inward current flowing during the rise phase of the action potential. This is due to the fact that the local currents passing through the cells immediately before the action potential are larger in magnitude with a faster rise in potential, so the membrane potential in these cells reaches the threshold level earlier than in the case of currents of smaller magnitude (see Fig. 3.4) . Of course, these local currents flow through the cell membrane immediately after the propagating action potential has passed, but they are no longer able to excite the membrane due to its refractoriness.

Rice. 3.5. Normal action potentials and responses evoked by stimuli at different stages of repolarization.

The amplitude and increase in rate of responses evoked during repolarization depend on the level of membrane potential at which they occur. The earliest responses (a and b) occur at such a low level that they are too weak and unable to spread (gradual or local responses). Response B represents the earliest of the propagating action potentials, but its propagation is slow due to the slight increase in speed as well as the low amplitude. Response d appears just before complete repolarization, its rate of amplification and amplitude are higher than for response c, since it occurs at a higher membrane potential; however, its rate of spread becomes slower than normal. Response d is observed after complete repolarization, therefore its amplitude and depolarization rate are normal; hence, it spreads quickly. PP - resting potential.

The long refractory period after excitation of cardiac cells is due to the long duration of the action potential and the voltage dependence of the sodium channel gating mechanism. The rise phase of the action potential is followed by a period of hundreds to several hundred milliseconds during which there is no regenerative response to a repeated stimulus (Fig. 3.5). This is the so-called absolute, or effective, refractory period; it usually spans the plateau (phase 2) of the action potential. As described above, sodium channels are inactivated and remain closed during this sustained depolarization. During the repolarization of the action potential (phase 3), inactivation is gradually eliminated, so that the proportion of channels capable of reactivation constantly increases. Therefore, only a small influx of sodium ions can be elicited by the stimulus at the onset of repolarization, but such influxes will increase as the action potential continues to repolarize. If some of the sodium channels remain unexcitable, then the evoked inward Na+ flow can lead to regenerative depolarization and hence an action potential. However, the rate of depolarization, and therefore the speed of propagation of action potentials, is significantly reduced (see Fig. 3.5) and is normalized only after complete repolarization. The time during which a repeated stimulus is able to evoke such graded action potentials is called the relative refractory period. The voltage dependence of the elimination of inactivation was studied by Weidmann, who found that the rate of rise of the action potential and the possible level at which this potential is evoked are in an S-shaped relationship, also known as the membrane reactivity curve.

The low rate of rise of action potentials evoked during the relative refractory period causes their slow propagation; Such action potentials can cause several conduction disturbances, such as delay, attenuation and blocking, and can even cause excitation circulation. These phenomena are discussed later in this chapter.

In normal cardiac cells, the incoming sodium current responsible for the rapid rise of the action potential is followed by a second incoming current, smaller and slower than the sodium current, which appears to be carried primarily by calcium ions. This current is usually referred to as a slow inward current (although it is only such in comparison to the fast sodium current; other important changes, such as those observed during repolarization, are probably slower); it flows through channels which, due to their time- and voltage-dependent conductivity characteristics, have been called slow channels (see Fig. 3.3). The activation threshold for this conductance (i.e., when the activation gate d begins to open) lies between -30 and -40 mV (compare: -60 to -70 mV for sodium conductance). The regenerative depolarization caused by the fast sodium current usually activates the conduction of the slow incoming current, so that during the later rise of the action potential, current flows through both types of channels. However, the Ca 2+ current is much smaller than the maximum fast Na + current, so its contribution to the action potential is very small until the fast Na + current becomes sufficiently inactivated (i.e., after the initial rapid rise of the potential). Since the slow incoming current can only be inactivated very slowly, it contributes mainly to the plateau phase of the action potential. Thus, the plateau level shifts towards depolarization when the electrochemical potential gradient for Ca 2+ increases with increasing concentration of 0; a decrease in 0 causes the plateau level to shift in the opposite direction. However, in some cases there may be a contribution of calcium current to the rise phase of the action potential. For example, the action potential rise curve in frog ventricular myocardial fibers sometimes exhibits a bend around 0 mV, at the point where the initial fast depolarization gives way to a slower depolarization that continues until the peak of the action potential overshoot. It has been shown that the rate of slower depolarization and the magnitude of overshoot increase with increasing 0 .

In addition to their different dependence on membrane potential and time, these two types of conductivity also differ in their pharmacological characteristics. Thus, the current through fast Na + channels is reduced by tetrodotoxin (TTX), while the slow Ca 2+ current is not affected by TTX, but is enhanced by catecholamines and inhibited by manganese ions, as well as by some drugs, such as verapamil and D - 600. It seems very likely (at least in the frog heart) that most of the calcium needed to activate the proteins that contribute to each heartbeat enters the cell during the action potential through the slow inward current channel. In mammals, an available additional source of Ca 2+ for cardiac cells is its reserves in the sarcoplasmic reticulum.

MF changes occur not only directly at the points of application of the cathode and anode to the nerve fiber, but also at some distance from them, but the magnitude of these shifts decreases with distance from the electrodes. Changes in MF under the electrodes are called electrotonic (kat-electroton and an-electroton, respectively), and behind the electrodes - perielectrotonic (kat- and an-perieelectroton).

An increase in MF under the anode (passive hyperpolarization) is not accompanied by a change in the ionic permeability of the membrane, even at a high applied current. Therefore, when a direct current is closed, excitation does not occur under the anode. In contrast, a decrease in the MF under the cathode (passive depolarization) entails a short-term increase in Na permeability, which leads to excitation.

The increase in membrane permeability to Na upon threshold stimulation does not immediately reach its maximum value. At the first moment, depolarization of the membrane under the cathode leads to a slight increase in sodium permeability and the opening of a small number of channels. When, under the influence of this, positively charged Na+ ions begin to enter the protoplasm, the depolarization of the membrane increases. This leads to the opening of other Na channels, and, consequently, to further depolarization, which, in turn, causes an even greater increase in sodium permeability. This circular process, based on the so-called. positive feedback, called regenerative depolarization. It occurs only when Eo decreases to a critical level (Ek). The reason for the increase in sodium permeability during depolarization is probably due to the removal of Ca++ from the sodium gate when electronegativity occurs (or electropositivity decreases) on the outer side of the membrane.

The increased sodium permeability stops after tenths of a millisecond due to sodium inactivation mechanisms.

The rate at which membrane depolarization occurs depends on the strength of the irritating current. At weak strength, depolarization develops slowly, and therefore, for an AP to occur, such a stimulus must have a long duration.

The local response that occurs with subthreshold stimuli, like AP, is caused by an increase in sodium permeability of the membrane. However, under a threshold stimulus, this increase is not large enough to cause a process of regenerative depolarization of the membrane. Therefore, the onset of depolarization is stopped by inactivation and an increase in potassium permeability.

To summarize the above, we can depict the chain of events developing in a nerve or muscle fiber under the cathode of the irritating current as follows: passive depolarization of the membrane ---- increased sodium permeability --- increased flow of Na into the fiber --- active depolarization of the membrane -- local answer --- excess Ec --- regenerative depolarization --- action potential (AP).

What is the mechanism for the occurrence of excitation under the anode during opening? At the moment the current is turned on under the anode, the membrane potential increases - hyperpolarization occurs. At the same time, the difference between Eo and Ek grows, and in order to shift the MP to a critical level, greater force is needed. When the current is turned off (opening), the original level of Eo is restored. It would seem that at this time there are no conditions for the occurrence of excitement. But this is only true if the current lasted a very short time (less than 100 ms). With prolonged exposure to current, the critical level of depolarization itself begins to change - it grows. And finally, a moment arises when the new Ek becomes equal to the old level Eo. Now, when the current is turned off, conditions for excitation arise, because the membrane potential becomes equal to the new critical level of depolarization. The PD value when opening is always greater than when closing.

Dependence of the threshold strength of a stimulus on its duration. As already indicated, the threshold strength of any stimulus, within certain limits, is inversely related to its duration. This dependence manifests itself in a particularly clear form when rectangular direct current shocks are used as a stimulus. The curve obtained in such experiments was called the “force-time curve.” It was studied by Goorweg, Weiss and Lapik at the beginning of the century. From an examination of this curve, it follows first of all that a current below a certain minimum value or voltage does not cause excitation, no matter how long it lasts. The minimum current strength capable of causing excitation is called rheobase by Lapik. The shortest time during which an irritating stimulus must act is called useful time. Increasing the current leads to a shortening of the minimum stimulation time, but not indefinitely. With very short stimuli, the force-time curve becomes parallel to the coordinate axis. This means that with such short-term irritations, excitation does not occur, no matter how great the strength of irritation.

Determining useful time is practically difficult, since the point of useful time is located on a section of the curve that turns into parallel. Therefore, Lapik proposed using the useful time of two rheobases - chronaxy. Its point is located on the steepest section of the Goorweg-Weiss curve. Chronaximetry has become widespread both experimentally and clinically for diagnosing damage to motor nerve fibers.

It was already indicated above that depolarization of the membrane leads to the onset of two processes: one fast, leading to an increase in sodium permeability and the occurrence of AP, and the other slow, leading to inactivation of sodium permeability and the end of excitation. With a steep increase in stimulus, Na activation has time to reach a significant value before Na inactivation develops. In the case of a slow increase in current intensity, inactivation processes come to the fore, leading to an increase in the threshold and a decrease in the AP amplitude. All agents that enhance or accelerate inactivation increase the rate of accommodation.

Accommodation develops not only when excitable tissues are irritated by electric current, but also when mechanical, thermal and other stimuli are used. Thus, a quick blow to a nerve with a stick causes its excitation, but when slowly pressing on the nerve with the same stick, no excitation occurs. An isolated nerve fiber can be excited by rapid cooling, but not by slow cooling. A frog will jump out if thrown into water with a temperature of 40 degrees, but if the same frog is placed in cold water and slowly heated, the animal will cook, but will not react by jumping to a rise in temperature.

In the laboratory, an indicator of the speed of accommodation is the smallest slope of the current increase at which the stimulus still retains the ability to cause AP. This minimum slope is called the critical slope. It is expressed either in absolute units (mA/sec) or in relative ones (as the ratio of the threshold strength of that gradually increasing current, which is still capable of causing excitation, to the rheobase of a rectangular current impulse).

Figure 4. Goorweg-Weiss force-time curve. Designations: X - chronaxy, PV - useful time, P - rheobase, 2р - force of two rheobases

The "all or nothing" law. When studying the dependence of the effects of stimulation on the strength of the applied stimulus, the so-called "all or nothing" law.

According to this law, under threshold stimuli they do not cause excitation ("nothing"), but under threshold stimuli, excitation immediately acquires a maximum value ("all"), and no longer increases with further intensification of the stimulus.

This pattern was initially discovered by Bowditch while studying the heart, and was later confirmed in other excitable tissues. For a long time, the "all or nothing" law was incorrectly interpreted as a general principle of the response of excitable tissues. It was assumed that “nothing” meant a complete absence of response to a subthreshold stimulus, and “everything” was considered as a manifestation of the complete exhaustion of the excitable substrate’s potential capabilities. Further studies, especially microelectrode studies, showed that this point of view is not true. It turned out that at subthreshold forces, local non-propagating excitation (local response) occurs. At the same time, it turned out that “everything” also does not characterize the maximum that PD can achieve. In a living cell, there are processes that actively stop membrane depolarization. If the incoming Na current, which ensures the generation of AP, is weakened by any influence on the nerve fiber, for example, drugs, poisons, then it ceases to obey the “all or nothing” rule - its amplitude begins to gradually depend on the strength of the stimulus. Therefore, “all or nothing” is now considered not as a universal law of the response of an excitable substrate to a stimulus, but only as a rule, characterizing the features of the occurrence of AP in given specific conditions.

The concept of excitability. Changes in excitability when excited. Excitability parameters.

Excitability is the ability of a nerve or muscle cell to respond to stimulation by generating PD. The main measure of excitability is usually rheobase. The lower it is, the higher the excitability, and vice versa. This is due to the fact that, as we said earlier, the main condition for the occurrence of excitation is the achievement of a critical level of depolarization by the MF (Eo<= Ек). Поэтому мерилом возбудимости является разница между этими величинами (Ео - Ек). Чем меньше эта разница, тем меньшую силу надо приложить к клетке, чтобы сдвинуть мембранный потенциал до критического уровня, и, следовательно, тем больше возбудимость клетки.

Pflueger also showed that excitability is a variable quantity. The cathode increases excitability, the anode decreases it. Let us recall that these changes in excitability under the electrodes are called electrotonic. The Russian scientist Verigo showed that with prolonged exposure to direct current on the tissue, or under the influence of strong stimuli, these electrotonic changes in excitability are perverted - under the cathode, the initial increase in excitability is replaced by its decrease (the so-called cathodic depression develops), and under the anode, the reduced excitability gradually increases . The reason for these changes in excitability at the poles of direct current is due to the fact that the value of Ek changes with prolonged exposure to the stimulus. Under the cathode (and during excitation), Ek gradually moves away from the MP and decreases, so that a moment comes when the difference E0-Ek becomes greater than the initial one. This leads to a decrease in tissue excitability. On the contrary, under the anode Ek tends to increase, gradually approaching Eo. In this case, excitability increases, as the initial difference between Eo and Ek decreases.

The reason for the change in the critical level of depolarization under the cathode is the inactivation of sodium permeability due to prolonged depolarization of the membrane. At the same time, permeability to K increases significantly. All this leads to the fact that the cell membrane loses its ability to respond to irritating stimuli. The same changes in the membrane underlie the already discussed phenomenon of accommodation. Under the anode, under the action of current, the inactivation phenomena are reduced.

Changes in excitability when excited. The occurrence of AP in a nerve or muscle fiber is accompanied by multiphase changes in excitability. To study them, a nerve or muscle is exposed to two short electrical stimuli following each other at a certain interval. The first is called annoying, the second - testing. Registration of PDs arising in response to these irritations made it possible to establish important facts.

Figure 5. Changes in excitability during arousal.

Designations: 1- increased excitability during a local response; 2 – absolute refractoriness; 3- relative refractoriness; 4- supernormal excitability during trace depolarization; 5 – subnormal excitability during trace hyperpolarization.

During a local response, excitability is increased, since the membrane is depolarized and the difference between E0 and Ek falls. The period of occurrence and development of the peak of the action potential corresponds to the complete disappearance of excitability, called absolute refractoriness (unimpressibility). At this time, the testing stimulus is not capable of causing a new PD, no matter how strong this irritation is. The duration of absolute refractoriness approximately coincides with the duration of the ascending branch of AP. In fast-conducting nerve fibers it is 0.4-0.7 ms. In the fibers of the heart muscle - 250-300 ms. Following absolute refractoriness, the phase of relative refractoriness begins, which lasts 4-8 ms. It coincides with the AP repolarization phase. At this time, excitability gradually returns to its original level. During this period, the nerve fiber is able to respond to strong stimulation, but the amplitude of the action potential will be sharply reduced.

According to the Hodgkin-Huxley ion theory, absolute refractoriness is caused first by the presence of maximum sodium permeability, when a new stimulus cannot change or add anything, and then by the development of sodium inactivation, which closes Na channels. This is followed by a decrease in sodium inactivation, as a result of which the ability of the fiber to generate AP is gradually restored. This is a state of relative refractoriness.

The relative refractory phase is replaced by a phase of increased (supernormal) excitability And, coinciding in time with the period of trace depolarization. At this time, the difference between Eo and Ek is lower than the original one. In motor nerve fibers of warm-blooded animals, the duration of the supernormal phase is 12-30 ms.

The period of increased excitability is replaced by a subnormal phase, which coincides with trace hyperpolarization. At this time, the difference between the membrane potential (Eo) and the critical level of depolarization (Ek) increases. The duration of this phase is several tens or hundreds of ms.

Lability. We examined the basic mechanisms of the occurrence and propagation of a single excitation wave in nerve and muscle fibers. However, in the natural conditions of an organism’s existence, not single, but rhythmic volleys of action potentials pass through nerve fibers. In sensitive nerve endings located in any tissue, rhythmic discharges of impulses arise and spread along the afferent nerve fibers extending from them, even with very short-term stimulation. Likewise, from the central nervous system along the efferent nerves there is a flow of impulses to the periphery to the executive organs. If the executive organ is skeletal muscles, then flashes of excitation occur in them in the rhythm of impulses arriving along the nerve.

The frequency of impulse discharges in excitable tissues can vary widely depending on the strength of the applied stimulation, the properties and condition of the tissue, and the speed of individual acts of excitation in a rhythmic series. To characterize this speed, the concept of lability was formulated. By lability, or functional mobility, he understood a greater or lesser rate of occurrence of those elementary reactions that accompany excitation. A measure of lability is the largest number of action potentials that an excitable substrate is capable of reproducing per unit time in accordance with the frequency of applied stimulation.

Initially it was assumed that the minimum interval between impulses in a rhythmic series should correspond to the duration of the absolute refractory period. Precise studies, however, have shown that with a repetition frequency of stimuli with such an interval, only two impulses arise, and the third drops out due to developing depression. Therefore, the interval between pulses should be slightly greater than the absolute refractory period. In the motor nerve cells of warm-blooded animals, the refractory period is about 0.4 msec, and the potential maximum rhythm should be equal to 2500/sec, but in fact it is about 1000/sec. It should be emphasized that this frequency significantly exceeds the frequency of impulses passing through these fibers under physiological conditions. The latter is about 100/sec.

The fact is that usually in natural conditions the tissue works with the so-called optimal rhythm. To transmit impulses with such a rhythm, a great force of stimulation is not required. Studies have shown that the frequency of stimulation and the rheobase of the current capable of causing nerve impulses with such a frequency are in a peculiar relationship: the rheobase first falls as the frequency of the impulses increases, then increases again. The optimum is for nerves in the range from 75 to 150 pulses/sec, for muscles - 20-50 pulses/sec. This rhythm, unlike others, can be reproduced very persistently and for a long time by excitable formations.

Thus, we can now name all the main parameters of tissue excitability that characterize its properties: rheobase, useful time (chronaxy), critical slope, lability. All of them, except the last one, are in inversely proportional relationships with excitability.

The concept of "parabiosis". Lability is a variable value. It can change depending on the state of the nerve or muscle, depending on the strength and duration of the irritations falling on them, on the degree of fatigue, etc. For the first time, I studied the change in the lability of a nerve when it is exposed to first chemical and then electrical stimuli. He discovered a natural decrease in the lability of a nerve section altered by a chemical agent (ammonia), called this phenomenon “parabiosis” and studied its patterns. Parabiosis is a reversible condition, which, however, with the deepening of the action of the agent causing it, can become irreversible.

Vvedensky considered parabiosis as a special state of persistent, unfluctuating excitation, as if frozen in one section of the nerve fiber. Indeed, the parabiotic site is negatively charged. Vvedensky considered this phenomenon to be a prototype of the transition of excitation to inhibition in nerve centers. In his opinion, parabiosis is the result of overexcitation of a nerve cell by too much or too frequent stimulation.

The development of parabiosis occurs in three stages: equalizing, paradoxical and inhibitory. Initially, due to a decrease in accommodation, individual current pulses of low frequency, provided they are of sufficient strength, no longer produce 1 pulse, but 2,3 or even 4. At the same time, the threshold of excitability increases, and the maximum rhythm of excitation progressively decreases. As a result, the nerve begins to respond to impulses of both low and high frequencies with the same frequency of discharges, which is closest to the optimal rhythm for this nerve. This is the equalizing phase of parabiosis. At the next stage of development of the process, in the region of threshold intensities of stimulation, the reproduction of a rhythm close to optimal is still preserved, and the tissue either does not respond to frequent impulses at all, or responds with very rare waves of excitation. This is a paradoxical phase.

Then the ability of the fiber for rhythmic wave activity decreases, the amplitude of the AP also decreases, and its duration increases. Any external influence reinforces the state of inhibition of the nerve fiber and at the same time inhibits itself. This is the last, inhibitory phase of parabiosis.

Currently, the described phenomenon is explained from the perspective of the membrane theory by a violation of the mechanism of increasing sodium permeability and the appearance of prolonged sodium inactivation. As a result, Na channels remain closed, it accumulates in the cell and the outer surface of the membrane retains a negative charge for a long time. This prevents new irritation by lengthening the refractory period. When approaching a site of parabiosis with frequently successive APs, the inactivation of sodium permeability caused by the altering agent is added to the inactivation that accompanies the nerve impulse. As a result, excitability is reduced so much that the conduction of the next impulse is completely blocked.

Metabolism and energy during excitement. When excitation occurs and occurs in nerve cells and muscle fibers, metabolism increases. This is manifested both in a number of biochemical changes occurring in the membrane and protoplasm of cells, and in an increase in their heat production. It has been established that when excited, the following occurs: increased breakdown in cells of energy-rich compounds - ATP and creatine phosphate (CP), increased processes of breakdown and synthesis of carbohydrates, proteins and lipids, increased oxidative processes, leading in combination with glycolysis to the resynthesis of ATP and CP, synthesis and destruction of acetylcholine and norepinephrine, other mediators, increased synthesis of RNA and proteins. All these processes are most pronounced during the period of restoration of the membrane state after PD.

In nerves and muscles, each wave of excitation is accompanied by the release of two portions of heat, of which the first is called initial, and the second - delayed heat. The initial heat generation occurs at the moment of excitation and constitutes an insignificant part of the total heat production (2-10%) during excitation. It is assumed that this heat is associated with those physicochemical processes that develop at the moment of generation of PD. Delayed heat generation occurs over a longer period of time, lasting many minutes. It is associated with those chemical processes that occur in the tissue following a wave of excitation, and, in the figurative expression of Ukhtomsky, constitute the “metabolic tail of the comet of excitation.”

Carrying out stimulation. Classification of nerve fibers.

As soon as an AP occurs at any point in a nerve or muscle fiber and this area acquires a negative charge, an electric current arises between the excited and neighboring resting sections of the fiber. In this case, the excited section of the membrane acts on neighboring sections as a direct current cathode, causing their depolarization and generating a local response. If the magnitude of the local response exceeds the Ec of the membrane, PD occurs. As a result, the outer surface of the membrane becomes negatively charged in the new area. In this way, the excitation wave propagates along the entire fiber at a speed of about 0.5-3 m/sec.

Laws of conduction of excitation along nerves.

1. The law of physiological continuity. Cutting, ligating, as well as any other impact that disrupts the integrity of the membrane (physiological, and not just anatomical), creates non-conductivity. The same thing occurs with thermal and chemical influences.

2. Law of bilateral conduction. When irritation is applied to a nerve fiber, excitation spreads along it in both directions (along the surface of the membrane - in all directions) at the same speed. This is proven by the experience of Babukhin and others like him.

3. Law of isolated conduction. In a nerve, impulses propagate along each fiber in isolation, that is, they do not pass from one fiber to another. This is very important as it ensures precise addressing of the pulse. This is due to the fact that the electrical resistance of the myelin and Schwann sheaths, as well as the intercellular fluid, is much greater than the resistance of the nerve fiber membrane.

The mechanisms and speed of excitation in the non-pulpal and pulpal nerve fibers are different. In the pulpless excitation extends continuously along the entire membrane from one excited area to another located nearby, as we have already discussed.

In myelin fibers, excitation spreads only spasmodically, jumping over areas covered with the myelin sheath (saltatory). Action potentials in these fibers arise only at the nodes of Ranvier. At rest, the outer surface of the excitable membrane of all nodes of Ranvier is positively charged. At the moment of excitation, the surface of the first interception becomes negatively charged with respect to the adjacent second interception. This leads to the emergence of a local electric current that flows through the intercellular fluid, membrane and axoplasm surrounding the fiber from interception 2 to 1. The current emerging through interception 2 excites it, causing the membrane to recharge. Now this area can excite the next one, etc.

Jumping of the AP over the interinterceptual area is possible because the amplitude of the AP is 5-6 times greater than the threshold required to excite not only the next one, but also 3-5 interceptions. Therefore, microdamage to the fiber in the interinterceptor areas or in more than one interception does not stop the functioning of the nerve fiber until the regenerative phenomena involve 3 or more adjacent Schwann cells.

The time required for the transfer of excitation from one interception to another is the same for fibers of different diameters, and is 0.07 ms. However, since the length of the interstitial sections is different and proportional to the diameter of the fiber, in myelinated nerves the speed of nerve impulses is directly proportional to their diameter.

Classification of nerve fibers. The electrical response of an entire nerve is the algebraic sum of the PD of its individual nerve fibers. Therefore, on the one hand, the amplitude of the electrical impulses of the whole nerve depends on the strength of the stimulus (as it increases, more and more fibers are involved), and secondly, the total action potential of the nerve can be divided into several separate oscillations, the reason for which is the unequal speed of impulse conduction along the different fibers that make up the whole nerve.

Currently, nerve fibers are usually divided into three main types based on the speed of excitation, the duration of various phases of action activity, and structure.

Type A fibers are divided into subgroups (alpha, beta, gamma, delta). They are covered with a myelin sheath. Their conduction speed is the highest - 70-120 m/sec. These are motor fibers from the motor neurons of the spinal cord. The remaining type A fibers are sensitive.

Type B fibers are myelinated, predominantly preganglionic. Conduction speed - 3-18 m/sec.

Type C fibers are pulpless, with a very small diameter (2 microns). The speed of conduction is no more than 3 m/sec. These are most often postganglionic fibers of the sympathetic nervous system.

GENERAL PHYSIOLOGY

CENTRAL NERVOUS SYSTEM

The physiology of the central nervous system (CNS) is the most complex, but at the same time the most responsible chapter of physiology, since in higher mammals and humans the nervous system performs the function of connecting parts of the body with each other, their relationship and integration, on the one hand, and the function connections between environmental agents and certain manifestations of the body’s activity, on the other. The successes of modern science in deciphering the entire complexity of the nervous system are based on the recognition of a single mechanism of its functioning - the reflex.

Reflexes are all acts of the body that occur in response to irritation of receptors and are carried out with the participation of the central nervous system. The idea of a reflex was first formulated by Descartes and developed by Sechenov, Pavlov, and Anokhin. Each reflex is carried out thanks to the activity of certain structural formations of the nervous system. However, before we analyze the structural features of the reflex arc, we must get acquainted with the structure and properties of the functional unit of the nervous system - the nerve cell, neuron.

Structure and functions of a neuron. Back in the last century, Ramon y Cajal discovered that any nerve cell has a body (soma) and processes, which, according to structural features and function, are divided into dendrites and axons. A neuron always has only one axon, but there can be a lot of dendrites. In 1907, Sherrington described the ways neurons interact with each other and introduced the concept of synapse. After Ramon y Cajal showed that dendrites perceive stimulation and the axon sends impulses, the idea was formed that the main function of a neuron is perception. processing and sending information to another nerve cell or to a working organ (muscle, gland).

The structure and size of neurons vary greatly. Their diameter can range from 4 microns (cerebellar granule cells) to 130 microns (Betz giant pyramidal cells). The shape of neurons is also varied.

Nerve cells have very large nuclei that are functionally and structurally connected to the cell membrane. Some neurons are multinucleated, for example, neurosecretory cells of the hypothalamus or during neuronal regeneration. In the early postnatal period, neurons can divide.

In the cytoplasm of the neuron, the so-called Nissl's substance is a granule of the endoplasmic reticulum rich in ribosomes. There is a lot of it around the core. Under the cell membrane, the endoplasmic reticulum forms cisterns responsible for maintaining the K+ concentration under the membrane. Ribosomes are colossal protein factories. The entire protein of a nerve cell is renewed in 3 days, and even faster when the function of the neuron increases. The agranular reticulum is represented by the Golgi apparatus, which seems to surround the entire nerve cell from the inside. It contains lysosomes containing various enzymes and vesicles with mediator granules. The Golgi apparatus takes an active part in the formation of vesicles with the mediator.

Both in the cell body and in the processes there are many mitochondria, the energy stations of the cell. These are mobile organelles that, due to actomyosin, can move to where energy is needed in the cell for its activity.

LAWS OF DC ACTION ON

EXCITABLE TISSUE.

Polar law of current action. When a nerve or muscle is irritated by direct current, excitation occurs at the moment of closing the direct current only under the cathode, and at the moment of opening - only under the anode, and the threshold of the closing shock is less than the breaking shock. Direct measurements have shown that the passage of electrical current through a nerve or muscle fiber primarily causes a change in the membrane potential under the electrodes. In the area of application to the surface of the anode tissue (+), the positive potential on the outer surface of the membrane increases, i.e. In this area, hyperpolarization of the membrane occurs, which does not contribute to excitation, but, on the contrary, prevents it. In the same area where the cathode (-) is attached to the membrane, the positive potential of the outer surface decreases, depolarization occurs, and if it reaches a critical value, an AP occurs in this place.

MF changes occur not only directly at the points of application of the cathode and anode to the nerve fiber, but also at some distance from them, but the magnitude of these shifts decreases with distance from the electrodes. Changes in MP under the electrodes are called electrotonic(respectively cat-electroton and an-electroton), and behind the electrodes - perielectrotonic(cat- and an-perieelectroton).

The increase in membrane permeability to Na upon threshold stimulation does not immediately reach its maximum value. At the first moment, depolarization of the membrane under the cathode leads to a slight increase in sodium permeability and the opening of a small number of channels. When, under the influence of this, positively charged Na+ ions begin to enter the protoplasm, the depolarization of the membrane increases. This leads to the opening of other Na channels, and, consequently, to further depolarization, which, in turn, causes an even greater increase in sodium permeability. This circular process, based on the so-called. positive feedback, called regenerative depolarization. It occurs only when E o decreases to a critical level (E k). The reason for the increase in sodium permeability during depolarization is probably associated with the removal of Ca++ from the sodium gate when electronegativity occurs (or electropositivity decreases) on the outer side of the membrane.

The increased sodium permeability stops after tenths of a millisecond due to sodium inactivation mechanisms.

To summarize the above, we can depict the chain of events developing in a nerve or muscle fiber under the cathode of the irritating current as follows: passive depolarization of the membrane ---- increased sodium permeability --- increased flow of Na into the fiber --- active depolarization of the membrane -- local response --- excess Ec --- regenerative depolarization --- action potential (AP).

Dependence of threshold stimulus strength on its duration. As already indicated, the threshold strength of any stimulus, within certain limits, is inversely related to its duration. This dependence manifests itself in a particularly clear form when rectangular direct current shocks are used as a stimulus. The curve obtained in such experiments was called the “force-time curve.” It was studied by Goorweg, Weiss and Lapik at the beginning of the century. From an examination of this curve, it follows first of all that a current below a certain minimum value or voltage does not cause excitation, no matter how long it lasts. The minimum current strength capable of causing excitation is called rheobase by Lapik. The shortest time during which an irritating stimulus must act is called useful time. Increasing the current leads to a shortening of the minimum stimulation time, but not indefinitely. With very short stimuli, the force-time curve becomes parallel to the coordinate axis. This means that with such short-term irritations, excitation does not occur, no matter how great the strength of irritation.

Dependence of the threshold on the steepness of the increase in stimulus strength. The threshold value for irritation of a nerve or muscle depends not only on the duration of the stimulus, but also on the steepness of the increase in its strength. The irritation threshold has the smallest value for rectangular current impulses, characterized by the fastest possible increase in current. If, instead of such stimuli, linearly or exponentially increasing stimuli are used, the thresholds turn out to be increased and the more slowly the current increases, the greater. When the slope of the current increase decreases below a certain minimum value (the so-called critical slope), the PD does not occur at all, no matter to what final strength the current increases.

This phenomenon of adaptation of excitable tissue to a slowly increasing stimulus is called accommodation. The higher the rate of accommodation, the more steeply the stimulus must increase in order not to lose its irritating effect. Accommodation to a slowly increasing current is due to the fact that during the action of this current in the membrane processes have time to develop that prevent the occurrence of AP.

In the laboratory, an indicator of the speed of accommodation is the smallest slope of the current increase at which the stimulus still retains the ability to cause AP. This minimum slope is called critical slope. It is expressed either in absolute units (mA/sec) or in relative ones (as the ratio of the threshold strength of that gradually increasing current, which is still capable of causing excitation, to the rheobase of a rectangular current impulse).

The "all or nothing" law. When studying the dependence of the effects of stimulation on the strength of the applied stimulus, the so-called "all or nothing" law. According to this law, under threshold stimuli they do not cause excitation ("nothing"), but under threshold stimuli, excitation immediately acquires a maximum value ("all"), and no longer increases with further intensification of the stimulus.

The concept of excitability. Changes in excitability when excited.

Static polarization– the presence of a constant potential difference between the outer and inner surfaces of the cell membrane. At rest, the outer surface of the cell is always electropositive relative to the inner one, i.e. polarized. This potential difference, equal to ~60 mV, is called resting potential, or membrane potential (MP). Four types of ions take part in the formation of potential:

sodium cations (positive charge),
potassium cations (positive charge),
chlorine anions (negative charge),
anions of organic compounds (negative charge).

In extracellular fluid high concentration of sodium and chlorine ions, in intracellular fluid– potassium ions and organic compounds. In a state of relative physiological rest, the cell membrane is well permeable to potassium cations, slightly less permeable to chlorine anions, practically impermeable to sodium cations and completely impermeable to anions of organic compounds.

At rest, potassium ions, without energy expenditure, move to an area of lower concentration (to the outer surface of the cell membrane), carrying with them a positive charge. Chlorine ions penetrate into the cell, carrying a negative charge. Sodium ions continue to remain on the outer surface of the membrane, further increasing the positive charge.

Depolarization– shift of MP towards its decrease. Under the influence of irritation, “fast” sodium channels open, as a result of which Na ions enter the cell like an avalanche. The transition of positively charged ions into the cell causes a decrease in the positive charge on its outer surface and an increase in it in the cytoplasm. As a result of this, the transmembrane potential difference is reduced, the MP value drops to 0, and then, as Na continues to enter the cell, the membrane is recharged and its charge is inverted (the surface becomes electronegative with respect to the cytoplasm) - an action potential (AP) occurs. The electrographic manifestation of depolarization is spike or peak potential.

During depolarization, when the positive charge carried by Na ions reaches a certain threshold value, a bias current arises in the voltage sensor of the ion channels, which “slams” the gate and “locks” (inactivates) the channel, thereby stopping further entry of Na into the cytoplasm. The channel is “closed” (inactivated) until the initial MP level is restored.

Repolarization– restoration of the initial level of MP. In this case, sodium ions stop penetrating into the cell, the permeability of the membrane for potassium increases, and it quickly leaves it. As a result, the charge of the cell membrane approaches the original one. The electrographic manifestation of repolarization is negative trace potential.

Hyperpolarization– increase in MP level. Following the restoration of the initial value of MP (repolarization), there is a short-term increase in comparison with the resting level, due to an increase in the permeability of potassium channels and channels for Cl. In this regard, the membrane surface acquires an excess positive charge compared to the norm, and the MP level becomes slightly higher than the original one. The electrographic manifestation of hyperpolarization is positive trace potential. This ends the single cycle of excitation.