acid–base homeostasis

acid–base homeostasis All living things depend on water. Life consists of a highly complex series of chemical reactions occurring in aqueous media. Among the most important factors in the composition of these fluids are the concentrations of hydrogen ions and hydroxide ions, which determine the acidity or alkalinity of the fluid. The maintenance of suitable concentrations of these ions is called acid–base homeostasis.

The cells of the most primitive marine organisms are bathed directly by the sea. The environment of such cells is very variable, being at the mercy of the tides and winds. As evolution proceeded, organisms walled off some of this watery environment and took it as their own, to provide a specialized fluid surrounding the cells. This fluid is thus, in evolutionary terms, the ‘sea within us’; it is called the extracellular fluid, to distinguish it from the fluid inside cells, the intracellular fluid. In higher animals, the extracellular fluid is further subdivided into that in the circulating blood (the plasma, in which the blood corpuscles are suspended) and that which is outside the walls of the blood vessels (the interstitial fluid, filling the interstices between the body's cells). There is continuous interchange of fluid across the walls of capillaries between the interstitial fluid and the blood plasma; this serves to mix the extracellular fluid. Small molecules and ions in solution move freely between the components of the extracellular fluid.

As animals became more advanced, control mechanisms evolved to minimize changes in the composition of the extracellular fluid, thereby providing a stable environment for the cells of the body. The importance of this was first recognized by the French physiologist Claude Bernard (1813–78), who described the extracellular fluid as the ‘milieu intérieur’ or the ‘internal environment’ of the body. The tendency of the body to stabilize the composition of the extracellular fluid is called homeostasis, which means ‘staying similar’. Such stability had to be achieved before higher animals could evolve. In the words of Joseph Barcroft (1938), ‘To look for high intellectual development in a milieu whose properties have not become stabilized is to seek music amongst the crashings of a rudimentary wireless or the ripple patterns on the surface of the stormy Atlantic.’

Water, then, is the substrate of life. Most standard laboratory solvents act merely as vehicles and take no part in chemical reactions between chemicals dissolved in them (the solutes). Water has the remarkable property of itself participating in many of the chemical reactions that occur in it; this is because water molecules show a very weak tendency to dissociate into hydrogen ions and hydroxide ions, according to the chemical reaction:

Reaction 1

H2O	⇌	H+	+	OH-
water		hydrogen		hydroxide
molecule		ion		ion

This chemical reaction demonstrates that, in pure water, hydrogen ions and hydroxide ions are present in equal concentrations; thus pure water is said to be neutral. When there are solutes present, the solution is also called neutral if the concentrations of hydrogen and hydroxide ions are the same. However, a solution is acid if the concentration of hydrogen ions exceeds that of hydroxide ions and alkaline if the concentration of hydroxide ions exceeds that of the hydrogen ions.

A hydrogen ion is a proton — a hydrogen atom that has lost its electron. An acid is a chemical that releases protons; it is called a proton donor. A base, which is a chemical that takes up protons, is known as a proton acceptor. If an acid is added to an equal amount of base, the protons released by the acid are all taken up by the base and the resulting solution is neutral.

Acid and base production in the body

Various chemical reactions in the body produce acids and bases: if they are simultaneously generated in equal amounts they will chemically combine and neutralize each other. If production of one or other predominates, then body fluids tend to become acid or alkaline. If the acid or base is produced continuously, a steady state can be maintained only when production is matched by the elimination of the excess acid or base from the body.

carbon dioxide is produced as one of the main end products of the aerobic metabolism of energy-yielding chemicals derived from the food that we eat. Carbon dioxide is not itself an acid, but in aqueous solution it reacts with water to yield hydrogen ions and bicarbonate ions, according to the chemical reaction:

Reaction 2

CO2	+	H2O	⇌	H+	+	HCO-3
carbon		water		hydrogen		bicarbonate
dioxide				ion		ion

Metabolizing cells continuously liberate carbon dioxide, and therefore acid, into our body fluids. The carbon dioxide diffuses to the blood, where a little remains dissolved but most is chemically combined. When the blood reaches the lungs the carbon dioxide is released and diffuses out of the blood into the gas in the alveoli of the lungs. The refreshing of the alveolar gas by breathing results in the carbon dioxide being expelled from the body and into the atmosphere. Since carbon dioxide can be eliminated as a gas, it is called a volatile acid. All other acids in the body are called non-volatile acids, or fixed acids.

Non-volatile acids.

When a healthy person exercises maximally, the exercising muscles cannot obtain all the energy that they need by aerobic metabolism (using oxygen) and must in addition metabolize anaerobically (i.e. without oxygen). This results in the breakdown of glucose to lactic acid, via a series of chemical reactions that release energy but do not require oxygen. This is a normal physiological situation in which excess non-volatile acid is released into the body fluids. The excess acid is subsequently taken up from the blood by the liver where most of the lactic acid is reconverted to glucose.

Hydrogen ions are produced as an end product of the oxidation of sulphur-containing amino acids derived from proteins in the diet; this yields sulphuric acid. The metabolism of phospholipids, nucleic acids, and other phosphorus-containing chemicals yields phosphoric acid. Certain organic acids are formed during the metabolism of carbohydrates and fats; normally these acids are further oxidized to carbon dioxide and water, but in certain circumstances they may accumulate.

A pathological example is diabetes mellitus, which has been called ‘starvation in the presence of plenty’. Here, although the concentration of glucose in the blood is high, the tissues are unable to metabolize it properly. Instead of using glucose, the body derives energy from excessive breakdown of lipids to yield so-called ketone bodies, including aceto-acetic and β-hydroxy-butyric acids. An excess of these fixed acids accumulates in the body.

Surplus alkali

accumulates when a person persistently vomits gastric contents. Acid is secreted into the gastric contents by cells in the wall of the stomach as part of the digestive process. This secretion of acid is accompanied by an equal movement of alkali from the acid-secreting cells in the opposite direction into the body fluids, so loss of acid in vomitus results in a surplus of alkali in the body.

Defence of hydrogen ion concentration.

The body has several lines of defence to accommodate surplus acid or base. The extracellular fluid, the contents of the cells, and bone all provide chemical buffering. A buffer is a system of chemicals that combines with an excess of hydrogen ions or hydroxide ions. Buffering therefore tends to stabilize the hydrogen ion concentration. It minimizes changes but does not alter the total acid or base load in the body. The final disposal of surplus fixed acid or base may be via metabolic pathways in the body, as described for lactic acid in the healthy exercising person. If such mechanisms are not available, then the excess acid or base must be expelled from the body, via the lungs and kidneys — the homeostatic processes of respiratory compensation and renal compensation.

Respiratory compensation.

The aeration of the lungs influences the hydrogen ion concentration of the blood by regulating the amount of carbon dioxide expelled from the body into the atmosphere. Other things being equal, an increase in the volume of air breathed in and out leads to a washing-out of carbon dioxide from the body, and hence a lowering of the hydrogen ion concentration of the body. In reaction 2, the concentration of carbon dioxide falls so the reaction is driven to the left, with a reduction in the number of hydrogen ions in the body. Conversely, a reduction of breathing results in a rise in hydrogen ion concentration in the body.

In a healthy person, the concentration of carbon dioxide in the arterial blood is usually held constant by appropriate aeration of the lungs. The depth and rate of breathing are controlled by special centres in the brain, which influence the nerves that cause contraction and relaxation of the muscles of respiration. In a person with a surplus of fixed acid in the body, such as in maximal muscular exercise or in uncontrolled diabetes mellitus, the shift towards acidity (detected by chemoreceptors — specialized sensory structures) stimulates breathing. As a result, the concentration of carbon dioxide falls below normal. This in effect removes some of the excess hydrogen ions. In this way breathing can help to bring the hydrogen ion concentration back towards normal, despite the excess of fixed acid in the body. This is respiratory compensation.

Renal compensation.

Whereas the lungs regulate the amount of volatile acid (carbon dioxide) in the body, the kidneys regulate other acids and bases by excreting acidic or alkaline urine. In healthy people on a mixed diet, although the food itself is neutral, its metabolism releases an excess of non-volatile acid, and the kidneys must match this by excreting acidic urine as a normal necessity. The food of vegetarians yields an excess of base and the urine of healthy vegetarians is alkaline. In patients with renal damage the contribution of the kidneys is compromised; a feature of renal failure, in a person on a mixed diet, is an accumulation of acid in the body.

The hydrogen ion concentration in aqueous solutions

One way of expressing the concentration of a substance is in moles of the substance per litre of solution. A mole of a substance is its molecular weight in grams. For hydrogen ions, the concentration is conventionally described as a pH value: the pH is the negative logarithm of the hydrogen ion concentration expressed in moles per litre. As the hydrogen ion concentration of a solution becomes higher, its pH becomes lower — more acidic. In a neutral solution at a temperature of 25°C, the hydrogen ion concentration is 10^-7 moles per litre, or 100 nanomoles/litre (1 nanomole = 10^-9 mole). This corresponds to a pH value of 7.0. In a neutral solution at 37°C, the hydrogen ion concentration is 157 nanomoles/litre. In the arterial blood plasma of a normal person at rest, the hydrogen ion concentration usually lies in the range 35 to 45 nanomoles/litre, with an average of 40. The hydrogen ion concentration of plasma is therefore normally about a quarter of that for a neutral solution at body temperature. A rise in plasma hydrogen ion concentration towards that of a neutral solution will result in death in most people. By contrast, the hydrogen ion concentration of the intracellular fluid is normally close to that of a neutral solution.

The range of hydrogen ion concentration in disease

In persons with acid–base disorders, hydrogen ion concentration may be as low as 20 or as high as 80 nanomoles/litre, this being the usually tolerable range for survival. Thus a 4-fold range is compatible with life. This is a much larger variation than the range tolerated for certain other chemicals, for instance sodium ions, chloride ions, and water itself. For short periods of time, it is possible for the hydrogen ion concentration to go beyond these limits, particularly on the acid side.

Enzymes and hydrogen ion concentration.

Ultimately the regulation of hydrogen ion concentration is important in keeping conditions ideal for the biological catalysts, enzymes. These enzymes are essential for the chemical processes of life, both inside cells and in the extracellular fluids. Enzymes consist of complex protein molecules: there are sites on these molecules that attract and release hydrogen ions. Enzymic activity depends on the molecule being in the correct state of ionization; if an enzyme is associated with an excess of hydrogen ions or has lost many hydrogen ions, its enzymic activity is reduced or abolished. This is why enzymes operate optimally at a given hydrogen ion concentration. Enzymes on the surfaces of cells, which are bathed in extracellular fluid, operate optimally at the hydrogen ion concentration of extracellular fluid. Intracellular enzymes operate optimally at the hydrogen ion concentration of intracellular fluid.

Effects of disturbances of hydrogen ion concentration.

In disease states, deviation from normal hydrogen ion concentration usually occurs in association with other serious pathological processes, and it may be difficult to specify the effects of altered hydrogen ion concentration alone. With a high hydrogen ion concentration, there is a widespread relaxation of smooth muscle, including the muscle in the walls of blood vessels: this results in a severe drop in arterial blood pressure, with circulatory collapse. When elevation of hydrogen ion concentration is prolonged, minerals are leached from bones, causing them to become weak mechanically; the condition of osteoporosis.

A low hydrogen ion concentration occurs as a result of overbreathing, in which carbon dioxide is blown off excessively in the lungs. The condition occurs in certain otherwise normal people who overbreathe as a reaction to stress. A reduction in hydrogen ion concentration unveils sites on protein molecules that attract positive ions. Other positive ions then tend to attach to these binding sites instead of hydrogen ions. An ion of importance in this respect is calcium; a lowering of hydrogen ions leads to a lowering of the concentration in the body fluids of calcium ions, the condition of hypocalcaemia. This leads to an increase in the excitability of nerve fibres, resulting in the occurrence of spontaneous action potentials. These cause hypocalcaemic tetany — involuntary uncoordinated contractions of skeletal muscles — bizarre subjective sensations, and numbness.

The balance of hydrogen and hydroxide ions influences our bodily functions out of all proportion to the minute concentrations of these ions in biological fluids. The adverse effects arising from disturbances of hydrogen ion concentration are due to interference with the normal harmonious interaction of the many thousands of enzymes on which life depends.

Oliver Holmes

Bibliography

Holmes, O. (1993). Human acid–base physiology. Chapman and Hall Medical, London.

See also body fluids; carbon dioxide; enzymes; homeostasis; hyperventilation; kidneys; respiration.