2. Advanced Physiology (part 6, Acid-base Balance)
Isfahan University of Technology
Advanced Physiology (part 6, Acid-base Balance)
By: A. Riasi
(PhD in Animal Nutrition & Physiology)
Animal Sci. Dep. Isfahan University of Technology

3. Acid-base balance
Three aspects that ECF and ICF are crucial to the whole animal and to its individual cells:
The osmotic balance
Total fluid volume of the body
Acid –base status
Three aspect of the ECF and ICF that are crucial to the whole animal and to its individual cells:
1- Osmotic balance is determined primarily by the total concentration of major solutes.
2- Total fluid volume of the body directly affects circulatory pressure
3- Acid-base balance of body fluid may alters by hydrogen ions (measured as pH), This is crucial to the entire organism because protein structure and function is typically highly dependent on the concentration of hydrogen ions around them.

4. Acid-base balance
If balance is to be maintained, input must equal output
The quantity of any particular substance in the ECF is considered a readily available internal pool. The amount of the substance in the pool may be increased either by transferring more in from the external environment (such as via the gut or the integument) or by metabolically producing it within the body. Substances may be removed from the body by loss to the outside (through excretion, sweating, and so forth) or by being used up in a metabolic reaction. If the quantity of a substance is to remain stable within the body, its input must be balanced by an equal output by means of excretion or metabolic consumption. This relationship, known as the balance concept, is extremely important in maintaining homeostasis. Not all input and output pathways are applicable for every body fluid constituent. For example, salt is not synthesized or altered metabolically by organisms, so the stability of salt concentration in body fluids depends entirely on a balance between salt intake and salt excretion. The ECF pool can further be altered by transferring a particular ECF constituent into storage within cells or certain extracellular features (bladder fluid). If a body as a whole has a surplus or deficit of a particular stored substance, the storage site can be expanded or partially depleted to maintain the ECF concentration of the substance within homeostatically prescribed limits. For instance, after a mammal has absorbed a meal, when more glucose is entering the plasma than is being consumed by the cells, the excess glucose can be temporarily stored in liver cells in the form of glycogen. This storage depot can then be tapped between meals as necessary to maintain the plasma glucose level when no new nutrients are being added to the blood by eating. It is important to recognize, however, that internal storage capacity is limited. Although an internal exchange between the ECF and a storage depot can temporarily restore the plasma concentration of a particular substance to normal, in the long run any excess or deficit of that constituent must be compensated for by appropriate adjustments in total body input or output. Some exchanges between the pool and the remainder of the body involve structures with functions beyond mere storage. Consider calcium: It is an essential component of an animal’s skeleton for support, but it is also is necessary as a cellular messenger and trigger of muscle contraction. If plasma and cell calcium fall too low, calcium may be taken out of the shell or skeleton. This process differs from simple storage, which serves no additional purpose. Some body constituents may be poorly controlled. For example, the plasma volume and composition of many osmoconformers passively changes with the external environment, forcing individual cells to adjust at least in part on their own. Some constituents undergo frequent and/or large disturbances. Salt and H2O can be lost to the terrestrial environments to varying degrees through the digestive tract (vomiting, diarrhea), skin (sweating), lungs (panting), and elsewhere without regard for salt or H2O balance in the body. Hydrogen ions are uncontrollably generated internally (especially during muscle activity) and added to body fluids. If possible, compensatory adjustments must be made for these uncontrolled changes.
Adapted from Animal Physiology by Sherwood et al. 2013

5. Acid-base balance
The balance extremely important in maintaining homeostasis.
Some constituents undergo frequent and/or large disturbances.
Salt and H2O can be lost to the terrestrial environments to varying degrees through the:
Digestive tract (vomiting, diarrhea)
Skin (sweating)
Lungs (panting)

6. Acid-base balance
Hydrogen ions are uncontrollably generated internally (especially during muscle activity) and added to body fluids.
If possible, compensatory adjustments must be made for these uncontrolled changes.

7. Acid-base balance
In contrast to the close similarity between plasma and interstitial fluid, the composition of the ECF as a whole differs considerably from that of the ICF in all animals. Each cell is surrounded by a highly selective plasma membrane that permits passage of certain materials while excluding others. Movement through the membrane barrier occurs by both passive and active means and may be highly discriminating. Among the major differences between the ECF and ICF are:
1. Cellular proteins that cannot permeate the plasma membranes to leave the cells.
2. Cellular organic osmolytes (typically higher in the ICF than in the ECF).
3. Na+and K+ and their attendant anions: In most organisms, Na+ is the primary ECF cation, and K+ is the primarily ICF cation. This is due in part to action of the membrane-bound Na+/K+ ATPase pump that is present in all cells (although this is not the only factor). The unequal distribution of Na+ and K+, coupled with differences in membrane permeability to these ions, is responsible for the electrical properties of cells, including the action potentials in excitable tissues. Except for the extremely small electrical imbalance in the intracellular and extracellular ions involved in membrane potential, the majority of the ECF and ICF ions are electrically balanced. In the ECF, Na+ is accompanied primarily by the anion Cl−and to a lesser extent by HCO3− (bicarbonate). In the ICF, K+ is accompanied primarily by the anion PO43−(phosphate) and by the negatively charged proteins trapped within the cell. Although all cells’ plasma membranes display selective permeability, cells are typically permeable to H2O. The movement of H2O between the plasma and the interstitial fluid across capillary walls is governed by relative imbalances between capillary blood pressure (a fluid, or hydrostatic, pressure) and colloid osmotic pressure. In contrast, the net transfer of H2O between the interstitial fluid and the ICF across plasma membranes occurs as a result of osmotic effects alone because these fluids have very low hydrostatic pressures.
Adapted from Animal Physiology by Sherwood et al. 2013

8. Acid-base balance
The composition of the ECF as a whole differs considerably from that of the ICF in all animals.
The major differences between the ECF and ICF are:
Cellular proteins that cannot permeate the plasma membranes.
Cellular organic osmolytes (typically higher in the ICF Vs. ECF).
Na+and K+ and their attendant anions:
In most organisms, Na+ is the primary ECF cation, K+ is the primarily ICF cation.

9. Acid-base balance
The majority of the ECF and ICF ions are electrically balanced.
In the ECF, Na+ is accompanied primarily by the Cl− and to a lesser extent by HCO3− .
In the ICF, K+ is accompanied primarily by the anion PO43− and by the negatively charged proteins trapped within the cell.

10. Acid-base balance
The acid-base balance refers to the precise regulation of free [H+] and [OH-] concentration in the body fluids.
Acids are a special group of hydrogen-containing substances.
A strong acid has a greater tendency to dissociated in solution than does a weak acid.
Acids are a special group of hydrogen-containing substances that dissociate when in solution to liberate free H+ and anions. Many other substances (for example carbohydrates) also contain hydrogen, but they are not classified as acids. Because the hydrogen is tightly bound within their molecular structure and is never liberated as free H+.

11. Acid-base balance Acid-base balance in body fluids
Adapted from Animal Physiology by Sherwood et al. 2013

12. Acid-base balance The normal pH of arterial and venous blood
Acidosis exists whenever the blood pH falls below 7.3
Alkalosis occurs when the blood pH is above 7.45
Death can occur if arterial pH falls outside of the range of
The pH of venous blood is slightly lower than that of arterial blood (7.35 vs 7.45) because of H+ generated by the formation of H2CO3 from CO2 picked up at the tissue capillaries. Alkalosis occurs when the blood pH is above 7.45.
Note that the reference point for determining the body’s acid-base status is not neutral pH (6.81 at 37◦C), but the normal plasma pH of 7.4. Thus a plasma pH of 7.2 is considered acidotic even though in chemistry a pH of 7.2 is considered basic.

13. Acid-base balance
Adapted from Animal Physiology by Sherwood et al. 2013

14. Acid-base balance
Fluctuations in hydrogen ion concentration have profound effect on body chemistry.
Even small changes in [H+] have dramatic effect on proteins.
The most prominent whole body consequences of fluctuations in [H+] are changes in excitability of nerves and muscle cells.
Even slight deviations in [H+] alter the shape and activity of protein molecules, for example, respiratory pigments do not deliver oxygen properly. Also because enzymes are roteins, a shift in the body’s acid-base balance disturbs the normal pattern of metabolic activity catalyzed by these enzymes. Some cellular chemical reactions are accelerated; others are depressed.
Increased [H+] (acidosis) depress the central nervous system. In contrast, the major effect of alkalosis is overexcitability of the nervous system, first the peripheral and later the central nervous system.

15. Acid-base balance
Hydrogen ions are continually being added to body fluids
Metabolic activities are main source for H+ in the body fluids
Normally, H+ is continually being added to the body fluids by:
Carbonic acid formation
Inorganic acid produced during the breakdown of nutrients
Organic acid resulting from intermediary metabolism
Hydrogen ions are continually being added to body fluids as a result of metabolic activities. The input of hydrogen ions must be balanced an equal output.
Cellular oxidation of nutrients yields energy, with CO2 and H2O. CO2 and H2O spontaneously react to form H2CO3. H2CO3 mostly dissociated to liberate free H+ and HCO3-.

16. Acid-base balance CO2 + H2O H2CO3 H+ + HCO3- C.A. CO2 + OH- HCO3-
In some cell types such as erythrocytes, the reactions rapidly catalyzed by the enzyme carbonic anhydrase (CA). Although in an indirect way the change in OH- intern causes a change in H+ formation from water. These reactions are rapidly reversible and proceeding in either direction depending on the concentrations of the substances involved as dictated by the low mass action.
Within vertebrate systematic capillaries, the CO2 level in the blood increases as metabolically produced CO2 enter from the tissues. This drive the reaction to the acid side. In the lungs the reaction is reversed: CO2 diffuses from the blood to the environment. The resultant reduction in CO2 in the blood drives the reaction toward the CO2 side.
CO2 + OH HCO3-
C.A.
H2O H+ + OH-

17. Acid-base balance
Sulfuric acid and phosphoric acid are produced in the body.
Fatty acids and lactic acid that are produced during intermediary metabolism partially dissociate to yield free H+.
In certain disease additional acids may be produced.
Dietary protein and other ingested nutrient molecules contain sulfur and phosphorus. When these molecules are breakdown sulfuric and phosphoric acids are produced as by-products.
In diabetes mellitus large quantities of keto acids may be produced as a result of abnormal fat metabolism.

18. Acid-base balance Three line of defense against changes in [H+]:
Chemical buffer systems
Respiratory mechanisms of pH control
Excretory mechanisms of pH control

19. Acid-base balance There are four buffer system in the vertebrate body:
CO2-HCO3- buffer system
The peptide and protein buffer system
The hemoglobin buffer system
The phosphate buffer system

20. Acid-base balance The Co2-HCO3- buffer system in the ECF.
An important example a buffer system in the body is carbon dioxide-bicarbonate. It is very effective ECF buffer system, for two reasons:
1- HCO3- is abundant in the ECF.
2- More importantly, key components of this buffer pair are closely regulated. The kidney regulate HCO3-, and the respiratory system regulates CO2, which generates H2CO3.
Because of this relationship, not only do both the kidneys and respiratory organs normally participate in pH control but also, renal or respiratory dysfunction can induce acid-base imbalances by altering the [HCO3-]/[CO2] ratio.
Adapted from Animal Physiology by Sherwood et al. 2013

21. Acid-base balance
The most plentiful buffers on the ICF are the cell proteins.
The most important buffering amino acid is histidine.
Hemoglobin (Hb) in erythrocytes buffers the H+ generated.
The phosphate buffer system consists of an acid phosphate slat (NaH2PO4) and a basic phosphate salt (Na2HPO4).
The phosphate system serve as an excellent urinary buffer.
Proteins are excellent buffers because their contain both acidic and basic groups that can bind or release H+.
The most important buffering amino acid is histidine. Because it is the only one with a pK close to 7. In addition, muscles of some birds and mammals have large concentrations of dipeptides containing histidine.
The phosphate buffer system consists of an acid phosphate slat (NaH2PO4) that can donate a free H+ when [H+] falls and a basic phosphate salt (Na2HPO4) that can accept a free H+ when the [H+] rise.
Even though the phosphate pair is a good buffer, its concentration in the ECF is rather low, so it is not very important as an ECF buffer. Because phosphates are more abundant within the cells, this system contributes significantly to intracellular buffering.

22. Acid-base balance
The respiratory system plays an important role in acid-base balance through its ability to alter ventilation
The excretory systems contribute powerfully to control of acid-base balance by controlling both hydrogen ion and bicarbonate concentrations in the ECF. The excretory organs require hours to days to compensate for changes in body fluid pH, compared to the immediate responses of the buffer systems and the few minutes of delay before respiratory system responds.
During renal compensation for acidosis for each H+ excreted in the urine a new HCO3- is added to the plasma to buffer, by means of CO2-HCO3- system.

23. Acid-base balance
The excretory organs are the third line of defense against changes in [H+] in body fluids.
In mammals, the kidneys are the most potent acid-base regulatory mechanism.
The kidneys can remove of H+ from any source
The kidneys can variably conserve or eliminate HCO3-
The excretory systems contribute powerfully to control of acid-base balance by controlling both hydrogen ion and bicarbonate concentrations in the ECF. The excretory organs require hours to days to compensate for changes in body fluid pH, compared to the immediate responses of the buffer systems and the few minutes of delay before respiratory system responds.
During renal compensation for acidosis for each H+ excreted in the urine a new HCO3- is added to the plasma to buffer, by means of CO2-HCO3- system.

24. Acid-base balance
The kidneys control the pH of the body fluids by adjusting three interrelated factors:
H+ excretion
H2CO3- excretion
Ammonia secretion

25. Acid-base balance Hydrogen ion excretion by the kidneys
The kidneys eliminate H+ derived from sulfuric, phosphoric, lactic, and other acids.
Although lungs can adjust H+ by eliminating CO2, However the task of eliminating H+ derived from sulfuric, phosphoric, lactic, and other acids rest with the kidneys. Almost all the excreted H+ enters the urine by means of secretion and for this reason urine is usually acidic, having an average pH of 6.0. No only do the kidneys continuously eliminate the normal amount of H+ that is constantly being produced from non-CO2 sources, but they can also alter their rate of H+ secretion to compensate for changes in [H+] arising from abnormalities in the concentration of CO2.

26. Acid-base balance pH Regulation: Excretion
The magnitude of H+ secretion depends on a direct effect of the plasma’s acid-base status on the kidneys’ tubular cells.
No neural or hormonal control is involved. When the [H+] of the plasma passing through the peritubular capillaries is elevated above normal, the tubular cells respond by secreting greater than usual amounts of H+ from the plasma into the tubular fluid to be excreted in the urine. Actually the kidneys cannot raise plasma [H+] by reabsorbing more of the filtered H+.
Adapted from Animal Physiology by Sherwood et al. 2013

27. Acid-base balance pH Regulation: Excretion
The H+ secretary process begins in the tubular cells with CO2 that has come from three sources:
The CO2 diffused from plasma
The CO2 diffused from the tubular fluid
CO2 that has been metabolically produced within the tubular cells.
Under the influence of carbonic anhydrase, CO2 and H2O increase H+ and HCO3-. An energy dependent carrier in the luminal membrane then transports H+ out of the cell into the tubular lumen. In part of the nephron, the carrier is a Na+-H+ exchanger. Thus H+ secretion and Na+ reabsorption are partially linked.

28. Acid-base balance
The kidneys adjust H+ excretion to compensate for changes in both carbonic and noncarbonic acids.
The kidneys regulate plasma [HCO3-] by two mechanisms:
Variable reabsorption of the filtered HCO3- back to the plasma.
Variable addition of new HCO3- to the plasma.

29. Acid-base balance pH Regulation: Excretion
Hydrogen ion secretion coupled with bicarbonate reabsorption (mammalian kidney). Because the disappearance of a filtered HCO3- from the tubular fluid is coupled with the appearance of another HCO3- in the plasma, HCO3- is considered to have been reabsorbed.
Hydrogen ion secretion and excretion coupled with the addition of new HCO3- to the plasma. (mammalian kidney). Secreted H+ does not combine with filtered HPO42- and is not subsequently excreted until all the filtered HCO3- has been reabsorbed. Once all the filtered HCO3- has combined with secreted H+, further secreted H+ is excreted in the urine, primarily in associated with urinary buffers such as basic phosphate. Excretion of H+ is coupled with the appearance of new HCO3- in the plasma. The new HCO3- represents a net gain rather than being merely a replacement for filtered HCO3-.
Adapted from Animal Physiology by Sherwood et al. 2013