12.5 Transport of Gases

Hemoglobin-Oxygen Binding

Oxygen binds to hemoglobin in a pattern called cooperative binding: binding of the first oxygen molecule causes a conformational change in hemoglobin that allows the second molecule of oxygen to bind more readily. And, as each subsequent oxygen molecule binds, the binding of the next molecule is facilitated until all four heme sites are occupied by oxygen. The opposite occurs as well: after the first oxygen molecule dissociates and is “dropped off” at the tissues, the next oxygen molecule dissociates more readily.

When all four heme sites are occupied, the hemoglobin is said to be saturated. When one to three heme sites are occupied, the hemoglobin is said to be partially saturated. When considering the blood as a whole, the percent of the available heme units that are bound to oxygen at a given time is called hemoglobin saturation. Hemoglobin saturation of 100% means that every heme unit in all of the hemoglobin molecules in the body is bound to oxygen. In a healthy individual with normal hemoglobin levels, hemoglobin saturation generally ranges from 95% to 99%.

Relationship Between P_O2 and Hemoglobin Saturation

Local P_O2 (for example P_O2 in the lung environment or in the systemic tissue environment) is an important factor that determines the binding of oxygen to and dissociation of oxygen from hemoglobin. An oxygen–hemoglobin dissociation curve is a graph that describes the relationship of local P_O2 to the percent saturation of hemoglobin with oxygen (Figure 12.5.2).

From an oxygen-hemoglobin dissociation curve, we can gain insight regarding hemoglobin-oxygen affinity. Hemoglobin-oxygen affinity refers to the ability of hemoglobin to bind oxygen. Due to the cooperative binding described above, the affinity of an oxygen molecule for hemoglobin increases as more oxygen molecules are bound. Therefore, in the oxygen–hemoglobin saturation curve, as the P_O2 increases, a proportionately greater number of oxygen molecules are bound by hemoglobin. Not surprisingly, the oxygen–hemoglobin saturation/dissociation curve also shows that the lower the P_O2, the lower the percent saturation of hemoglobin with oxygen. As a result, the P_O2 plays a major role in determining the degree of binding of oxygen to heme at the site of the respiratory membrane, as well as the degree of dissociation of oxygen from heme at the site of body tissues.

The conditions in which hemoglobin loads oxygen and dissociates from (unloads) oxygen, illustrated in the oxygen–hemoglobin saturation/dissociation curve, are adaptive for delivering different amounts of oxygen to different tissues throughout the body depending on their metabolism. Highly active tissues, such as exercising muscle, rapidly use oxygen to produce ATP, lowering the partial pressure of oxygen in the tissue to about 20 mm Hg. The partial pressure of oxygen inside capillaries is about 100 mm Hg, so the difference between the two becomes quite high, about 80 mm Hg. As a result, a greater number of oxygen molecules dissociate from hemoglobin and enter the tissues.

The reverse is true of tissues, such as adipose (body fat), which have lower metabolic rates. Because less oxygen is used by these cells, the partial pressure of oxygen within such tissues remains relatively high, resulting in fewer oxygen molecules dissociating from hemoglobin and entering the tissue interstitial fluid. Although venous blood is said to be deoxygenated, some oxygen is still bound to hemoglobin in its red blood cells. The amount of oxygen in venous blood after leaving the tissues is called the venous reserve, which can be used when tissues suddenly demand more oxygen.

Additional Factors Affecting Hemoglobin-Oxygen Affinity

Factors other than P_O2 also affect hemoglobin-oxygen affinity. For example, a higher temperature decreases hemoglobin-oxygen affinity, which promotes hemoglobin and oxygen to dissociate faster, whereas a lower temperature increases affinity These differences in affinity at different temperatures are seen in Figure 12.5.2. When comparing the curves at 10C and 20C, for example, it can be seen that at 10C, the hemoglobin is almost 100% saturated at a P_O2 of just over 20 mmHg and at 20C, it is not 100% saturdated until just over 40 mmHg.

The chemical 2,3-bisphosphoglycerate (BPG) also affects hemoglobin-oxygen affinity. 1,3-BPG is produced during glycolysis, and certain cells, including erythrocytes, are able to convert this to 2,3-BPG. As 2,3-BPG levels increase, hemoglobin-oxygen affinity decreases. Therefore, the greater the concentration of 2,3-BPG, the more readily oxygen dissociates from hemoglobin, despite its partial pressure.

The pH of the blood is another factor that influences hemoglobin-oxygen affinity (Figure 12.5.2). The Bohr effect is a phenomenon that arises from the relationship between pH and oxygen’s affinity for hemoglobin: a lower, more acidic pH lowers hemoglobin-oxygen affinity, in other words it promotes oxygen dissociation from hemoglobin. In contrast, a higher, or more basic, pH increases affinity.

What causes pH changes that result in the Bohr effect? Increased carbon dioxide levels can lead to an increase in H+ concentration, which in turn lowers pH. Furthermore, blood pH may become more acidic when other acidic byproducts of cell metabolism, such as lactic acid, are released into the bloodstream.

Hemoglobin of the Fetus

The fetus has its own circulation with its own erythrocytes; however, it is dependent on the mother for oxygen. Blood is supplied to the fetus by way of the umbilical cord, which is connected to the placenta and separated from maternal blood by the chorion. The mechanism of gas exchange at the chorion is similar to gas exchange at the respiratory membrane. However, the partial pressure of oxygen is lower in the maternal blood in the placenta, at about 35 to 50 mm Hg, than it is in maternal arterial blood. The difference in partial pressures between maternal and fetal blood is not large, as the partial pressure of oxygen in fetal blood at the placenta is about 20 mm Hg. Therefore, there is not as much diffusion of oxygen into the fetal blood supply. The fetus’ hemoglobin overcomes this problem by having a greater affinity for oxygen than maternal hemoglobin (Figure 12.5.3). Both fetal and adult hemoglobin have four polypeptide subunits, but structural differences (different amino acid sequences) between two of the subunits of fetal hemoglobin and adult hemoglobin cause fetal hemoglobin to have a greater affinity for oxygen than adult hemoglobin. Specifically, fetal hemoglobin does not response to BPG as strongly as adult hemoglobin, so therefore has a greater affinity for oxygen.

Dissolved Carbon Dioxide

Although carbon dioxide is not highly soluble in blood, a small fraction—about 7%—of the carbon dioxide that diffuses into the blood from the tissues dissolves in plasma. The dissolved carbon dioxide then travels in the bloodstream and when the blood reaches the pulmonary capillaries, the dissolved carbon dioxide diffuses across the respiratory membrane into the alveoli, where it is then exhaled during pulmonary ventilation.

Carbon Dioxide Transported as Bicarbonate

A large fraction—about 70%—of the carbon dioxide molecules that diffuse into the blood is transported to the lungs as bicarbonate. Most bicarbonate is produced in erythrocytes after carbon dioxide diffuses into the capillaries, and subsequently into red blood cells. There, carbon dioxide combines with water to form to form carbonic acid (H₂CO₃), which dissociates into two ions: bicarbonate (HCO₃^–) and hydrogen (H⁺). The following formula depicts this reaction:

This reaction occurs spontaneously, but also is sped up by the action of the enzyme carbonic anhydrase (CA) that catalyzes the formation of carbonic acid from carbon dioxide and water. Bicarbonate tends to build up in the erythrocytes, so that there is a greater concentration of bicarbonate in the erythrocytes than in the surrounding blood plasma. As a result, some of the bicarbonate will leave the erythrocytes and move down its concentration gradient into the plasma in exchange for chloride (Cl^–) ions. This phenomenon is referred to as the chloride shift and occurs because by exchanging one negative ion for another negative ion, neither the electrical charge of the erythrocytes nor that of the blood is altered.

At the pulmonary capillaries, the chemical reaction that produced bicarbonate (shown above) is reversed, and carbon dioxide and water are the products. Much of the bicarbonate in the plasma re-enters the erythrocytes in exchange for chloride ions. Hydrogen ions and bicarbonate ions join to form carbonic acid, which is converted into carbon dioxide and water by carbonic anhydrase. Carbon dioxide diffuses out of the erythrocytes and into the plasma, where it can further diffuse across the respiratory membrane into the alveoli to be exhaled during pulmonary ventilation.

Carbaminohemoglobin

About 23% of carbon dioxide is bound by hemoglobin and is transported to the lungs. Carbon dioxide does not bind to iron as oxygen does; instead, carbon dioxide binds amino acid moieties on the globin portions of hemoglobin to form carbaminohemoglobin, which forms when hemoglobin and carbon dioxide bind. The following formula depicts this reversible reaction:

Similar to the transport of oxygen by heme, the binding and dissociation of carbon dioxide to and from hemoglobin is dependent on the partial pressure of carbon dioxide. Because carbon dioxide is released from the lungs, blood that leaves the lungs and reaches body tissues has a lower partial pressure of carbon dioxide than is found in the tissues. As a result, carbon dioxide leaves the tissues because of its higher partial pressure, enters the blood, and then moves into red blood cells, binding to hemoglobin. In contrast, in the pulmonary capillaries, the partial pressure of carbon dioxide is high compared to within the alveoli. As a result, carbon dioxide dissociates readily from hemoglobin and diffuses across the respiratory membrane into the air.

In addition to the partial pressure of carbon dioxide, the oxygen saturation of hemoglobin and the partial pressure of oxygen in the blood also influence the affinity of hemoglobin for carbon dioxide. Hemoglobin that is saturated with oxygen does not readily bind carbon dioxide. However, when oxygen is not bound to heme and the partial pressure of oxygen is low, hemoglobin readily binds to carbon dioxide.