The Physiology of Transport Substances in the Blood (Sodium)
By Professor Marcel Uluitu, M.D. Ph.D.
Co-Authored by Diana Popa (Uluitu), M.D.
Department of Microbiolgy, Immunology and Molecular Genetics
[Editor’s Note: This paper is presented as Part I 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 One (of six chapters) and Section 1 of Chapter Two]
regulating functions: Body unity,
control and coordination of its functions are achieved by means of nervous,
humoral and physico-chemical mechanisms.
The humoral mechanism regulating the functions of the
body recognizes the transport of substances as a means by which it provides for
the needs of every tissue metabolic activity, synthesis of own substances,catabolites removal, etc. The humoral pathway is enabled as
a result of the analysis by the nervous system of the internal environment,
through feedback mechanisms, of the level of normal concentrations of
constituents of the body and their balance within the three spaces, including
nutriments, new compounds synthesized in some specific tissues, catabolites,
etc. Humoral pathway activation mechanisms depend on the role of these
substances in the economy of the body (composition, physico-chemical structure,
functional role, the energy structure of the body, etc.).
The physico-chemical pathway includes the body
composition and the circulating and structural substances which interact by
means of trace energy and have significance in the processes of transport in
the blood. The physico-chemical route of regulation depends on the composition
and structural-functional lability of proteins. These substances are in
constant motion, ensuring a local and global uniformity.
Transport of substances in plasma is in a state of
trace energy interaction ionic, electrostatic interactions, Van der Waals
forces, hydrogen bonds,
Disorders in the substance transport mechanisms in the
blood generate a special pathology whose recognized causes are deficiencies
(anemia ,acidosis, etc.) ,genetic disorders (Wilson’s disease involving
Cu),endocrine diseases involving Ca ,abnormal excitability neuromuscular
disorder, behavioral-type constitutional disorders (involving the transport of
The General Structure of the Body.
of Substances in the Blood.
Sodium is a chemical element in Group I of the periodic table. Very widespread in Nature, it is at the same time the monovalent cation best represented in the blood. It is extensively studied in both kingdoms because of its association with multiple processes.
It is associated with metabolic and enzymatic processes acting as cell activator. It is mainly involved in the cell membrane functions. It is an extra cellular cation and is present more especially in blood. In the excitable cells, the action potential is also identified under the Name of sodium potential. It is an activator of the heart, in vitro. It has an important role in the electrical manifestations of the excitable membranes of cells; neurons, cell rods, excitoconductor cardiac tissue, etc.
At the synapse level it acts in conjunction with acetylcholine. A seriously low concentration of sodium is not compatible with life. Sodium blood homeostasis is assured by a very complex regulatory system starting with food intake and continuing with transport in the blood, sodium distribution, and elimination by the kidney, the digestive tract, the skin, etc. Such mechanisms are nervously and hormonally regulated (adrenal cortical, natriuretic hormone), osmoregulatory mechanisms, mechanisms of cellular and molecular emergency. In case of acute intake increased, sodium is retained temporarily in the connective tissues, interstitial tissue and fatty tissue in order to maintain sodium concentration.
In the cell membranes, it works through
sodium ion channels interacting with the anionic sites of the proteins in their
structure. Thus, the information conveyed by the cation depends on the local
ion concentration and on the size of their ionic radii, varying according to the
number of hydrating water molecules. Its action can be antagonised in the ion
pore region of the Na channel, by neurotoxines.
The regulation of sodium activity in the blood depends on its interaction with proteins. Sodium chemical activity determines the capacity of response of nervous structures by the generation of an action potential. The fraction of chemically active sodium in the blood highlights the role of physical and chemical interactions in the body. Determination of total blood sodium with classical methods (physical, chemical, etc.) after removal of macromolecular organic compounds has the same value as the basic analysis of the composition of living organisms. It is a sort of "Chemical anatomy." The physiological role of Na+ can be established only by determining its chemically active form while maintaining the full composition of plasma. There are multiple interactions among plasma constituents. Despite the small energy values of such interactions, their number is particularly important.
The method for determining the chemical
activity of blood Na+ described in this monograph has as the
reference system the energy of interaction, E, between serotonin (5-hydroxitriptamin = 5HT) and the
polyanion heparin (Natural components of blood). If there is Na+ in
the solution, whose interaction with heparin is accomplished by energy EE, the interaction 5HT-heparin no longer takes place and 5HT
goes out of the dialysis pouch
In the normal groups of both species studied, there are subjects in which the chemical activity of cations (Na+ up to 95%) antagonizes the interaction between heparin and 5HT, the latter leaving the dialysis pouch.
Prof. Alexandre Monnier (biophysicist at the Sorbonne) said that throughout his entire life he strongly believed that Na+ is circulating in the blood in a state of interaction with proteins, but he never had a method to prove it. The statement is repeated in a letter presented in facsimile.
Individuals in whom Na+ antagonizes the reaction heparin/5HT present with increased neuro-muscle hyper excitability expressed in the form of behavior disorders of a constitutional type in humans, state of alert on EEG, poor concentrated attention, good distributive attention, disorders in the regulation of the cardiac-homodynamic function, while rats are prone to audiogenic convulsions, hyper mobility in open areas, exaggerated intake of Nail, mineral-corticoid function deficiency.
The body can be divided into interdependent compartments in point of transport mechanisms: INTRAVASCULARLY, INTERSTITIAL ENDOCELULAR.
This division suggests the existence of two major
types of transport of substances: transport of the substance within the same
space (blood, interstitial, intracellular) and another transport between the
three COMPARTMENTS, across separator walls consisting of semi permeable
membranes and epithelia. The intravascular space communicates through capillary
walls with the interstitial space and the latter with the endocellular space
through cell membranes. Transmembrane transport, well-studied in both living
and artificial membranes takes place under multiple influences: blood pressure,
osmotic pressure and colloid osmotic pressure, concentration gradients,
electrochemical gradients, etc.
The term "space" includes multiple interdependent structures, having close embryonic origin. The embryonic origin of interdependence is preserved by the chemical composition whose origin is the secretion of macromolecules in the cells of every compartment. Macromolecules are secreted by vascular endothelial cells and by other host tissues as well. Thus, a local, complex functional structure is created. The structure acts in an integrated manner. This phenomenon is known to organize and include the three spaces. In each of the three anatomical structures the three spaces communicate among them. The chemical composition of the compartments is maintained constant within the general concepts of "internal medium" and "homeostasis". In this context, the segment medium is maintained constant by the transport of substances between the compartments. The substances in the three spaces have oligoenergetic interaction. The complex connection between compartments is mediated by semipermeable mentioned structures. The knowledge of the physical and physico-chemical force enables a more precise understanding of the fundamental state of structural elements and their functions. The following will deal with transport processes, mainly in the blood, with particular focus on the relationships between transport of Na+ in the blood and functional status of the excitable and unexcitable structures.
The Blood-Vascular Space
vascular tree is made up of the arteries, the capillaries and the veins. The
vascular wall (artery) is made up of three layers: the outer layer - tunica
adventitia, the second layer - tunica media, consisting of elastic and smooth
muscle fibers and, finally, tunica intima. Typically, the capillary wall is
made up of only a unicellular layer of endothelial cells which is surrounded by
a basement membrane on the outer side. At this level exchanges are taking place
between blood and the extra vascular space. It is an active physical and
chemical space separated by a cellular layer and an extra cellular layer having
a restrictive selective action for interstitial and blood components. For every
organ and tissue there are structural and functional features of the
capillaries that control the local exchanges.
Blood is the circulating tissue that irrigates all body cells. It circulates in a closed system at variable speed given by the activity of heart pump, the elasticity of vessels and size variations in different parts of the tree. Blood is composed of a cell system (red cell, white blood cells, platelets) associated with respiratory functions, antimicrobial defense, haemostasis and a liquid intercellular system where the cells are floating – the plasma. Between the dissolved substances in the blood there are chemical, physical interactions resulting in the particular distribution of such substances. One should note leukocytes and platelets contain 5-60 times more amino acids than plasma and erythrocytes. Serotonin is also virtually wholly carried on platelets (219,220)
The blood tissue communicates with the
extra vascular interstitial space and through it with all body cells,
sustaining them and participating in the regulation of their function. In their
turn they affect the biochemical composition and physico-chemical properties of
the blood. This maintains the chemical and physiological homeostasis of the
inner medium within limits compatible with life. Blood plays a key role through
its circulating function as a transporter and participates alongside the
nervous system to maintaining, adjusting and adapting the body functions.
The total volume of blood is 5.5 liters
in adults, of which 3.5 liters (55%) is represented by plasma, and 45% of
volume contains blood cells (haematocrit). The volume of blood varies with sex,
age. The haematocrit varies with physical effort, environment temperature,
altitude, age of pregnancy, etc. The color of blood is red, with shades
depending on its gas content and Nature: oxygen, carbon dioxide, carbon oxide-
accidentally. Density varies with gender (1061 in men and 1057 in women)
consistent with haematocrit values. Viscosity, the resistance against the flow
by friction with the neighboring areas of blood components and the vascular
wall has values of 4.7 to 4.4 in men and in women, respectively.
2.3. Blood plasma
Plasma represents the liquid phase of the blood. It is a transparent, slightly yellow solution wherein blood cells are floating. It is a complex solution with heterogeneous composition of inorganic and organic substances which are interacting among themselves, with the solvent (water) and the vascular wall and their components. The solvent and the compounds with low molecular weight are in balance with the substances of the same kind in the extra vascular space.
2.3.1. Composition of plasma
Organs with intense metabolic activity (permanently or occasionally) have intense thermo genesis and efferent blood temperature is higher. This increase in temperature affects the stability of plasma solution and therefore the physical properties of plasma. Blood temperature is also variable (37.7 C - 40 C) in various organs, depending on the intensity of the metabolic processes specific to their function (liver, brain) or on functional requirements (muscles).
18.104.22.168. Density and viscosity.
The lower density of plasma (1027) is
due to the protein. It is low in hypoproteinemia (hepatitis, nephropathy with
intense albuminuria, inanition, consumptive diseases).
Viscosity is defined by
22.214.171.124. Osmotic pressure
It is a colligative property (68)
representing the force that the particles of the solvite are exerting on the
vessel wall. The chemical composition of blood varies between certain limits in
different regions in point of concentration of protein, gas (O, CO, etc.) H,
various electrolytes, some catabolites resulting from the tissues activity, etc
Another property of a colligative
solution depends on the concentration
of particles in the solution. This property is the "freezing point"
or "cryoscopy point."
Osmotic pressure varies with the intensity of tissue metabolism. It is 6.7 atmospheres (matching cryoscopic point is 0.560 C) and is given by the concentration of particulate substances (dissociated plus non dissociated) in plasma: Na, K, Ca, glucose, etc.. Under normal circumstances this is given, up to 90% by Na. Osmotic pressure is a condition for cell division in the processes of excitability.
The plasma colloid osmotic pressure
(PCO) is produced, in addition to the substances mentioned by dissolved
proteins. They do not pass through the capillary membrane. Plasma protein
content is 2 -3 times higher than the interstitial content (7-8 gm vs. 2-3 gm).
The contribution of proteins to promote PCO is unequal as shown in Table 3.
At the level of capillaries, local forces are acting
that create a slight pressure imbalance according to Table. 4
The solubility of proteins depends on their Nature and chemical structure, the solution pH, the degree of ionization, the ionic composition of the environment (salt concentration and Nature of salts), the dielectric constant of the environment, the ionic composition of the environment, including the type of side groups of protein. The role of the solvent: water is bound by polar interactions to the ionized groups and by the hydrogen bond to the peptidic bond. Water binding is minimal at the izoelectric pH of proteins.
Electrolytes in low concentration favor protein solubilisation and stabilize the solution. If the electric charges on the protein molecules are neutralized by the addition of salts, proteins precipitate by salefier (178). Electrolytes in high concentration destroy the water interaction with the protein molecule and separate them. Non-electrolytes may also dehydrate macromolecules through interaction with water and decrease the solubility of proteins through a process of pseudo-hyper concentration.
The ability of electrolytes to influence water
dissolving power follows Hofmeister's liotropic series. (52):
The solubility of the proteins increases in solutions with high a dielectric constant (52) and in the presence of dipole ions.
An important role is also played by the attraction and repulsion forces existing on the surface of molecules in solution. In the two segments, arterial and venous, there occur composition changes of water, electrolytes, various other molecules that can cross the capillary wall as well as a result of loading with catabolites and other products of local secretion. Also at this level, there occur variations in the concentration of macromolecules retained by the capillary wall, as, for example, the increase by 20% of the concentration of protein in the blood during the formation of primary glomerular ultra filtrate. H-ions concentration increases in venous plasma.
126.96.36.199. Physical factors of plasma stability.
There are many physical conditions of stability. Among them one could list Brownian motion, continuous flow of blood, rheology factors depending on the type of blood flow in vessels, etc. The flow of a liquid through a closed system of straight, cylindrical tubes is laminar. The liquid is moving in parallel, immiscible layers alongside the vessel wall. Otherwise, the layers are mixed, form whirling areas where plasma is shaken. In these areas the lumen of the vessels is altered naturally (the valvular cardiovascular blood pressure, fast-growing areas of vascular bed, and under conditions of temporary exertion of some organs in the precapllary region), or in pathological conditions. An important physical factor is represented by the large specific surface of the solvite substances (relative to the surface, the particle size with an average of 3.5 mμ of a gram of substance). The surface grows even larger as a result of hydration (178).
2.3.4. Plasma functions (78, 136) are listed only:
B) - the body's defense mechanism and the immune response.
The folding of the polypeptide chain is conditioned by the amino acid composition and the distribution of polar and unpolar groups (Table No. 11). They control the folding of protein molecules (160124,15,16,17). Hydrophobic sites are accommodated inside of the molecule thus avoiding contact with water and creating globulin structures. Hydrophilic polar side chains are distributed on the external surface where they can interact with water and other polar molecules. The hydrogen bond is important in keeping together the various segments of the folding molecule.
The additional covalent bonds between the chains and disulfuric bridges contribute to the stabilization of the three-dimensional structure of the extra cellular proteins. Molecular specificity results from the interactions between their various structural elements and the molecules in their environment. They are based, in addition to covalent bonds, on hydrogen bonds, phosphate bonds, saline bonds, etc.The distribution of various atoms on the surface of the molecule, makes each protein unique and able to interact with specific molecular and other surfaces and with some smaller molecules.
Each protein has different segments that are repeated in the macromolecule. The polypeptides, in the solution, take a unique spatial arrangement as a result of noncovalent interactions in the protein so that its energy could be minimal. Noncovalent bonds are established very quickly with no catalysts and they are effective by aggregation. Inside the protein molecule there is a dielectric environment which favors interactions, is associating to reduce contact with water, forming a large number of contacts unpolar.
188.8.131.52. The structure of the protein.
measurements of distances and angular values connecting the amino acids in the
polypeptide chain established the following primary characteristic of
The residue of proline prevents the - spinning, and the chain is bent at an angle of 130. The residue glycocol (no side chain) confers fexibility interrupts the structure , and changes slightly the chain direction. Other amino acids: valine, isoleucine, treonine induce steric disturbances. Serine forms hydrogen bonds at alcoholic group and prevents the helix stability. Cysteine creates disulphur briges and a rigid polypeptide chain, hindering formation of the helix. The - structure has the shape of a folded sheet. In this structure the maximum of hydrogen bonds is achieved between CO and NH. The hydrogen bonds are intercatenary and polypeptides are arranged in the shape of sheets. The most stable configuration is the structure with antiparallel chains (chains are directed from the "N" terminal to the C terminal and the other vice versa).
Radicals "R" are arranged on alternating sides of the polypeptide chain. Between sheets there are hydrogen bonds connecting the "R" groups. Distances between the sheets are 5.7 and 3.5 Ǻ alternatively. The structures are frequent in globular proteins, especially in immunoglobulins. A simple - structure is formed of a polypeptide chain bent on itself, forming two antiparallel segments identified as the -tower.
184.108.40.206.3. Tertiary structure.
This includes the secondary structures as spatial units: domain and motifs. The packaging is noncovalent and by carbon interactions between the radicals "R" at C of the structure, or unorganized. The bonds are determined as follows: (1) hydrogen bonds between the OH groups of the amino acid residue tironyl, tirosyl, with amide groups of glutamyl and asparaginyl (2) ionic bonds between radicals with negative charge of lisinyl, arginyl, histidyl with and without polar radical charge (3) hydrophilic interaction between the residue unpolar amino acids valine, leucine, isoleucine, alanine, phenylalanine (4) links between the cysteine residue distant covalent regions of the molecule.
A polypeptide chain adopts the configurations and until it satisfies all the affinity of radicals "R" under steric conditions influences when the final conformation results, the best possible compromise of stable energy and space. Therefore, the decisive factor to obtain the tertiary conformation given is again its genetically induced primary structure whose primary spontaneous structure depends on the chemical composition. The plasma globular proteins have on polar groups on their surface. The unpolar radicals are included within the protein molecule.
The organization of the "domains" is a structural intermediate form between the secondary and tertiary structures. Because of this, it is identified as "secondary superstructure" or "superstructure domain." Domain "is a continuous piece of the primary structure of polypeptide chain, packed up as a functional entity with its own secondary and tertiary structure. The "domains" are part of the less organized part of the chain, allowing flexible dynamic segments of their field. "Domains" are packagings of -helix and - sheet, forming globular compact units. It contains a number of 50 - 350 amino acid residues. Protein may be constituted in a domain or more connected with each other through long chains of open polypeptides. Through these connections large molecules are formed, identified as “protein ensembles” or “protein complexes” in which the subunits are linked with a large number of noncovalent bonds. In the extra cellular environment they are often stabilized by disulphur bridges. So a "domain" of protein appears as a basic core of a protein which is composed mainly of a - sheet,-helix or both. These structures allow long hydrogen bonds that stabilize the inside of the molecule where water has no access to form hydrogen bonds with the oxygen or polar carbon with the hydrogen of peptide bond. Proteins can be formed through recombination of pre-existing polypeptides "domains" with supramolecular structures of complex type enzyme, protein filaments, membranes, etc. Domains are the underlying structure of proteins diversification. They are the basis of "analogous" proteins (different proteins with similar functions) and of "homologous" proteins (similar proteins with different functions).
220.127.116.11.4. Quaternary structure.
The assembling of the protomers to oligomers is accomplished only when the contact areas are complementary and have a large number of atoms, and the bonds are close to the level where the Van der Waals are active. The protomers of homologue proteins of different species do not associate although they contain the information to be decoded. The interaction capacity explains the formation of supramolecular structures. Perturbation of a protomer annihilates the oligomer function.
18.104.22.168. Electric charge of proteins.
(a) in an alkaline environment H+ is
released, so it acts as an acid (see also acid-basic equilibrium):
In both cases a reaction of neutralization is
described, with formation of salts: Na-protein ate, in the first case (178, 68),
protein clorhydrate (macrocation) in the second case.
Electrophoresis in a liquid phase (Moving boundary electrophoresis Tselios). It was used by us as well for research activity. It requires a Tisselius apparatus. It is using 1 -2 ml of blood serum that is diluted with 2 ml.buffer Michaelis-Wideman, pH = 7, 4, ionic strength = 0.118. First, it is dialyzed in buffer at 40 C for three hours. Dialysis continues for a second time for another hour after changing the buffer. Direct current of 150 volts is used.
Two photographic exposures of the two branches of the
device are performed, upward and downward, after 45 min. and 75 min. migration.
One calculates the mobility (fig. 1) of the fractions obtained, with the
Figure 1.Electrophoretic mobility (=cm/V)of three plasma protein fractions of normal children and children with behavioral constitutioNal disorders and transport of Na in the ionic state. (230)
Different proteins have different ways to change the variations of pH. The adsorbents can be very different, and eluents infinitely increase the technical possibilities. Ion exchange resins (Dowex 1 and Dowex 50) have ion charges on the surface of the calcium phosphate gel type. The cellulose ion exchange has ionizing groups with affinity for many proteins. The covalent bonds allow cellulose stability ionizing groups. An example of the group is DEAE cellulose and carboxymethyl cellulose, an ion exchanger for basic proteins. Phosphorilate cellulose (P cellulose) and sulfoethyl cellulose (SE-cellulose) are cationic exchangers with stronger acidic groups that retain the negative charges to very low pH. Other derivatives are guanetidil cellulose (G-cellulose) for very high pH, triethylaminocellulose anionic exchanger, sefadex is an ion exchanger with cross-links. Chromatography with molecular sieve or gel filtration uses sefadex, gel of granulated polyacrilamid, agar and agarose. So this is a way of sifting molecules by size, along with electrochemical separation. The more sensitive methods used for detecting and dosing are the radioimmunologic (RIA) and the immunoenzymologic ones (ELISA).
22.214.171.124. Classification of plasma proteins
126.96.36.199.1 Electrophoresis classification.
Table 6 the percentage content of prostetic groups in
certain plasma proteins (132)
One notes the better expressed transporter role of proteins with sugars as a dominant group, the transport of lipids belonging more especially to lipoproteins.
[The remainder of Chapter Two will be featured in the upcoming September-October issue of this Journal.]
Professor Marcel Uluitu, M.D. Ph.D. began his
scientific activity in Physiology in 1953 at the
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
Dr. Diana Popa (Uluitu) is a
researcher in the Department of Microbiolgy, Immunology and Molecular Genetics
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