The Physiology of Transport Substances in the Blood (Sodium)

   

By Professor Marcel Uluitu, M.D. Ph.D.

Spiru Haret University

Bucharest, Romania

 

Co-Authored by Diana Popa (Uluitu), M.D.

Department of Microbiology, Immunology and Molecular Genetics

University of Kentucky, Lexington, Kentucky, USA

 

[Editor’s Note: This paper is presented as Part IV of a series of chapters from the new book “The Physiology of Transport Substances in the Blood (Sodium)”; subsequent chapters will be featured in upcoming issues of this Journal. This segment features Chapter Five]

 

Chapter 5

Endocellular Compartment

         5.1. Short presentation.
It consists of all parenchymal cells and of those supporting the body. Cell (Hooke, 1665) is "the unity of biological activity capable of autoreproduction in an environment free of other systems alive" in the current acceptance (Loewy and Siekevitz, 1963 cit. 68), an extension of the cellular theory of Schleiden and Schwann, 1935 .

The cell is bordered by a polarized membrane with a selective permeability which separates it from the extracellular environment. Its content - cytoplasm - is divided by endocellular membranes in which are included organic cellular and genetic centers, the nucleus.The cell organites include mitochondria, Golgi apparatus, lysosomes, plastides, various pigments, vacuoles, endoplasmic reticulum, ribosomes, cytoplasmic connections, microtubules. The Eukaryota membrane (68) is a thin , non- rigid structure , to cover the cell and mediates its interaction with cellular environement (71). It is composed of ectoplasm, fine-grained superficial layer  and more consistent endoplasm. Cell membrane has an average thickness of 7.5 A. It consists of proteins, fat and carbohydrates. Plasmalema is a semi permeable selective structure. At its level there take place processes of transport some of them which do not need metabolic energy , as diffusion, osmosis, facilitated diffusion and endergonic transport processes (active transport, endocytosis, exocytosis). The cells are polarized, have a potential electric and all respond to external stimuli through the cell membrane.

 

 

       5.2. Cell types.

 

The cells are divided into: non excitable, excitable and autoexcitable, classification which  takes into account: (1) their ability to respond to stimuli with a wave of depolarisation which is propagated along excitable  cell structures and (2) the absence of propagation of depolarisation in non excitable ones.
Non excitable group are: hepatocytes,  connective cells , epithelial cells, glandular cells, macrophages, cillias cells, glia cells . These modify the membrane potential by stimulation , but do not transmit the stimulus, as a potential of action. The ionic flux has low amplitude and produces specific cellular response.
Excitable cells include nervous and muscular cells. In these cells permeability changes, depolarisation of membranes, result in large variations of electrochemical potential  propagating as potential of action through these structures.
Autoexcitable cells are represented by the excitoconductor system (51, 116, 78) and by some neurons.The cells of the sinoatrial nodule develop normal rhythm impulses: internodule ways nodule transmit stimuli to the atrio-ventricular nodule.

From here , through the  Hiss bundle, the stimulus passes  into the Purkinje network.The autoexcitabile nerve cells are located  in the brain at the level of the respiratory center.
Cells with similar function and form held together by a support matrix form a tissue. Support matrix is secreted by parenchymal cells. Tissue cells having the same function form part of an organ. In the tissue there is the intercellular fluid as an element of structure and not as a floating medium for cells .The intercellular fluid  changes and is removed with difficulty, which makes tissue not to be a  suspension cell. Tissues are classified in epithelial, connective tissue, muscle, nervous, blood, expressing their dominant position.

 

 

         5.3. Excitability
Depends on the presence of various  monovalent and bivalent ions. Analyses regarding the relationship between living organisms and the environment  have emerged already in the 17th century. Glisson (1587 - 1677)  notes its general characteristic, J. Brown (1725 - 1788) also includes interactions between the internal organs.
At present, "excitability is defined as the ability to react with energy consumption to changes in the external environment and internal cells (68, 78) in their efforts to preserve their genetic condition."

      The response expresses stimulus conversion of energy to biological  energy and is in itself an exchange of information between cells and the modification of the environment elements.  
To provoke a response, the stimulus must fulfil  certain conditions: threshold intensity producing the cell responses, to  act for a measurable time interval, to have a certain rapidity , to have a time necessary to restore the structure of repetitive stimuli.
Excitability depends on the  resting potential, on the intensity of cellular metabolic processes, on the  physical-chemical status and on the chemical composition of the extracellular environment (covered extensively in the previous chapters) and speed recovery of the polarization.

Plants respond by: growth, Turgor (mimosa), tropisms (phototropism). The animal body responds as a whole, coordinated and integrated by the activity of the nervous system, ensuring promptness of response and that of the endocrine system, through  which the response to stimuli is prolonged. Multicellular  animals respond to stimuli by muscle movements, secretions, emission of light, electrical discharge,  complex reflex responses. In higher animals, the reflex arc involving the nervous system by the receiving areas, nervous pathways, peripheral effector areas, cellular responses by white blood cells, ciliated epithelial cells, etc.. The  adaptative response follows within the limit of variation around a genetical average rate ,compatible with life.

The response of integral or fragmentary receiver structures can be recorded and quantified as physical magnitudes (electrical, mechanical, metric, vegetative, pressional, secretive, exocrine or endocrine, metabolic processes intensity), psychological (psychic functions, psychic aptitude, behavior, psychological adjustment, social performance, etc.). The integrated answer involves the body's internal communication between the three spaces separated by the known biological membranes. The parenchymal cells prepare their envirommrnt (basic substance or their own extracellular matrix) of reactive elements ,compatible to the functional specific faetures (111, 21). The response of the body is developed with the participation of mono-and bivalent electrolytes present in the three spaces, in concentrations the  characteristic to each.

 

 

         5.4 Cell membrane.
The cell membrane (5) represents cell cover, ensuring the separation of the cytosole from the extracellular environment, mediates cell relations with elements of the same type of information, through informative connections of electrical nature and by metabolite products. At her level there are  selective transport and excitability processes. The cell membrane structure is  dynamic, fluid, semipermeable. All membranes are made up of lipids, carbohydrates and poteins. Lipids are the major component. It is a film of 5nm thickness, with 2 layers, where the proteins are included. .

Carbohydrates are located on the external side of the membrane. They are rich in  anionic groups and interact with the elements of the interstitium.The membrane proteins ensure cell excitability and at the same time the transport of soluble substances (56). Protein molecules are dissolved in the two-layered lipids  (5). They interact with the space matrix. They ensure the transport of substances involved in excitability and the connection with the cell cytoskeleton of neighboring cells (78). There are especially glycoproteins (78, 131). It describes two types of proteins (78): the integral proteins, which cross the entire thickness of the membrane, and peripheral proteins (2, 5) attached to the surface of the membrane. Integral protein are structural elements, forming  ionic  channels: for water, Na, K, Ca, acetylcholine.

         5.4.1. Ionic  channels.
Na channels (2, 185) have  approx. 0.35 nm. They  open on both sides of the cell membrane (Fig.16). On the external face there is the  opening orifice called "por" or activation gate.Orifice  on the face endocellular is called inactivation gate(3). The Na channel is formed (78) of a single unique peptide, rich in carbohydrate residues and sialic acid with many anionic groups (2.5). From the molecular point of view, the Na channel has three homologue, unidentical subunits,,,. The  group is involved in the activation of the gate with the other two (78,11,6). Na channels have two transmembrane domains, with the COO and Na groups  situated intracellularly (78). They are structured as a pattern made up of  the helix  and a  sheet , antiparallel bound by two bridges of SH. On the extracellular face there are glycosylates residues rich in anionice sites , which explains (140) the local accumulation of Na⁺ cations around the pole activator. The inside of the Na channel is rich in anionic terminal polar groups of aminoacids. They also have in their composition glicosylates and sugars : N-acetyl hexozamine, N-acetylneuraminic acid (55). Na channels have the ability to select the Na⁺ ions from a mixture of different cations. Na channels are surrounded by areas with hydrophobia Lipid structures , by means of which some physical properties of the channel are structured : viscosity, thickness, surface tension, intervening in the dynamics of pores. Therefore , the  Na channel appears as a complex proteo-lipid structure with a specific role.

 

 

         5.4.1.1. Methods of studying the Na channel.

The study of Na channel is made by micromethods (18)of patch clamping type  , methods of fluctuations analysis, methods of radioisotopes, biochemical, electrorecording , the use of neurotoxins , that brought a note of accuracy because of the binding structures specific channels contributing decisively to decipher their function. (31 , 180, 196, 214, 119, 135).

 

 

          5.4.1.2. Distribution of Na channels.

Na channels are widely distributed in biology, including plant cells and bacteria (73, 123, 4, 207). In mammals (rats and rabbits) they are present in the muscles in the neuromotor plate and tendons (11, 73, 30, 7). It is also found in the pancreas, brain, testicles, bone and less in the kidney and colon (25). In nervous tissue it is on the neuron membrane, the some membranes  and at the level of  postsynapsis membrane , on synaptosoms , acting  as excitator receptors (78).

 

 

5.4.1.3. Classification of Na channels .

 
Ion channels are polymorphous from the structural and functional point of view  and require the use of different criteria for classification. First of all ,  affinity and the ability to transport various ions can be taken into account: Na⁺, K⁺, Ca²⁺, acetylcholine , for which they have high specificity. Na channels can be classified acc. to their interaction with neurotoxins and with H (145, 180, 196). Some  Na channels are blocked by amilorid (18, 113, 114). Others are activated by veratridine (18, 122) and under the action of amilorid decreases the height of the potential action. These channels have significance in pathology , in genetical arterial hypertension, cystic fibrosis, in hyperaldosteronism (178). K channels are smaller and have no negative charge. But they have the same topography as the Na (3, 5)

Channels of acetylcholine from the neuronal soma and from the  postsynaptic region  also allow the transport of sodium.

    Figure 16. Schematical representation of the Na channel. (78)

 

5.4.1.4. Na channel function.

Na channels initiate and lead the potential action (PA) in the axons, neurons, muscle synapses. They work as receptors of environmental change through transitional changes in Na⁺ conductance on the surface membrane (207). They have an excitator role on postsynaptic membrane (78). The resting potential of neuron soma is of-65 mV (lower than the peripheral fibers of - 90 mV) explained by the difference in the concentration of Na⁺: high in the interstitial fluid (Figure 17) and very low , intracellularly . (78)

 

Due to the fact that  the level of synapses , the Na channels allow the faster movement of it and to neutralize a part of the neuron negative charges and increases the potential of membrane from -65 mV to - 45 mV, which facilitates the production of postsynaptic excitatory PA (78) . Channels-voltage Na and K play a role in defining the rate of repolarization, adding itself to the action of Na pump.

     Figure 17. Distribution of Na, K, Cl through the neurosoma membrane: PA origin on the soma (78)

 

 

 

5.4.1.5. Na channels – pharmacological targets.

 
Ionic Na channels also function  as pharmacological receptors with therapeutic implications in local anaesthesia and anticonvulsant therapy (107). They are molecular targets for neurotoxines: tetrodotoxin and saxitoxin (65, 180, 182) that block the channels of Na  by acting unpon various segments (47). The neurotoxins (Table 19) block the channels of Na, fixing themselves on anionic places  instead of Na⁺ ions on the external face of the membrane near the activation orifice.

 

 

Table. 19: classes of toxins acting on the Na channel. (119)

 

Toxin                                           pharmacological effects

Tetrodotoxin and saxitoxin (STX and TTX)        blocks currents of Na 

Liposoluble  molecule                           causes persistent activation

                                                of Na⁺ channels

veratridin

batrachotoxin

aconitin

grayanotoxin

Scorpion α toxin from  North Africa,               slows specific                                                                                                                  North American and polypeptide β toxin of Anemona. inactivation of Na⁺.                                              

Scorpion toxin from central and south American    partially blocks Na⁺           Centruroides suffusus (CSS II) Tityus serrulatus  channels and creates partially (Tityus Y).                             a new type of channel                                                                               

                                                  on the lower potential                              
                                                  

 

 

pyrethroids                                      changes the closing of
                                                 rapid Na channels .

ciguatoxin                                       increases Na                                                                                                                                 

                                                                                                                      permeability.

 

 

In Na channels of electrophorus electricus , on polipeptides of inner canalului.The specificity of interaction of neurotoxins with Na channels allowed their use as molecular targets (31). The action of neurotoxins decreases in  acid environment due to the antagonism H⁺ (32), which remain fixed on polypeptide carboxyil groups, fixing place of neurotoxins as well. STX is less influenced by the acid medium. The most active compound is pyrethroid (123). Neurotoxins’ action is not influenced by procaine.

 

                 5.4.2. Transport through membranes.

The cell membrane has selective properties for different substances: nutritive, metabolic, functional specific substances synthesized in the body. The  conditions regarding the transport of the substance show that it take place  through pores existing in the membranes  , through the spaces between the protein molecules, between these and the ion channels and through ion channels , that allow the passage of water and polarized hydrophilic substances (56). Non-polar hydrophobic  substances are transported through areas rich in lipids of the membrane (25, 78)

  Membrane permeability  changes under the influence of factors which modify  excitability as well: stimulation, spontaneous decrease of the resting potential, through the accumulation of Na⁺ in the extracellular space, by the action of pharmacological agents.
Transmembrane transport is made by active and passive processes (Fig. 16).
The passive transport of the  lipophylic substance  is done by separate portions of the membranes and the polar substances are transported through the areas described.
Active polar substances transport is made by osmosis and diffusion, under the influence of (136) of concentration and electrochemical gardients(106).

               Diffusion and electrodiffusion takes place through the intermolecular spaces and ion channels which they can interact with. The mechanism has decisive importance in the passage of Na⁺. The  facilitated diffusion is made by means of transporters with which the transported substance interact (134). Such a mechanism is known as "ligand gating" and the resulting molecule acts on an activated gate of the Na channel, modifying the  conformation and activating the gate. The diffusion rate is equal to the resultant of the molecules passage in both directions through the membrane. Transport of Na is facilitated (2) by the richness of anionic charges presented above. Thus, it has been calculated, that, in a single cycle, up to 7000 Na⁺ ion pass through a channel .  The active transport has a greater degree of specificity. It is consuming energy. In this transport there participate pumps of Na.-K, the Ca  mechanisms as well and countertransport. In this type of transport an important part is played by the metabolism in maintaing the membrane structure and activation of transport .

     Figure 18. Conditions to determine the neural membrane potential: A = when the membrane potential is caused only by diffusion K⁺; B = when the membrane potential is caused by diffusion K⁺ and Na⁺, C = membrane potential is caused by diffusion K⁺, Na⁺ to which is added the Na⁺ , K⁺ (78) pump.

      

 5.4.3. Membrane potential.

Cell membranes are polarized. This is due to selective permeabilities and the different environment on the two sides: the endocellular face  is in contact with cytoplasm and intracytoplasmic formations, the external face is in contact with the interstitial matrix. The size of the potential is - 100 mV (Figure 15) depending on the cell - animal or vegetal (68): the giant axon of mollusc or plant cells (Wallonia Holicystis). The endocellular surface has negative charges and the extracellular surface , positive charges.

 

 

Table 20. Chemical composition of the extracellular and intracellular (78) environement.

 

  Compound             extracellular            intracellular                                                  
  (mEq%o)               

 

     Na                 140                       10  
     K                40                        140
     Ca                 24                          0,0001.
     Mg                  1,2                       58
     CL               103                          4
     HCO                 28                         10
     Phosphates            4                         75
     SO                   1                          2
     Glucose               90                         0-20 mg/dl

            Aminoacids                                  30mg/dl                                                   200 mg/dl        

            Cholesterol            0.5                        2 - 95,0
     Fosfolipids            -                           -
     Neutral fats           -                           -
     p0                    35                         20
     PCO                   46                         50
     pH                    7.4                         7,0
     proteins               2/dl                       16/dl

 

 

            The membrane potential is due to the concentration gradients of (Table 20) of each ion , chemical potential of the main electrolytes: Na⁺ and K⁺ (Bernstein, 1902). The resting potential (RP) is persistent and is maintained as long as the cell is alive and active .It reaches  "0" when ions are in balance .The potential value of the membrane (PM) which prevents an ion diffusion through the membrane is the Nernst potential.

                  

                             5.4.3.1. Nernst potential.

Its size is given by the ion concentration  on both sides of the membrane and expresses the trend direction of diffusion. Its value is calculated by eq. Of Nernst at body temperature:
 

           Eq.16. EMF (mV) = 61 log C / C where:
                                             C and C = concentration on  faces internal and external membrane.
                                             + And - refers to cation, anion respectively
                                             Iis value is = - 61 mV inside

The membrane potential (PR) of excitable cells in basic conditions has a value of  - 90 mV in the interior as compared to the interstitial fluid. By the activity of the  Na-K pump there  are actively transported in opposite directions and their results an unequal distribution of the 2 (Table 20) (56) on the two sides (Figure 16). The gradients of concentration are retained by the activity of these structures, ion channels for Na and K of membrane proteins. The K channel in the excitable membrane, in resting position  is 100 times more permeable than the for K⁺ than the Na  channel for Na⁺. The resting potential is maintained only by K ions (in excitable tissues).

The gradient of Na⁺ in the cell membrane has a small role in maintaining or is invalid in maintaining the resting potential (68). There results an added PR of - 86mV due to the great permeability for K⁺ and non permeability for Na⁺. To this is also  added the contribution of the electogenic Na, K pump (Fenn, Hodgkin, Keines) (Figure 16), out of which 4 Na⁺ ions are  remove from the cell and 3 K⁺ ions pumped  inside. This resting potential becomes -90 mV. There is also added the low activity  of Na⁺  ions (233) because of the interaction with extracellular proteins. PM of - 90 mV is maintained by the fact that the gates activation of Na channels are closed , so they are inactive, although the inactivation gate is open, but ineffective.

There are other cationic  gradients  instead of K+, such as Ca2+. Anionic contribution to the PR is given by their presence in the cell: organic anions resulting from the metabolism (acetate, piruvat, milk, amino acids, inorganic anion such as phosphate, sulphate) collectively called "X-" and  they not are outside the cell , rich in Cl- (Table No. 20). Maintaining resting potential depends on oxygen, thus on the energy consumption. In the absence of oxygen, K+ is lost but not completely , because of anaerobic glycolyte processes, which may be stopped by specific toxins (iodacetic acid, fluorizin, physical factors as well as the  equilibrium of Donan). They also maintain the Na+ ion pump , in their absence the K+ gradient disappering as well. The polarized state and so the cell excitability is maintained by consumption of energy.The complex functional membrane so structured and maintained is presented as a metastable state which responds to the variations of environmental cells , at a certain excitability threshold with a defined rate between the intensity and duration of stimulus. The response is differentiated by the three types of cells and metastable state is essential to produce action potential. 5.4.4.The Action Potential of excitable tissues (Potential of Na). The response of excitable and autoexcitabile cells to stimuli spreads through rapid changes of the Resting Potential in the Action Potential. Action Potential (AP) represents a temporary change of Resting Potential (RP), following the initiation of a state of excitation, a change of selectivity for ion membrane, with increased permeability to Na+ and increased PM (Du Bois Reymond). Variation of potential is biphasic , like a sequence of differences of potential, with an exclusive role of Na (78, 94, 3, 147). AP begins with a sudden change of RP, initiated under the law "all or nothing", which is transmitted non-decremential (68, 78) as a wave of depolarisation (3) along the excitable structure (Figure 19). AP initiation takes place when RP increases by 1/5-1/3 of its max. value i.e from -90 mV to - 70 mV. The process requires about 6 x 10 electrons. The value of -60 mV represents the threshold of stimulation. At this time there take place the conformation changes of the protein of the Na channel gates  , activating and increasing permeability for Na (89). The cation is attracted by the multitude of negative charges of the Na channel gates which invades the cell. It results  an increase in membrane potential (MP) to induce the opening of more Na channels . Sodium spreads through the aqueous environment of the channel and through the interaction with local negative groups . The direction of Na+ flow  depends on MP and on the gradient of concentration. After depolarization , ionic  currents show three effects: (1) rapidly increasing Na+ conductance, followed by (2), a slow decrease of Na+ conductance, so a process of inactivation of Na+ and (3) a slow increase of the K+ conductance (Figure 19). These changes increase the depolarisation reaching -100 mV and over. Depolarisation of the membrane grows up to the positivation of the interior of the cell through  Na+ , which invades it. During this period permeability for Na+ increases 500 up to 5,000 times, while permeability for K+ increases of only 30 times, and K+ is lost in measurable quantities (19). In addition to the changes mentioned at the point of stimulation there take place other changes in membrane properties: the ohmic resistance decreases from 1000 to 25 ohm / cm, it highlights the ionic exchange between the two surfaces of the membrane, RP is cancelled, the membrane polarity changes . In this phase there is  a steep increase in AP branch upwards (Figure 19). AP is produced (68) exclusively by Na+ (48, 147) and it can be also called potential of Na (Fig.20). MP is a potential of K+, Na having a contribution of 1%. High speed of growth of AP involves a very large number of Na+ ions  in a short period of time. AP height depends only on sodium in the extracellular medium(3, 68). The decrease of Na+ content is accompanied by a decrease in AP height. Cations which penetrate the cell membrane diminish  (45) the  height of the spike.Some neurotoxins (Table 20) with high affinity for the gates activation channel of Na (32, 45, 108) of nerves and miocite (118), but do not block the K gates . So, Na+ is the current conductor during the growth  during AP. Replacing it with another cation, which does not penetrate as fast as the membrane XNa (choline clorhydrat) lowers the height of spike. The same effect is achieved in proportion to the Na+ decrease . Gates function is regulated by two mechanisms (113): (1) voltage gating. In this case molecular conformation of gates respond to the transmembrane electric potential. When there is an intense negative charge on the internal face of membrane , the Na gates remain closely closed. But when this charge is lost , the gate opens. This mechanism is the main cause of AP. Some gate channel protein open by other molecules bound  with proteins. This induces a conformational change in a protein molecule that opens or closes the gate. This is called " ligand gating ” and the substance becomes bound ligand. This is important in the synaptic trasmission neuron-neuron and  neuron-muscle for the acetylcholine transport .            Figure 19. Changes of  Na+ and K+ conductance during  PA evolution. Na+ conductance increases 5000 times at the  beginning of the PA and of K+ only 30 times in subsequent stages of the PA (78)   5.4.4.1. Restoration of resting potential.   The growth of AP with overshoot is followed by a series of events which have membrane manifestations resulting in the restoration of RP. Restoration of ionic polarization preceeds the fiber restoration. Membrane repolarization in RP is slower than depolarisation and starts from the spike peak by activating Na and K pumps, which transport active K+ to the cell, and the membrane regains polarization. During resting, the voltage-gate of channel K is closed and ion can not cross out. Increased MP from -90 mV to potential "0", changing the voltage induces a slow change of conformation and opens the K channel gate, located on the membrane endocellular face and thus K+ leaves the cell. The process is slower than the opening of the Na channels activation gates. The same increase in voltage also closes the gate of the inactivation of the Na channel and so it remains blocked, increasing the inner positivation, even if K+ leaves the cell. So an increase of MP takes place , closing the Na+ gate  channels (3, 78 ) and lowers the penetration of Na+ , but K+ continues to grow outside , because the closing of K channels gates is slower . It can be concluded that depolarisation and repolarisation membranes are under the control gate voltage of Na channel (78), but the speed of repolarisation is provided by the voltage gate of the channel K. The right branch of the slower spike, (Figure 19, is produced by the inactivation of Na channel by closing the activation gate and arresting  Na+ in the cell. The channel will reopen in the end , close to the fulfilment  of repolarisation. At the same time, the K pump function comes into operation ,coupled to that of Na and restore RP (250), giving this process an endergonic character.          Figure 20. Flows of Na + and K + in the giant axon of sepia. (Shaded columns: RP. White Columns: after stimulation by 100 cycle / sec) (3)

         

5.4.4.2. Dendrites potential.

Dendrite generally present a local unpropagated local decremented potential. In these structures the  Na⁺  entry and K⁺ exit are simultaneous processes , differentiating themselves from the  mechanism of ionic movements described in the case of axons and muscles. The degree of response is determined by the number of opened  Na and K channels and by the duration and size of each opened  channel. So, these unpropagated potentials  intervene in the sensitive neurons function  and in synapses , allowing the passage of information and its integration.

 

 

 5.4.4.3.The propagation of action potential.

The propagation  of the depolarization wave is made by current sources represented as movement of Na⁺ (Hodkin and Huxley)along the  fiber. Propagation of AP is still dependent on Na⁺.
The theory of superficial nervous impulse conduction, the disturbed local potential that induces electric potential on the surface. It is more important in dendrites,  where excitability is local, graded  and decremential and  AP appears by summation of stimuli.

 

The Saltatory theory of  PA conduction is found again in myelinisation fibers and the jump is made from a Ranvier node to another, where the nerve membrane is in contact with the extracellular environment. This is the preferred modality of transmission in central nervous system. Sensory receptor cells respond to specific stimuli (45). Receptor stimulation affects the frequency discharges, but not the height of impulse. There takes place the frequency modulation of a single type of message. RP recovery is made by energy consumption,from the phosphate macroergic links. Polarization is regained during the relative refractory period, when the membrane becomes again impermeable to Na+.

 

 

                  5.4.5.The action potential of autoexcitable tissue.The role of Na.

 

The action potential of autoexcitable cells is studied best on the excitoconductor heart system(sino-atrial nodes, atrioventricular nodes, Hiss bundle, Purkinje network), smooth muscles, some brain nuclei (neurons respiratory center).
Autoexcitability  is due to the incapacity of embryonic fibers and of autoexcitable  neurons to maintain constant the RP membrane. This is in relation to the time overlap and endogenous stimuli. During the diastole, when the resting potential is maximum, depolarization is slow and continuous until the  discharge  threshold of -60 m V -70 mV through changes of conformation of proteins and probably through accumulation of Na⁺ in the cell and the opening of Na gates takes place and the AP is started. The potential is slow, has no overshoot, has a value of - 55 mV to a minimum - 60 mV, with a duration of 200 msec. In the heart there are no fast Na channels, AP is not sensitive to tetrodotoxin but only to Mn^{2+ .} In this case , the role of Na⁺ is much diminished , K⁺ having a greater role in the genesis and transmission of AP. The mechnism of rhytmicity of sinoatrial node recognizes the existence of an MP in diastole of -55 mV to-60 mV,  negativity which is caused by the flow of Na⁺ in the fiber. Depolarization initiated here is transmitted directly to atriale muscle fibers. Polarization of the ventricular fibers is - 85 - 90 mV. In the myocard there are three types of membrane ion channels with a role in the development of AP. (78): (1) fast sodium channels, (2) slow-calciun sodium channels, (3) K-channels. The opening of fast sodium channels in a few milliseconds is responsible for the rapid emergence of a spike AP observed in the ventricular muscle caused by the rapid influx of Na in the fiber. AP plateau is caused by ventricular slower opening of the channals of Na-Ca , which delay tenth of a second . Finally ,  the activation of K channels increases and the diffusion of a large amount of K⁺ outside of fiber and the  return to  RP takes place . The smaller negativity of only   RP-55mV explains why the fast Na channels are more inactive, i.e, they are blocked because all the  time MP remains less negative than -60 mV for several msec , the gate of internal and inactive membrane and channels remain closed. This , only the slow channels Na-Ca can be opened and thus they can be activated and produce an AP. AP is thus slow and produces the  discharge of the ventricular muscle. Autoexcitation of atrial sinus fibers  also recognizes sodium as the main element. Ions of Na⁺ tend to penetrate into the fibers of the node membrane through multiple channels and the influx of positive charges increases gradually during diastole. When it comes to the threshold voltage of -40 mV the channels Ca-Na are activated and both ions quickly enter the cell causing AP. So , the Na flow through through the fiber sinus is the cause of their autoexcitation.This Na⁺ flow does not produce a continuous depolarization , it occurs because of the inactivation of Na-Ca channels in 100 - 150 msec. After opening or concomitant increase  ,the number of K channel closed increases. So , there ceases the function of Na-Ca channels and there increases the outside diffusion of the cell K and  AP ends . But  the closure of K channels is delayed ,  this is lost from the cell and thus increases the negativity on the internal face of this membrane , which is hyperpolarized. There follows the installation of RP - 55 mV-60 mV. The hyperpolarization is not maintained continuously , because in the last few hundreds of a second after  AP, more and more K channels close  and the Na⁺  flow compensates cellular  negativity and leads to -40 mV threshold of excitation.

 

[Chapter 6 will be featured in the upcoming March-April 2010 issue of this Journal.]

 

 

Professor Marcel Uluitu, M.D. Ph.D. began his scientific activity in Physiology in 1953 at the Physiology School (Medical School) Cluj-Napoca, in Romania. He continued his scientific activity in Physiology in Bucharest at the Institute of Physiology and Pathophysiology Daniel Danielopolu until 2004, at which time he retired as Director of the Institute; he had held this position since 1990. His research work includes studies of the central nervous system physiology relating to the transmission of information in the nervous centers; cerebral excitability, using methods, in their evolution, from the determination on reactive isolated organ, to the most complex physical and chemical methods, in the present. In his research of chemical mediation he studied acetylcholine, serotonin, and their connection with the cerebral metabolism.

Professor Uluitu has also investigated cerebral tissue excitability, studying the structure modification of the protein macromolecules, and the physiological and pathopysiological processes in which are involved Sodium and Lithium. He implemented an original method for physical and chemical processes which involve the chemic active sodium, in normal processes and in the cerebral excitability dysfunctions, in human and in experimental model (animal). These results of this work gave him the chance to outline the chapter herein relating to the physiology of substances transport in the blood. This is based on the physical and chemical interaction between blood components.

His papers are included in the collections of the U.S. National Library of Medicine and the U.S. National Institute of Health. He is a member of the Romanian Academy of Medical Sciences.

 

Dr. Diana Popa (Uluitu) is a researcher in the Department of Microbiology, Immunology and Molecular Genetics at the University of Kentucky in Lexington, Kentucky, USA. She attended Medical School at Vasile Goldis University in Arad, Romania, and graduated in 1998; during summer breaks at medical school she volunteered at the Institute of Physiology D. Danielopopu in the physiology and microbiology laboratories as well as in the clinic. After completing medical school and a one year internship, she worked as a Research Assistant at the Danielopopu Institute for three years before coming to the University of Kentucky. In addition to her medical thesis, which focused on the actions of Lithium on the central nervous system, since coming to the United States she has published numerous additional papers relating to Lithium and other substances. In continuing her on-going studies, Dr. Popa is currently pursuing a Master’s degree in Public Health at the University of Kentucky.