How the blood carries oxygen and carbon dioxide
The blood carries oxygen and carbon dioxide with the help of proteins, because neither gas dissolves well in water. Haemoglobin takes up oxygen in the lungs and releases it in the tissues, and most carbon dioxide travels as bicarbonate. The amount of carbon dioxide in the tissues mainly controls the pH of the body's fluids, and that pH mainly controls the breathing rate.
The need for transport proteins
Blood is far better than water at carrying oxygen and carbon dioxide. Both gases are nonpolar molecules, so they dissolve well in lipids and poorly in water. They are an example of the dilemma of transport: they cross cell membranes easily, but the problem is getting oxygen to the cells and carbon dioxide away from them. The body solves this problem by making proteins. Red blood cells have three important proteins that make it possible for the blood to transport enough of both gases for the body's needs: the red pigment haemoglobin, the enzyme carbonic anhydrase 1 and the membrane transport protein solute carrier family 4 member 1 (SLC4A1).
Water is a poor solvent for nonpolar molecules, including oxygen and carbon dioxide. So the watery portion of the blood can hold only a little of each, not enough for the body's needs. The blood carries a lot of oxygen because red blood cells contain haemoglobin, which serves as a transport protein for oxygen. It carries a lot of carbon dioxide partly because some binds to haemoglobin, but mainly because carbonic anhydrase in the red cells speeds the conversion of carbon dioxide to bicarbonate, which dissolves easily in water.
Two kinds of transport are at work. The heart works hard to pump the blood around the body, and this energy-consuming process is an example of active transport. The flow of the gases into and out of the bloodstream, and into and out of red blood cells, is an example of passive transport.
Haemoglobin
Haemoglobin is the red pigment in red blood cells (erythrocytes). It is a metalloprotein, meaning that it contains metal ions. Each molecule consists of four protein subunits, each bound to a molecule of haem. The subunits are two alpha and two beta subunits, and fetal haemoglobin has gamma subunits in place of the beta ones. Each haem is a porphyrin ring surrounding an electrically charged iron atom, Fe2+.
When haemoglobin meets a molecule of oxygen, a reduction–oxidation reaction takes place. The iron is oxidised, losing an electron to become Fe3+, and the oxygen is reduced, gaining an electron to become a superoxide anion. The superoxide anion then forms a complex with the Fe3+. Because each molecule contains four iron atoms, it can carry up to four molecules of oxygen, and a molecule saturated with oxygen is bound to four. The oxygenated form is called oxyhaemoglobin. The haemoglobin in red cells raises the blood's capacity to carry oxygen about 70-fold. Haemoglobin can also carry some carbon dioxide and some nitric oxide.
Haemoglobin has a higher affinity for carbon monoxide than for oxygen. Carbon monoxide binds to haemoglobin to form a stable complex, carboxyhaemoglobin, which cannot bind oxygen. That is why carbon monoxide poisoning can be deadly.
Haemoglobin plays an important role in carrying oxygen and carbon dioxide, but the red blood cells carry the haemoglobin. Haemoglobin is so reactive that it would cause problems if it were loose in the bloodstream.
The oxygen saturation curve
Haemoglobin is useful as a transport protein because it can pick up oxygen where oxygen is plentiful, where the partial pressure of oxygen (PO2) is high, and release it where oxygen is scarce. The oxygen saturation curve for haemoglobin shows this effect. Haemoglobin binds a lot of oxygen at high oxygen tension but cannot hold as much at low tension. So it can pick up oxygen in the lungs and release it in other parts of the body, such as the skeletal muscles.
In vitro the curve is sigmoidal, because the first oxygen molecule to bind alters the three-dimensional shape of the haemoglobin molecule, which makes it easier to bind the other three. Haemoglobin exists in two basic shapes, and deoxygenated haemoglobin is in a taut or tense (T) state. Once a molecule has picked up at least two oxygen molecules, it can move to the relaxed (R) state, which makes it easier to absorb the other two. This transition explains why the curve is sigmoidal. Hydrogen ions, chloride anions, carbon dioxide and organic and inorganic phosphates bind to sites other than the haem groups and can affect the transition between the two states. As a result, they can help to regulate what haemoglobin does.
What shifts the curve
Normal haemoglobin tested in vitro at pH 7.6, 7.4 and 7.2 gives a separate curve at each pH, and normal pH is very close to 7.4. Haemoglobin has a higher affinity for oxygen at a higher pH. So it would pick up even more oxygen in the high-pH environment of the lungs and release more in the lower-pH environment of the rest of the body. Higher oxygen affinity goes with high pH, low temperature and low 2,3-BPG, and lower affinity goes with low pH, high temperature and high 2,3-BPG. Conditions found in exercising muscle, such as low pH and high temperature, shift the curve to the right. This right shift lets haemoglobin deliver oxygen most efficiently where it is needed most.
People with sickle-cell disease have abnormal haemoglobin with a lower affinity for oxygen, so their curve is shifted to the right. The shift lets the blood unload more oxygen in poorly vascularised tissue, so the heart does not have to work harder to make up for the blood's low oxygen-carrying capacity. But the venous blood of these patients can become severely deoxygenated.
Carbon dioxide, pH and the bicarbonate buffer
Hydrogen ions have an important effect on haemoglobin's oxygen saturation curve, and some of them come from the carbon dioxide dissolved in the body's fluids. When carbon dioxide dissolves in water, some of its molecules react with water to form a bicarbonate anion and a hydrogen ion, in the reaction CO2 + H2O ⇌ HCO3− + H+, which carbonic anhydrase catalyses. The double-ended arrow means that the reaction is reversible.
pH, the power of hydrogen, measures how many hydrogen ions a water-based solution contains. Pure water with nothing dissolved in it has as many H+ ions as OH− ions, at a concentration of 1 × 10−7 moles per litre, which is a pH of 7, neutral. A tenfold rise in H+ ions, to 1 × 10−6 M, gives a pH of 6. Pure water exposed to the air drops to a pH of about 5.8, because of the hydrogen ions released by the reaction of carbon dioxide with water. This pH is a little higher than the amount of carbon dioxide that has reacted with the water would suggest, because some of the hydrogen ions bind to bicarbonate to form carbonic acid.
The reaction of bicarbonate with hydrogen ions, HCO3− + H+ ⇌ H2CO3, is also reversible. Carbonic acid is diprotic, meaning that it can give up as many as two hydrogen ions, but it is a weak acid. Only a small percentage of its molecules in solution give up even one proton to become bicarbonate, and an even smaller percentage give up both to become carbonate (CO3 2−). The bicarbonate and carbonate anions can act as a buffer. A buffer is a solution that resists changes in pH when acids or alkalis are added, and it is usually made of a weak acid, such as carbonic acid, and its conjugate base, such as bicarbonate. When hydrogen ions are added to a bicarbonate solution, many of them react with the bicarbonate to give water and carbon dioxide, which may leave the solution as a gas. That is why bubbles of carbon dioxide appear when an acid such as vinegar is added to baking soda (sodium bicarbonate).
Large amounts of acidic and alkaline substances enter the bloodstream during a normal day, yet the blood's pH is meant to stay steady at almost exactly 7.4. To keep it steady, the body relies on a buffer. When a strong acid such as hydrochloric acid is added to the blood, the bicarbonate mops up its hydrogen ions (HCl + HCO3− → H2CO3 + Cl−), so the pH drops little or not at all. When a strong base such as sodium hydroxide is added, the carbonic acid releases protons that bind the hydroxide ions (2NaOH + H2CO3 → Na2CO3 + 2H2O). Bicarbonate and carbonate then increase, but the pH rises little or not at all. Even a strong acid or base changes the pH of a buffered solution little until its buffering capacity is exhausted.
Carbon dioxide transport
Because carbon dioxide is poorly soluble in water, only a tiny amount of the carbon dioxide that the blood carries back to the lungs is dissolved. About 80% of it travels as bicarbonate ions, which are made in the red blood cells and released into the plasma. A small amount is bound directly to the protein portion of haemoglobin as carbaminohaemoglobin.
On its own, the conversion of dissolved carbon dioxide to bicarbonate is so slow that it would have no useful effect on gas transport. Carbonic anhydrase 1 in red blood cells speeds it up about a millionfold, and the faster reaction has three effects. First, it lowers the carbon dioxide concentration inside the red cells, which creates a gradient down which more carbon dioxide flows in from the surrounding tissue. Second, it generates hydrogen ions, which can bind to haemoglobin and help convert it to the tense state, so that it releases more oxygen. Third, it generates bicarbonate, which flows out of the red cell through SLC4A1 as its concentration inside the cell rises. SLC4A1 is an antiporter: it lets bicarbonate leave the cell passively and uses the resulting energy to import a chloride anion. The chloride then binds to haemoglobin and contributes to the tense state, so that haemoglobin releases more oxygen.
These effects explain the Bohr effect, in which low pH and a high partial pressure of carbon dioxide both shift haemoglobin's oxygen saturation curve to the right. So the blood can release even more oxygen in low-oxygen areas where there is a lot of carbon dioxide, a lot of lactic acid or both, as in exercising skeletal muscle.
When the carbon dioxide–rich blood returns to the lungs, it releases carbon dioxide and takes up oxygen. Some of this exchange is the result of simple diffusion. Chemical changes in the blood, basically a reversal of those in the tissues, also increase it. Carbonic anhydrase 1 speeds the reaction of bicarbonate with hydrogen ions to give water and carbon dioxide, and the carbon dioxide can then diffuse out of the red cell and out of the bloodstream. As the bicarbonate inside the red cell falls, bicarbonate flows back in and chloride flows out through SLC4A1. As the hydrogen and chloride ions in the red cell decrease, haemoglobin can move to the relaxed state and pick up more oxygen (the Bohr effect). As oxygen diffuses into the red cells, it tends to displace the carbon dioxide bound to haemoglobin (the Haldane effect), and that carbon dioxide can then diffuse out of the cell and out of the bloodstream.
The drive to breathe
A person whose blood stopped taking in oxygen would quickly die. Yet low oxygen levels, as the body's oxygen sensors detect them, have only a small effect on the drive to breathe. That is why pilots flying at high altitude in unpressurised aircraft would often pass out before they felt respiratory distress. Breathing rate is controlled mainly by the pH of the body's fluids, which in turn is controlled mainly by the amount of carbon dioxide in the tissues. A high partial pressure of carbon dioxide in the body's fluids means a low blood pH and so a strong drive to breathe. If the blood's buffering capacity is exceeded and its pH starts to rise or fall abnormally, the autonomic nervous system adjusts the breathing rate down or up to compensate.
In metabolic acidosis, the blood pH is abnormally low because metabolism produces excess acids, as in diabetic ketoacidosis or kidney failure. The strong drive to breathe can then produce deep, laboured breathing, called Kussmaul respiration. A person who cannot get rid of enough carbon dioxide has a low blood pH, and a fall below 7.35 caused by suppressed or impaired ventilation is called respiratory acidosis. Hyperventilation can lower the carbon dioxide in the blood abnormally, which raises the blood pH, and a rise above 7.45 from hyperventilation is called respiratory alkalosis.