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 II 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 Section II (of three sections) of Chapter Two (of six chapters)]



Measure what is measurable
and make measurable what is not,
   -- Galileo Galilei (from Ev.Z. 2008) Aminoacid composition
Plasma proteins contain all the 20 amino acids, but in different quantities. Best represented acids are: aspartic acid, glutamic acid(139), leucine and least represented are tryptophan, glycine, etc.



Table no. 7 The composition of amino acids in the plasma protein (gr/100gr of protein) (139)

Aminoacid            Albumin                  -glicoprotein        -lipoprotein               Transferrin    -globulin

lisine                       12, 3                                5, 03                               10, 62                          9, 15               8, 01

histidine                    3, 5                                1, 31                                 2, 61                          3, 12               2, 55

arginine                     6, 15                              3, 65                                6, 97                           5, 03               4, 45

aspartic acid            10, 4                               7, 44                                8, 26                          11, 37              9, 05

threonine                       5, 0                               4, 80                               5, 64                            3, 75              8, 90

serine                         3, 7                                2, 51                               5, 64                            4, 28             11 75

glutamic acid          17, 4                               10, 73                             19, 20                            9, 46            12, 49

Proline                       5, 1                                 2, 37                               4, 12                            4, 20              7, 90

Glicine                       1, 6                                 0, 82                               2, 53                            3, 98              4, 47

Alanine                         -                                     -                                  5, 63                            5, 47              4, 05

Cysteine                     0, 70                                0, 60                               3, 15                                -                    -

Valin                        7, 70                                2, 82                               6, 41                             5, 05             9, 42

Methionin                   1, 28                               0, 65                                  -                                1, 53             0, 90

Isoleucin                   1, 70                               3, 85                                  -                                2, 02             2, 59

Leucin                     11, 90                               5, 21                             17, 67                             8, 21             8, 57

Tirosin                      4, 06                                1, 99                               3, 43                            4, 91             6, 75

Phenylalanine             7, 80                                3, 02                              4, 69                             4, 90             4, 79

Tryptophan                   0, 19                                1, 25                                 -                                1, 66            3, 42


Plasma protein metabolism. Turnover of proteins is variable, according to the fraction considered. Globulins have a slower turnover. Protein synthesis is stimulated by some intermediates (130, 139). Degradation products of prothrombin stimulate its own synthesis. Cytokines have different effects on the well-differentiated hepatocytes with effects on acid phase protein synthesis and on plasminogen, etc. The main plasma proteins. Prealbumin.
It is an albumin rich in tryptophan. Electrophoretically, it has more mobility than albumins. It contains sugars (hexose, hexozamine) GM = 61,000. Plasma content is 30% mgr. Its most important role is that of thyroxine transporter.



 Albumin is the most significant fraction in point of quantity. Together with prealbumins, it migrates the fastest on the electrophoregram. Plasma content is 4.5-5.5 gm%. It is very soluble in water. It has a small molecule with G.M. = 69,000. It has an important role in colloid-osmosis, adjusting the hydro electrolytic equilibrium, in blood transport processes. Its molecule is spherical or ellipsoidal. It is a polydomenial molecule and has only amino acid residues (Table No. 7). The electrical charge is given by 96 lateral negative groups and a similar number of positive ones. At the physiological pH of the blood - 7.4, it has a large number of negative charges, 12 -15 COOH dissociated protons, histidil which gives more stability. The molecule is surrounded by a layer of water. Electrophoretic mobility in veronal buffer is 6.7 -7.4 x 10/cm/V/sec. The isoelectric point is pH = 4.7. The refoldings are fixed by disulphur bridges, which favor the binding of heavy metals. Albumins are resistant to denaturizing, which is important in the plasma. It is synthesized in the liver. Albumin is distributed between blood and the extra vascular space, having a small molecule. Half of its value in blood helps to maintain volume equilibrium between the two compartments and in transport processes. Synthesis depends on their intake of amino acids, on some hormonal actions (thyroxine, steroid hormones). Synthesis is stimulated by the loss of protein, by the products of their degradation and by the action of cytokines. They provide 75 - 80% of the colloid-osmotic pressure of plasma. They have also a role in maintaining the acid base equilibrium, reservoir of amino acids. They also bind carbon hydrates, hydrophobic compounds as free fatty acids, liposoluble vitamins, steroid hormones. For binding, a pocket of hydrophobic amino acid is formed that has a collar of cationic hydrophilic amino acids. Fatty acids are attached with their lyophilic end to the pocket and with their hydrophilic end to the collar (COO). More than half of serum lipids are transported on albumin even chilom. Serine protease inhibitor (serpine) is a group of glycoprotein in serum with inhibitory action on protease having protective action on the body. They represent about 10% of the total protein levels. The group includes antitrypsin, antichimotrypsin, antithrombin III, protein C inhibitor, macroglobulin. Inhibitory activity is relatively specific. They have no role in the transport of substances through blood.It is synthesized in the liver, macrophages, endothelial. GM = 735,000.

icrons. It binds the biliary salts, acids coloring, drugs (atropine, quinine, pilocarpine, digitalis, etc.). In pathology, hyperalbuminemia is insignificant. Hypoalbuminemia accompanies the nephrotic syndrome, chronic hepatitis, acute and chronic digestive diseases, burns, bleeding, malnutrition, etc. Glycoproteins.
They are compounds that contain carbohydrates covalently bound by proteins. Almost all glycoproteins contain hexozamine (glucozamin, galactozamin) and monosaccharides. Sialic acid is a frequent component (Table No. 8). It confers molecules some physical and chemical properties. The saccharoid fraction has more frequently a branched structure and consist in saccharoid residues. Sialic acid indicates the constant presence of glycoproteins. They are present in all globulins.

Table. 8.The% content of sugars in proteins (139).


                        Protein             Hexoze          Hexozamin            Sialic acid             Fucose


                    prealbumin               1, 1                 0, 15                           0                            0  

                   glycoprotein       15, 0               12, 00                       12, 00                       1 

                   ceruloplasmin            3, 0                 1, 90                         2, 00                       0, 18

                   haptoglobin               7, 8                 5, 30                         5, 20                       0, 20

                   macroglobulin3, 6                 2, 30                         1, 80                       0, 12

                   Acid glycoprotein                                                                            

                                                 12, 0               13, 00                       17, 00                       0, 60 

                     transferrin            2, 4                 1, 60                         1, 40                       0, 07 

                     fibrinogen              3, 2                 1, 00                         0, 80                       0, 00

                   glycoprotein     6, 7                 5, 80                         4, 40                       0, 20



2.4. Inorganic compounds of plasma.


2.4.1. Water.
It is a major constituent of living things and of the environment. It represents, on average, 80% of the living body with relatively large variations from one tissue to another. Water is "le milieu interieur" according to Claude Bernard (1878). In the absence of water is cells go dry.  Depending on their position on the evolutionary scale, or on special conditions they die or can revive their activity in the presence of water (68). Water has special properties compared to other substances, which determines the Nature of the physical and the biological world. It is part of the cell structure. It is the environment in which biochemical processes and physiochemical processes are carried out. In higher living things, water is distributed in the three spaces-Intravascular (5%) interstitial (15 -30%) and intracellular (40 - 50%) or, in average figures (44) in a body of 70 kg, water represents approximately 50 liters, of which 35 l is intracellular water, 3.5 l blood plasma, and 11,5 l interstitial water. (43). The structure of water
The structure of water (68) enables the understanding of its remarkable properties. A molecule of water has the shape of an isosceles triangle, a dipole arising from the existence of the two covalent links of the two atoms of hydrogen with oxygen (length = 0.99 A) which form an angle of 104,58, sides O ---- H being equal. Covalent links separate the negative charge of the oxygen atom from the positive charges of the atom of hydrogen. A dipole is formed with intensive electronic attraction to oxygen which turns negative the local area and leaves the hydrogen area with net positive charge. Since only two electrons in the layer 8 of oxygen interact with 2 protons, other two electrons attract two other charges of positive hydrogen from another molecule. Thus,  a group of water molecules is formed having the shape of a tetrahedron around the atom of oxygen, leaving the positive charges of a molecule of water to move to the other negatively charged area of another neighboring molecule. Every molecule of water thus tends to have four neighboring molecules, and each oxygen atom is the center of a tetrahedron with other oxygen atoms at a distance of 2.76 A (68). This structure is encountered not only the ice but is maintained up to the temperature of steam as a quasicrystaline structure. (Fig-3)


Figure 3. Water structure (68)

C:\Documents and Settings\Hoteteu\My Documents\My Pictures\MP Navigator\2008_05_06\IMG_0005.jpg The properties of water.
Water is a transparent, clear liquid, colorless in thin layers (53) It is a good solvent. It has a very high dielectric constant (80 to 20C) depending on the dipole momentum.This explains its capacity of good solvent and of an environment of electrolytic dissociation. The density of water is highest at 4 C and decreases in both directions of temperature, explaining why ice volume increases compared to water and why ice floats. Its freezing point is 0 C and its vaporization point is 100 C.
Other physical properties of importance in biology are specific heat (the amount of heat absorbed by the body - water - to raise its temperature by 1C) and latent heat (the amount of heat required to change the physical state of a body - water) both playing a particular role in thermoregulation. These unusual physical properties of water are due to the intense intermolecular attraction through the hydrogen bonds located between the covalent bond and the weaker Van der Waals forces. This type of interaction is electrostatic and binds two electronegative atoms (N, O) Water in the body.
Water is the environment in which vital processes are carried out: biochemical, physical-chemical and physiological processes, by means of the properties listed. It acts as a solvent in the processes of absorption, excretion and in the transportation of dissolved substances and of gas among the three compartments in the processes of thermoregulation and osmoregulation, and as an organic and inorganic solvent. The electrostatic interactions between the water dipole and some dissolved substances lie at the basis of ionic hydration as crystallization water. Aggregates formed by molecular hydrogen bonds in the form of cavities, as hydrates, identified as  "clatrate” compounds have a still insufficiently known role in biology.

2.4.2. Sodium. Chemistry of sodium
It is an alkaline metal in the same group as Li, K, Cs, Rb (153). It is very widespread in Nature in the form of salts (nitrates, carbonates, chlorides). NaCl is a crystallized substance containing aggregates of cations (Na) and anions (CL), each of them surrounded by six atoms with opposite charges that are very hydrophilic. It is soluble in water. In an electric field, Na+  migrates to the cathode (Faraday, 1854). Sodium ions are unpolarized. It is surrounded by six molecules of water with a large diameter when in a hydrated state (Tb, 9). It has one electric orbital less and it interacts with the water dipole.

Table 9: Influence of hydration on the dimensions of ions (51).
                            ion                                    in crystal                                     hydrated     

                            Na                                        0, 95                                            3, 58                   

                                K                                      1, 33                                            3, 31 

                               Cl                                      1, 81                                            3, 32   

                               Br                                      1, 95                                            3, 30  

                                I                                        2, 16                                           3, 79   Distribution of sodium.
It is present in both reigns. In the animal body, sodium is present in the three compartments (43, 44), in varying, specific concentrations. It is present in blood and in other liquid media (53) of the body, the interstice, including in the form of deposits, and in the endocellular medium. Equilibrium of sodium in the three spaces of the body.

Its distribution in the three spaces and among the components of each space complies with the laws of physical and chemical equilibrium (3, 57) with different functional meanings as follows: Equilibrium between intravascular Na (44) and extra vascular (interstitial) Na and between that the latter and intracellular Na. Within the intravascular space, there is a balance between Na in interaction with blood proteins and chemically active Na. In the extra vascular space (51) with a heterogeneous composition, there is equilibrium of sodium, between the forms of deposit, with Na in the liquid matrix. Na balance between the three spaces through separating membranes is achieved by diffusion (85) together with other substances such as water, K, etc. amino acids, and by active processes with various speeds. Water becomes uniform in the blood and the interstice within 30 seconds while the balancing of Na requires 60 minutes. Interstitial balance and intracellular balance is obtained for radioactive water in 120 minutes, for Nain 24 hours, and for in K in 25 minutes, showing that Na adjusting is independent of that of water (43). These types of general equilibrium are dependent on the balance between intake and elimination of the cation described by a polynomial (222, 223. 227). The total amount of Na in the body is 3500 - 4500 mEq of sodium (80 - 100 gm) (43, 44). It is present in an osmotic inactive form, of which 500 mEq of sodium (11.5 gm) in connective tissue, cartilage and 1.400 - 1900 mEq of sodium (32 - 45 gm) in the bones, skin tissue and adipose tissue. 30% of Na is osmotically active and participates in the tensio-osmo-regulation process. Of the total Na, 2800 to 3000 mEq of sodium, (41 -42 gm / kg) is the amount of exchangeable cation (Ganong and Harper cited by 44). This shows the active exchange between fixed, osmotically inactive Na (35, 57, 56) and Na circulating in the interstitial fluids and blood. This distribution of Na shows that in addition to metabolic, (34) osmotic and rheologic factors, different physical and chemical factors also have a contribution such as the multitude of anionic groups interacting with Na (240) Intravascular Na.
It circulates in the blood under two forms: bound and in an ionic, chemically active state. The summation of the two forms represents total natremia. Its value (145 mEq ‰ of sodium is a biological constant with close limits of variation: hyponatremia (136 mEq of sodium) and hypernatremia (160 mEq of sodium) (8, 187). Exceeding of these limitations (74) is associated with general disturbances which, uncorrected, are incompatible with life. Blood homeostasis of Na.
Blood Na homeostasis is maintained by complex neurohumoral and physical-chemical, biological mechanisms. In the capillary membrane, Na in excess goes into the interstice and is stored in the connective tissue, bone, and subcutaneous fat (82). In hyponatremia, correction is achieved by mobilizing deposits of Na, the exchangeable fraction. Other mechanisms recognize changes in blood mass through the migration of water in the tissues hypernatremia and dilution of blood Na, or its passage into tissues, that become inundated, in hyponatremia. In pathological conditions, there may develop an imbalance between the Na content of deposits and its plasma concentration. The resulting hypernatremia draws attention to the fact that the possibility of fixing Na on the deposit sites have been exceeded, or to the loss of water in relation to the content of Na (7, 75), when along with increased protein concentration there is increased natremia. Hyponatremia occurs (8) by Na loss: sweating, diabetes mellitus, gastrointestinal disorders, burns, hypodipsia, impaired adrenal cortex (14, 212) or after administration of drugs (67), lithium, vasopressin, etc. The role of sodium.
It is a cell activator (61). It plays a decisive role in the processes of cell excitability (83), the genesis and transmission of action potential (28). It influences the accumulation of amino acids in the extra cellular space.Na acts as an enzymatic activator (152). It induces allosteric changes to thrombin in blood coagulation (9, 40.49). Sodium is involved in the acetylcholinergic synaptic transmission (4) since it can pass through the channels of acetylcholine (94, 106). In the interstitial space, it forms electropositive, pericellular clouds with a role in the genesis of action potential (174, 179, 4). In baby rats (2 - 21 days old) there is a high density of Na currents around the cortical neurons that appears to control their intrinsic excitability at that age (6) Determination of plasma sodium. (2, 3, 43, 59, 58, 131, 101, 153, 211)
The interest for sodium has stimulated elaboration of a great number of methods for its quantitative determination in biological fluids and in the excitable structures. It occupies a central position in mental activity (179). Dosing it is difficult. It is diamagnetic. Compounds in which it is included have little coloring. To this, one should add the heterogeneity of the biological environment: high content of electrolytes, amphoteric substances, macromolecules, etc. Moreover, measuring of total Na content is irrelevant for deciphering its physiological role. For this purpose it is necessary to determine the active chemical Na, including the balance between the bound forms and the free, active form, membrane medium included (29, 35, 68, 149). Therefore, one is interested in the total content of Na, the concentration of chemically active Na the strength of binding forms interactions and the Nature of the transporter. Dosing methods are well-known biological, chemical, physico-chemical and physical. Biological methods.
They look at the chemical state of Na: sodium in the red cell, which changes slowly with the medium of suspension (70); in the muscle there is a fraction of sequestered Na, as in the oocyts of amphibians. In humans, using the principle of Gerbrandy to determine the fraction of bound electrolytes, it was concluded that 6-10% of plasma Na is bound (233). This very small fraction is explained by the fact that the venous stasis that accompanies the accumulation of H-ions, displaces Na from its interactions with proteins. Other results show that the chemical activity of Na and K falls, in the presence of protein as well as in the presence of fibrinogen. Chemical methods.
Their use requires a pre-separation of the cation from other compounds in solution with which Na interacts. Chemical methods are suitable for determining total Na in blood after precipitation and centrifugation. Estimation is performed by titrimetric methods. (86, 244). Physical methods.
(a) absorption in ultraviolet, visible in the X-ray
(b) emission spectroscopy
(c) electroanalyitcal methods (122) including potentiometry determinations with ion-selective electrode and voltammetry.
(d) isotopic

(e) nuclear activation
(f) chromatographic
      (a) absorption spectrophotometry and fluorimetry are based on the interaction of metal and of compounds that contain it with electromagnetic radiation, according to Beer-Lambert law expressing linear dependence of the absorption of radiation on concentration of the substance. In principle fluorimetric methods consist in the linear dependence between the excited molecules and light emission in the course of returning to the fundamental state, according to Stokes law. However, this requires chelating with organic compounds preferably with aromatic compounds, forming fluorescent compounds. Chelating and is also used in absorption spectroscopy. The methods require a prior separation, the most widely used one being the methods of separation by chromatography.
       (b) emission spectroscopy: Flamephotometry is a method of atomic emission, the atom is excited by flame and the intensity of emission is proportional to the atomic concentration. The Na emission lines are the D lines with a wavelength of 5890 and 5896 A. The method is applied for determination of total cations (Na and K). The organic substances are completely destroyed by combustion. It has great value for clinical use.
Flame-atomic spectrometry. The biological specimen is atomized and excitation is performed with a cathode lamp adjustable for specific wavelengths.
X-ray spectrometry uses atomic activation by means of X-rays and X radiation emitted is recorded.



      (c)Electro-analytical  methods (29, 74, 125, 142, 149, 150): Potentiometry with ion-selective electrodes measures the plating cell potential versus the reference potential "0" As a principle, the potential of the active electrode versus the reference potential is proportional to the concentration of active chemical species, selected by the ion-selective electrode similar to the H electrode in pH determinations. The method is used for determination of electrolytes in whole blood, undiluted plasma and other biological fluids (84). The ion - selective method produces the value of the active form of ionized Na and K mM /l, lower than values obtained by flame photometry, either because of Na binding protein or the formation of ion pairs (126). The precision of the method increases as the degree of dilution increases and is maximum for the basic condition: infinite dilution. The ion-selective electrodes can be used in vivo and in cell cultures (35) enabling the study of the Na / K during cell function. Anodic voltammetry also uses selective electrodes versus the reference, mercury electrode.
      (d) The methods include isotopic methods of analysis by dilution with isotopes.
      (e) Methods of nuclear activation (Neutron activation analysis = NAA). In this way the sample is irradiated with thermal neutrons and emits    radiation,,,, which can be determined.

(f). Chromatographic methods also require preseparation of cationic with various means: electrophoresis, precipitation, ultrafiltration, dialysis. Chromatography was originally used for the separation of organic species and subsequently to metallic ions. Adapting these methods for inorganic analysis was done by amending the two phases, stationary and mobile, simultaneously or successively, as needed (125), for the monovalent and divalent cations.  Chromatographic columns are made of glass or metal (aluminum) filled with inorganic or unpolar beds with different additions: tyramine, compounds in the crown for excellent separation of monovalent cations, followed by photometry (150, 179, 200, 201). Stationary phases may be liquid, cellulose, silicagel, polyacrilamide, alumina, alone or in mixtures adsorbent, inorganic ion exchangers (aluminosilicates rich in Na, K, Ca, Sr, Ba exchangeable with cations in the electrolyte solution, hydrated oxydes, etc.) Organic on exchangers: ion exchanging resins with varying degrees of acidity, resins of cationic polymerization, basic resins, chelated, amphotere resin that have incorporated complex agents, or chelating agents with a high capacity of selectivity, electrons exchanger resins, resins with varying degrees of porosity, with polar groups which gives them hygroscopicity, by interacting with ions which alter their Natural hydrophylia Na K Cs Rb Li. The stationary phase can be modified by impregnation with polysaccharide ions: heparin (179 ), dextransulphates, condroitinsulphates with sulphydrilic groups that set cations. Heparin (considerably reduces the retention of anions), biliary acids, etc. The impregnation of the stationary phase with special substances, allows the separation of anions and cations also according to their valence. The chromatographic separation enables one to obtain values comparable to other methods. The eluent can be chosen and prepared so as to allow selective elution also function of the fixed phase, HCl, tartaric acid, etc. Among the methods outlined, the vast majority do not meet the basic condition i.e., to keep intact the structure of the composition of the environment including macromolecules. The methods that use ion-selective electrodes meet these conditions to the largest extent, being also used in vivo. They require special attention for more convenient measurements. I presented the factors affecting the values of the chemically active Na+(231, 232, 233). Plasma Na+ is in interaction with a wide variety of anions and anionic sites on macromolecular compounds and in conformity with the law of multiple equilibrium, the energy intensity variables.



       2.5. Interactions between plasma components.


        2.5.1. General.
The physical, chemical processes and the transport of substances in the blood take place in conditions of constant temperature and pressure. These processes are controlled by concentrations, structural properties and their reactivity (162, 239). Substances dissolved in plasma are defined as ligands (L), transporter (T) and disturbing agents (159, 188). Ligands are soluble substances; they are very polymorphous, from electrolytes to proteins (161). The transporters (T) are most often protein-bearing reactive ionizing groups (12). They interact and are thus the conduct of their physiological role is assured. LT interactions depend on: (1) the Nature of the ligand, (2) the Nature and concentration of the carrier, (3) their affinity and type of interaction, (4) mechanisms for the release of ligand to the target, (5) modifying components involved in the physiological and pathological processes.

From the point of view of 2nd law of thermodynamics, transport occurs if there is a gradient different from "0" of one parameter.

The thermodynamic force generates a stream (94), whose final purpose is the destruction of the gradient. In living systems, however, regeneration of the gradient occurs at the same time with the cancellation of the gradient by means of general biological physical and chemical processes, and by means of metabolic processes. The Natural processes involved in gradient destruction are: diffusion, convection, osmosis, adsorption and absorption, capillarity, etc. The action of mechanical processes and the flow of fluids (blood, lymph) are added to those processes, speeding up the destruction of the gradient.



2.5.2. Ligand/transporter interaction (L / T) (101)
All the molecules attract one another from distances not compensated by repulsion forces (92,218). The LT bond is uncovalent, electrostatic, of low intensity, variable, nonspecific and therefore allows different combinations. Strength depends on the anion - cation distance, on for the number of opposite sign groups in the neighborhood, the number of water molecules around the ions, their polarizability (57, 56). The ligand observes the law of mass action for a bimolecular system.

[L] + [S] => [LS] where [L] = ligand [S] = site on the transporter: k = association, dissociation constant. The equation to balance measures the affinity of L for S, which is defined by the relationship:
K = [L] [S] / [LS]] = K / K
Determination of the constants K1 and K2 above in vitro, requires very pure and stable ligands and in order not to alter the data by the presence of nonspecific binding (231, 236, 167, 168, 224). One can use substances that allow the characterization of the competing set of particular places. The ligand-transporter association constant increases with temperature. There is an inverse correlation between serum protein concentration and affinity. The characterization of the physical-chemical interaction LT enables the determination the number of reactive sites on the transporter and of the equilibrium constant Kd. It defines the number of coordination - the number of molecules attached to the central ion according to the binding theory (Klotz, 112) which uses molecular orbitals and the theory of binding valence (10). Measuring of the transporter ligand is done through various methods: filtration, centrifugation, dialysis equilibrium (232). This method has enabled identification of the Na chemical activity in the blood. The criteria for specificity of LT binding are saturability, reversibility, physiological and pharmacological specificity. Binding stereospecificity is a measure of selectivity.

Studies of saturation of the process of interaction, enable the determination of binding parameters (218, 232, 233, 231, 224, 236): the density of binding sites (Bmax) (92). The kinetics of the LT interaction is being investigated on the basis of the law of mass action and of the Michaelis-Menten equation. The binding constant and the number of binding sites (Bmax) are calculated with the Scatchard equation (180):

                    B / F = Bmax-B / K (180)

The regression curve is right for a single set of interaction sites on the transporter. Non-linearity indicates the existence of several other sets of sites.
The role of LT interaction. The free fraction of the ligand is biologically active. The LT association also operates as a place of storage. In these conditions, the ligand is released gradually according to the multiple equilibrium theory (Klotz) (112, 143) as it is consumed in the target organs. Determining the two forms accompanying some disorders in cases of abnormal transport has etiopathogenic value. More and more data free is accumulated in favor of the need to investigate the mechanisms of blood transmission of some substances: hormones, electrolytes, suggesting the concept of blood transport pathology, the dynamics of this process including the association and dissociation of the LT complex.



       2.5.3. Types of L / T interaction.

 Ionic bonds.
Ionic bonds are interactions (147) between alkaline metals and ionic groups, especially the oxygenated ones, between which there is a partial transfer of electrons from metal to nonmetal (101, 153, 159, 213).

 Hydrogen bond.
The hydrogen bond (218, 147) appears as an auxiliary valence of hydrogen covalently bonded with a strongly electronegative atom (O2, N2). The most frequently encountered are those with proteins that act as a donor and acceptor of proton (12, 52):


          Table 10: Types of hydrogen bonds (52).

              - O-H. ....... O - H
              - O-H ........ O - C
              - N-H ........ O - C
              - N-N ,,,......N -
The Nature of the interaction is electrostatic, with an intermediate electronic distribution between the mezomeric forms. Bridges are usually the privileged directions imposed by the strongest interaction corresponding to co linearity. Van der Waals forces.
These are intermolecular forces of attraction between the fluctuating electrical charges (153). Interactions are established: between groups with opposing electrical charges as associations between pairs of ions forming saline bonds or interactions between positive groups and chargeless groups, or between polar groups without significant charge. Within the hydrophobic inside of the protein molecule, there is a dielectric medium which favors the polar interactions. Electrostatic interactions.
Electrostatic interactions act alone or in connection with the bonds discussed above. They operate between all molecules at a distance non-compensated by forces of repulsion. London forces of dispersion.
London dispersion forces operate between molecules and are due to the electric field of the dipoles with very short life induced by the nucleus-electron motion of a molecule. Physical forces of adsorbtion-desorbtion.
There are physical forces of adsorption / desorbtion on the surface of serum protein. The processes have no curve of saturation. The role of water.
Water plays an important role for development of transporter-ligand interactions (27). Water has a high dielectric constant because of its hydrogen bonds between molecules. Its molecules combine with ions and produce hydrates at the water dipole. Cation - association.
Association cation- is a form of interaction of cations with aromatic amino acids. It has been incompletely studied up to now, both as a functional mechanism and in point of its functional significance as another mode of transport for Na. Cation- interaction - is formed between Na and the  orbitals of aromatic amino acids. This interaction is uncovalent (49). It was identified through crystallography in 1960. Cation- associations are structural and functional aspects of static and dynamic energy of the protein.

The compound is formed of the ligand and the aromatic residues of the amino acid side-chains of protein. The ligands are cationic amino groups (68), alkaline metals, etc. The structures involved in the interaction with cations (Table 11) are aromatic amino acids or their residues from protein compositions, phenylalanine, tyrosine, tryptophan, pirolic ring of globular macromolecules (90), acting as a donor of electrons, and provides flexibility in environments with low polarity and favor cationic access to imidazolic level, preferred to form the cation -complex with smaller distances than Van der Waals forces. Cation - interactions are also established with polar and hydrophobic residues (48) between coordinated ligands to a metal cation. These coordinated ligands interact with asparagine, aspartic acid, glutathione, histidine, treonine, valine, (251), with two molecules of water (250), lisine (184). Aromatic rings have a well defined electronic  distribution whose result is that cations are arranged perpendicularly on a plane. The study of cation- associations is performed with computational methods, with mass spectroscopy, analysis of solid structures, crystallography, fluorimetry (emission of fluorescence analysis) of aromatic nucleus in interaction with metallic cations (Na, Li) (226). The mechanisms of -cation interactions are multiple. Forces of electrostatic attraction correctly describe the -cation interactions (48) between cation positive charge with quadrupolic momentum of the aromatic ring. Chemically, there are also cation- non-conventional interactions, where the electrostatic attraction is achieved without an input of electrons (184). In some cation- interactions there are phenomena of polarization deducted from the effects of perturbation of the potential of general molecular interaction. The polarization is accompanied also by electrostatic forces and by dispersion-repulsion forces. Molecular interaction through polarization enables the very quick binding of cations to aromatic compounds (42). From the analysis of the fluorescence emission of the solution containing aromatic amino acids and cations (Na, Li) one demonstrated the deactivation levels of radiative energy transition of the  orbitals (226) and established that the bases order of anions is


                      indol phenol benzene

in the interaction Li- when anions are reduced in the presence of a cation (96).
    The role of -cation association. This association is a favorable interaction in biology (184) in various proteins that interact with cationic ligands (250). They are involved in molecular recognition (9, 40) - at the interface protein - protein and stabilization and defining of the Native structure , (68, 157) in conformation and stability of metal-enzymes (68) and the functioning of the enzymes that have a metal coordination center (88, 68) and in the ion channel structure (37, 42). Sodium is non-polarizable and that is why it does not have a preferential relation to an aromatic compound. Its interaction in this association is electrostatic and perfectly describing the correlation between the self-regulator field of energy and the molecular electrostatic potential (42). These interactions are accompanied by coulombic forces, the transfer of charge and Van der Waals forces and orbital energy of molecules in which Na is merely a non-polarizable particle (42). It also established contacts with four carbonyl oxygen of leucine, proline, and valine tryptophan and two water molecules. In these conditions, Na has a binding character between migratory carbonyls of valine and tryptophane (37, 250). The association Na / phenylalanine is characteristic to IP-cation interaction in biological molecules. The phenyl ring has but a small contribution to these associations. Phenylalanine derivatives have a higher affinity for Na (65). Association with tryptophan confers substantial stability in the medium with low polarity (94). In these interactions, Na binds for electrostatic reasons, perpendicularly to the plane aromatic compound.

Table 11. Ionic composition of plasma (68)


protein groups, electrolytes, free amino acids, aromatic amino acids.

(1)    (2)     (3)   (4)    (5)      (6)        cation -


COOH   CH     Na   Cl aspartic  involved      tyrosine

OH    CHOH     K    SO glutamic     in         phenylalanine

CHO   CH    Ca   F  histidine quilibrium    tryptophan

CO    CH    Li    -   lysine     multiple     histidine

NH  CH    -     -   treonină      -         aspartic

=NH   CH     -     -    cystine        -       asparagine

CONHCH      -     -    arginine       -       treonine

CORNH   -       -     -       -           -       valine

SH      -       -     -       -           -       lysine

 (1) = hydrophilic radicals. (2) = radicals hydrophobia      




        2.6. Chemical activity of plasma electrolytes.


Research of X-ray diffraction (68, 153) showed that dry NaCl crystals are formed by ion Na and Cl just like in solution. Ions in water can move freely due to the dielectric constant of water. In a solution containing NaCl and polianions, there is a free equilibrium between free Na and Na retained around the polyanion through various interactions. The free fraction is quantitatively less than that measured by potentiometry or conductometry, therefore it does not show the results of dissociating theelectrolyte (153), (the vapor pressure, cryoscopic point) which would explain the number of particles resulting from dissociating them described by an equation of the type

                          NaCl Na + Cl

because there is no such equation, and also a constant k.


The chemical potentials”” and”” of the solution of NaCl (Debye-Huckel cit.153) are associated with their concentrations by the equations: 
                         =+ RTIc


                         =+ RTIc

, where c and c are concentrations of Naand Cl.
 and  are the coefficients of activity needed to apply the equations above. The values of the coefficients ranged from "0" and "1" value "1" is reached at infinite dilution.
                    Activity =x c (concentration)
                    = activity / concentration where, the activity is actually a concentration of ion in solution.

From this data there results an apparent decrease of the concentration of ions with opposite sign, by the attraction between them, with solvent molecules or anionic sites of proteins, when calculating the concentration, a value defined as " cation activity." Electrostatic forces decrease the free energy in parallel with increasing the concentration of salts and increase the coefficient of activity. The notion of "activity" is used correctly instead of "concentration" for electrolyte solutions, defining the actual capacity of interaction of free reactive forms . The activity of blood cations is an incompletely clarified concept due to the complexity of the environment that changes the free forms of cations. The values reported depend on the method used to determine them: the elimination or modification of proteins or by the accumulation of catabolic acids (121) or in the presence of purified proteins (137) or by methods that preserve the structure and function of macromolecules (228, 231, 232, 233) using competition of polyanion heparin for serotonin, - a method accepted and recommended by Al.Monnier (see facsimile). The results obtained with this method show that in the blood serum collected from different species, the activity is evident only after denaturizing by mechanically stirring the serum. According to this data, in humans and rats (normal) one cannot detect the cationic activity of sodium. This is in interaction with blood proteins (Table 11).


2.7.The transport of some substances in the blood.

2.7.1. General.

A chapter of such an expanse requires a thorough treatment, which is not our intention. The paper only aims to illustrate the problem with some substantial examples  in support of the idea of the physiopathologic significance and physiologic mechanisms of transport in the blood of certain substances, thus suggesting the opening of a new chapter of physiology, to explain the fundamental physical-chemical mechanisms at the molecular level.

2.7.2. Calcium. (68, 78, 204)
It is very well represented in the body. It has an important role in the processes of neuro-muscular excitability, the transmission of nervous influx, an antagonist of K and the sympathetic system, in haemostasis, in body static and dynamic, the bone structures of resistance.
Its distribution in the body is unequal. Of the total quantity of 1000 - 1500 gm., 99% is found in the bone, bound to the organic matrix of collagen, 1% in tissues and 0.1% extra cellular and plasma : 

                      Ca = 6Ca – Pr / 3 / Pr + Ca.

Binding to plasma proteins depends on their concentration, environment pH, H antagonizing the binding of Ca .
Ca  homeostasis is maintained by digestion intake, elimination by the kidney and bone metabolism. Digestive intake is reduced by prolonged treatment with antibiotics, in steatorrhea, the deficit of bile (hepatitis, cholestasia) that disturb the absorption of liposoluble vitamins, including those in group D, followed by perturbation in protein synthesis intestinal transport of calcium (Calcium bind protein (CBP). In this case, a chronic disorder occurs in the metabolism of calcium. such as spasmophilia, also interesting prevertebral muscles of the cervical vertebra, involved in the upright posture (234, 235). Hypercalcaemia is encountered in hemoconcentration, decalcification, bone rickets, osteomalacia, hipoparathyroidism, nephrophaty, etc.. It is accompanied by muscles hypotonia, constipation.



              2.7.3. Magnesium.
It is also a chemical element bivalent in the same group with calcium, unequally distributed in heart, liver, brain, bones, etc. Only 1% is present in the extra cellular environment. 35% of it is bound by albumine.In plasma and red cells, there is 1.5 - 1.8 mEq of magnesium of which 1.3 mEq bound to proteins. Its intake is under endocrine and vitamin control. Magnesium is involved, like calcium, in muscle excitability.

              2.7.4. Copper.
Copper (26) is involved in the processes of oxidoreduction and brain function. 90% of blood copper is transported bound firmly to ceruloplasmine, a-glycoprotein. 34% of that protein, is associated with copper. Under the influence of kelating agents, it loses copper and is whitened. The strength of interaction is different. Copper interacts with the carboxylic residues of the glutamic and aspartic acids. Perturbation induced in the copper transport is expressed as hepato-lenticular degenerescens (Wilson's disease) and psychosis.




          2.7.5. Iron.
On discussing the physiology and physiopathology (142) of iron, one must take into account the processes of transport and storage. Ferric iron is transported on transferrin (siderophilin), a -globulin which binds 1.25 mgr iron / gram protein. Under normal conditions, 30 - 40% of transferrin is saturated with iron. The mechanism of fixing iron to transferrin is regulated by "up" or "down" regulation controlled by the amount iron in the body. The amount of iron in the body is 4 gm, stored on ferritin whose various Names refer to the number of iron ions bound: apoferritin which has no iron, monoferritin with an iron atom, diferritin having two atoms of iron and hemosiderin, the form saturated with iron , 37%. The iron in plasma and interstitial iron is carried entirely to the target haematopoietic organs, attached to transferrin.


         2.7.6. Hemoglobin.
Hemoglobin is transported to the reticuloendothelial system on haptoglobin, a glycoprotein of the globulin fraction from plasma, a polycatenar molecule containing sugars 22.7%, 5.5% sialic acid. Low values of haptoglobin are present in hepatic failure and anemia.



         2.7.7. Oxygen.

Oxygen is transported through well studied, understood reaction, on hemoglobin and can be correctly described by the dissociation curve of oxyhemoglobin (78, 99).



         2.7.8. Serotonin.

Serotonin (219, 220), a biogenic amine derived from tryptophan is involved in the function of the nervous system as a synaptic mediator. It has importance in carcinoid pathogenesis. It is completely transported, under normal circumstances, attached to platelets. In pathological conditions, its transport is perturbed and 5HT is also present in a free state in plasma.



              2.7.9. H-ion. Acidic-basic equilibrium.


Metabolic processes going on in tissues generate H+ which affects the blood pH shifting it to the acidic side. Depending on the intensity of metabolic processes, there are differences of pH of the efferent blood of different organs. Difference of pH also exists between different segments of the vascular tree. The pH of arterial blood is 7.4 and that of the venous blood is 7.35. A constant concentration of H is maintained through two main mechanisms.

In the first stage, the physical-chemical processes of the blood buffer systems come into play for the maintenance of the acidic-basic balance (68, 78) (Henderson-Haselbach equation).
                   pH = pK + log [A] / [AH]


describing the couples of acid/base buffers. There are four buffer systems in blood: H CO/ NaHCO: NaHPO/NaHPO: acidic Hgb./ Hgb : Acidic protein  / Na protein.

In the mechanism of maintaining the blood pH, the most important role belongs to red cells and plasma proteins. Proteins intervene by their lateral and masked amino acid residues. Thus in the acidic environment, proteins accept a greater quantity of protons . At the level of elimination organs, protons are dissociated from the protein and removed. This is the second phase of mechanisms that maintain the blood pH. The concentration of hydrogen depends on age, activity, nictemer, digestion phase, etc.




           2.7.10. Circulation of hormones with transporters.
Chemical and functional heterogeneity of hormones is manifested in the mechanisms of transport in the blood (202). Some are transported in a free state while others are bound to transporters. Between these two forms there is equilibrium. The unbound fraction is biologically active.
The transporters are proteins in the blood, most of them isolated and well characterized. (Table. 12).



Table. 12. Transporters hormonal blood protein. (221)


Protein transporter                                                                         MW                       fluidic fractions number.


HSA     ( hormone serum albumin)                                              69.000                                  0

CBG     (corticosteroid binding globulin=transcortin)                 52.000                                26 

AAG    (  -acid glicoprotein )                                                 410.000                               42                                                
TEBG (testosterone-estradiol binding globulin) 94,000       32
TBG (tiroxyn binding globulin)             88,000           71
TBPA (tiroxyn binding prealbumin)         500,000            0
SHBG (sex hormone binding globulin)
IGF-BP (insulin like growth factor binding)



                      2. 7.10.1. Growth hormone (GH).
The growth hormone (GH = somatotrop). It has 191 amino acid residues in its  structure (242). Its molecular weight is 21,500. It has two sulphuric bonds. In the peripheral blood one can detect a series of oligomeres of GH (up to minimum one pentamer ). GH acts through somatomedins. It is secreted by acidophilic neurotrope cells in the hypophysis concentrated more on the lateral sides.

 Regulation of GH secretion is achieved through the nutritional status and the stress of organisms, of which the most important is the level of cellular proteins. Malnutrition stimulates by feedback (60.14) the secretion of growth hormone through hypothalamus with a regulatory loop that includes somatoliberine and somatostatine. At the hormone receptor level there occurs the separation of the polypeptide hormone from its plasma protein transporter. The molecular weight of the receptor is somewhat smaller than that of the original isolated receptor, the difference being given by glycosilation. Anomalies of the complementary DNA encoding for GH receptor are found in children with Laron dwarfism (syndrome of resistance to GH), proving the biological importance of the receptor.
Protein binding GH.If radiolabelled monomeric GH is incubated with human plasma, it produces two forms of high molecular weight, due to the presence of a protein binding, which is identical to the extra cellular domain of human growth hormone receptor. The absence of the binding protein from the plasma of Laron dwarfism patients who are running a deficit of GH receptor supports the existence of the relationship between protein binding of GH and receptor. 45% of GH has the molecular weight of 22KD, of which 20% complexes the  binding protein and 85% is involved with the regulating protein with great affinity. When the concentration of circulating GH highly exceeds the value of 10 ,20 g %o a relatively smaller proportion is linked to the transporter protein. Protein-bound GH is metabolized differently from the monomeric GH: it persists for more than 10 times in plasma and its volume of intravascular distribution represents twice the compartment, while monomeric GH is present in the extra cellular space. These two factors may increase the biological activity of hormone binding, but are counteracted by the competition for binding between receptor and circulating protein. Plasma protein concentration is constant for each individual. Plasma protein is higher in childhood and decreases with age.

It increases during slow wave sleep and during the intake of free fatty acids. It also increases during fasting in anorexia nervosa, cirrhosis. It decreases in obesity, the emotional disorders (emotional depression). GH stimulates skeletal growth, the growth of connective tissue, of the muscles, of the viscera. There are two hypotheses concerning GH actions: the first one admits a direct action on cells, the second insists on somatomedinic mechanisms, attributing a special role to IGFI,


Are represented by a group of polypeptides with low molecular weight (6.000-8.500 D) with insulinoid actions. Somatomedins are produced under the influence of GH. They are transported in plasma, bound to large protein molecules . Two proteins with insulin structure were isolated from the blood: IGFII and IGF1 (insulin like growth factor). The molecular weight of IGFI is 7000 D, its izoelectric point is 8.2. Its proinsulin amino acid sequence is formed from a small chain polypeptide (70 amino acids residue) This somatomedine differs from proinsulin in the C peptide: IGFI has a sequence of 12 amino acids while proinsuline has 35, with a different sequence between sequences 8 amino acids and 12 amino acids. At this level, proinsulin is cleaved before secretion, while the IHFI cleaves after secretion. IGFI synthesis is probably performed in the liver. 85% of IGFI is carried by a protein with GM = 100,000 and the rest by another protein with G.M. 50000 = D. Synthesis of the first transporter protein is dependent on Chin the event of a deficit of GH, this protein is replaced with protein MW = 50.000.The IGFI binding protein is identified as IGF - BP and can be used as an indicator of the secretion of growth hormone in acromegaly. Circulating somatomedine-transporter complexes are inactive and a separation process occurs in order to cross the capillary wall in the interstice and from here to the target cell. They appear early in the intrauterine life (week 20) when GH is not yet synthesized. IGFI receptors are already present. This decreases sharply after birth, in maternal blood. Somatomedins regulation is by GH, especially for IGFI. Adjusting secretion of hypophysary GH is achieved by inhibition of somatoliberin and stimulation of the release of somatomedine. Estrogens decrease IGFI concentration in normal subjects and in acromegaly. The biological effects are related to IGFI binding to cellular receptors on condrocytes, lymphocytes, adipocytes, fibroblasts. IGFI has tyrosinkinase properties, which IGFII does not have. Somatomedins are fundamental factors for the growth of cells, they mediate some cellular actions of GH.

They influence protidic and lipidic metabolism and, like insulin, stimulate the transportation of glucose and amino acids into muscles, but by different mechanisms than those of GH (36). They stimulate the formation of the organ and bone matrix, capturing sulphate and thymidine in condrocytes whose growth they stimulate. The somatomedinic hypothesis starts from the observation that the growth of the mitotic cartilage in vivo depends on the presence of GH inactive in vitro. It is known that IGFI and IGFII are components of the serum. IGFII is increased in acromegaly and low in growth hormone deficiency, suggesting that IGFI is the main mediator under the influence of GH, the locally produced IGFO contributes to the stimulatory effects of GH in particular to longitudinal growth.



    Thyroid hormones.
They are iodate derivatives of tyrosine: tetra and triiodothyironine which have thyreoglobulin as a precursor. Thyreoglobulin is present in colloidal thyroid follicles and plasma. Thyreglobuline is a glycoprotein. Electrophoretically it migrates with albumin. Thyroid hormones are transported in plasma almost entirely in a free state: T in a ratio of 0.04% and T in a ratio of 0.4% are bound. The unbound fraction is active on target cells and is operated by a feedback mechanism. Transport in the blood is important both to hormones (203)and plasma iodine which is organicized in the thyroid gland. Iodine is carried by the transport protein of iodine (iodine binding protein = PBI). Iodine is carried actively in the thyroid through a mechanism of sequestered iodine pump. Its content gives indications about circulating hormones. There are three Tbinding proteins in the plasma: thyroid hormone binding iodine (TBI) ( It is a glycoprotein monomer, with a concentration of 1-2 mg /dl, and a half-life of 5 days. It has only one binding site for T and T. It   carries 70% of thyroid hormones for which it has high affinity. In electrophoresis it migrates between and -globulin. TBPA with plasma concentration of 25mg/dl with the half-life of 2 days. It carries only T.

It carries only T. It has less affinity for the hormone. Carrying 20% of T. TBPA is synthesized in the liver. Albumin and prealbumiNa carrying 10% and 30% T, T. Capacity binding protein is influenced by certain conditions, and especially the TBG. Increased protein decreases the level of T and  temporarily increases secretion of hypophysial TSH , therefore the synthesis of T and T At the same time with modifications of binding protein concentrations or their capacity to interact with hormones there occur changes of hormones concentration. Converting T to T is dependent on deiodinase in the pituitary and liver. There are a multitude of(242) conditions in which TBG may modify its ability to bind thyroid hormones. T is deiodinated at T in peripheral tissues: liver, kidney, brain, thyroid. HT level (198) is not influenced by age though the proteins are modified: albumins concentration decreases and there occurs a high concentration of -globulins. TBG synthesis is accompanied by increased blood lipids that inhibit the binding of proteins to T transporter, TBG, TBPA and prealbumins, a process, called "thyroid hormone binding inhibitor = THBI. Thus, T binding decreases in the elderly who have a poor state of nutrition. THBI increases its activity if the TBG and albumins decrease. It therefore lowers the concentration of bound T and increases the free form especially if chronic respiratory, kidney, cardio-vascular diseases are present and accompanied by a decrease in T3 as well.

Adjustment of thyroid function is performed by classical mechanisms involving the thyroid, hypothalamus, pituitary and peripheral consuming hormones, with a feedback mechanism. HT complexity of action, with the associated transport mechanisms, requires in addition to clinical activity of the thyroid gland the highlighting of quantitative aspects by determining their concentration  and the investigation of transport mechanisms through several methods:
(1) Determination of iodine-related PBI.
(2) The analysis of state of competitive binding by determining competitive dislocation  of T4 from TBG.
(3) Radio immune methods.

(4) Measurement of serum T4 and T3. Dosing of T3 has no meaning, its values are always normal in the plasma.T4 values (70-150 mM% a) reflect binding forms.
(5). Dosing the quantity of free hormones by equilibrium dialysis method, against a buffer, in such a way that only the free hormone can dialyze. From the dial sate one determines the hormone radioimmunologically. The method has heuristic value.

(6) Analogue methods analogous. An HT antibody is added and one determines a derivative marked by HT (analog), which binds de -antibody and not the binding protein of T. Competition between the analogue and the free HT allows determination of free HT.
(7) Immunoanalysis in two stages: first, free HT is extracted by fixing on an antibody and in the second phase free HT marked on the antibody unoccupied sites is measured.



    Corticosteroid hormones.

Corticosteroid hormones are somewhat similar mechanisms of transport (246). The adrenal cortical has three distinct morphological, enzyme and secreting areas: the glomerular area secretes mineral corticoids (aldosterone, desoxycorticosteron): the fasciculated area secreting glucocorticoids (cortisol and corticosteron): the reticulata, which secretes sexoid hormones (dehidroepiandosteron, androsteron, oestrogens). Their blood levels vary with age, nictemer, the level of physical activity, etc.. Adrenal cortical hormones are derivatives of cholesterol (215, 216) with progesterone as their turntable. Adrenal cortical hormones, as in fact all steroids, are transported in the plasma, most of them protein-bound (54). A small fraction of bind to circulating red cells and a lesser part are in a free state. 20% of aldosterone and 5% of the amount of cortisol are associated with red cell. The proportion related to red cell is influenced by the concentration of total blood. Protein transport of corticosteroids (tb.nr13).

Table No 13. Transport of major corticoids (78)


       Hormone        %free        %albumin bound      %bound CBG

       Aldosterone      37              41                 22
       Cortisol          4               6                 90

The adjustment of cortisol secretion recognizes the general feed back mechanism having as the starting point the concentration of free hormone. In humans, CBG binds up to 25g / gm. As CBG becomes saturated, binding passes on to albumin. The adjustment of mineralocorticoids secretion has a more complex mechanism, involving, in addition to the common stimulus - the concentration of free hormone in blood-  the level of extra cellular fluid and of the blood, arterial pressure, Na and K concentration in plasma correlated with the renin-angiotens in the system. The corticosteroids pathology  recognizes as a mechanism, their synthesis, concentration and quality of plasma protein transporter, mainly CBG, (80) and finally the relative strength of the tissue toward the hormone, thus lowering their use. Structural changes in quality and reactive protein transporter works by increasing the processes of dissociating the complex CBG-cortisol. CBG activity is low in some types of stress (bacteria shock, fungi, or surgery, burns, operations in the abdomen and thorax, etc.).

Hypoalbuminaemia is also accompanied by a decrease in bound cortisol. These data confirm the importance of binding and transport mechanisms in the pathogenesis of endocrine disorders interesting the glucocorticoids. These processes are difficult to highlight in the case mineral corticoids processes, as binding and dissociation are fast and the hormone is bound for  less time. Adrenal sexed hormones have mechanisms of transport and binding similar to those of gonadal hormones. They are bound by SSBG glycoprotein (tb.12) and albumin for which they have lower affinity.


    Gonadal hormones.
Their synthesis takes place through the same mechanisms as those of other steroids. Synthesis has acetyl coenzyme A as a starting point (216). The sequence is: mevalonic acid, cholesterol, progesterone and finally steroid hormones.
Male gonadal hormones: testosterone is secreted by the Leydig interstitial cells together with androstendion and dehidroepiandrosteron. Plasma concentration of testosterone in adults is 0.65g/ml, of which 23% is bound. Androstendiol has a concentration of 100g/ml. And dehydrotestosteron concentration is of 30g/ml (23).

Testosterone circulates in a bound state, bound 100% to a β globulin, TEBG, having low capacity and to SHGB, together with dihydrotestosterone and androstendiol. Synthesis is driven by oestrogenization. TEBG is synthesized in the liver. It is generally admitted that senescence of the endocrine system refers to the ability and rhythm of glandular secretion, to the transport and metabolism of hormones in regulating the activity of systems and hormonal receptor sensitivity (88). Another part of testosterone (37%) circulates in a bound state, related to albumin, and a significant part is carried on CBG. Only 2% moves in a free state.

Beyond the age of 60, the plasma free fraction decreases and the albumin-bound fraction increases , due to the growth of increase its affinity for steroid. There is also an increase of affinity for SHBG, whose synthesis is stimulated by oestrogenization in the elderly.Progesteron however, induces a decrease of testosterone bound fraction. The metabolism occurs in the liver. The specific action of testosterone is to stimulate spermatogenesis.The non-specific effects refer to secondary sexual characteristics and metabolic effects. Secretion adjustment is achieved by feed back with a hypothalamus and hypophysis link acting through LH and FSH gonadoliberines and goNadotrophins.

 Female gonadal hormones are secreted, as other steroids, by glands of coelomic origin, the ovary which has three anatomic functional compartments: follicular, secreting mainly, oestrogen hormones (oestradiol and oestron); progestational, composed of lutein cells and thecal cells which have progesterone as a specific product, and stromal, made up of stromal cells secreting androgens (androstendion, dehidroepiandrosteron, etc.).. The ways of synthesing them are the same as those of all steroids (215, 216).

Oestradiol is transported bound to SHGB, albumin, and the CBG. Together with oestrone, it binds, in a proportion of 98 - 99% to particular sites, with strong interactions, and thus it regulates its activity also owing to the multiple possibilities of the ovary to synthesize oestrogen hormones. Due to this fact, their concentration is not relevant, and, in addition , it intervenes in the response capacity of tissues. Ovarian hormones circulate mostly bound to albumin and globulin transporters. SHBG has a small binding ability, but has high affinity. Oestradiol, progesterone and oestron bind to a lesser extent. In the elderly, cirrhosis and hypothyroidism patients, SHBG increases in parallel with the oestrogenisation of the person. SHBG concentration in plasma is 2-3 mg ‰. It is synthesized in the liver. Synthesis is stimulated by oestrogen and inhibited by androgen. Progestern and 17-hydroxyprogesteron are transported also on CBG. Albumin has little affinity for these hormones, but their binding capacity is greater than that of THBG. Ovarian hormones are distributed among various adipose tissue, digestive tissue, target organs: endometrium, myometer, brain, mammary tissue, kidney). The free forms of ovarian hormones have a catamenial rhythm. They are eliminated by the kidneys and in bile. Their action is specific on the target organ and unspecific on metabolism general. The transport of progesterone uses the same transporter as oestrogens (173). Its synthesis increases during pregnancy. Progesterone has an oestrus cycle. Metabolism takes place in the target organs as well. Its main activity is to differentiate cells of progestogen organs.


[The remainder of Chapter 2 will be featured in the upcoming November-December 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. 



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