The reader understands how oxygen and carbon dioxide are transported to and from the tissues in the blood.
- States the relationship between the partial pressure of oxygen in the blood and the amount of oxygen physically dissolved in the blood.
- Describes the chemical combination of oxygen with hemoglobin and the “oxyhemoglobin dissociation curve.”
- Defines hemoglobin saturation, the oxygen-carrying capacity, and the oxygen content of blood.
- States the physiologic consequences of the shape of the oxyhemoglobin dissociation curve.
- Lists the physiologic factors that can influence the oxyhemoglobin dissociation curve, and predicts their effects on oxygen transport by the blood.
- States the relationship between the partial pressure of carbon dioxide in the blood and the amount of carbon dioxide physically dissolved in the blood.
- Describes the transport of carbon dioxide as carbamino compounds with blood proteins.
- Explains how most of the carbon dioxide in the blood is transported as bicarbonate.
- Describes the carbon dioxide dissociation curve for whole blood.
- Explains the Bohr and Haldane effects.
The final step in the exchange of gases between the external environment and the tissues is the transport of oxygen and carbon dioxide to and from the lung by the blood. Oxygen is carried both physically dissolved in the blood and chemically combined to hemoglobin. Carbon dioxide is carried physically dissolved in the blood, chemically combined to blood proteins as carbamino compounds, and as bicarbonate.
Physically Dissolved
At a temperature of 37°C, 1 mL of plasma contains 0.00003 mL O2/mm Hg
A few simple calculations can demonstrate that the oxygen physically dissolved in the blood is not sufficient to fulfill the body’s oxygen demand (at normal Fio2 and barometric pressure). The resting oxygen consumption of an adult is approximately 250 to 300 mL O2/min. If the tissues were able to remove the entire 0.3 mL O2/100 mL of blood flow they receive, the cardiac output would have to be about 83.3 L/min to meet the tissue demand for oxygen at rest:
During strenuous exercise, the oxygen demand can increase as much as 16-fold to 4 L/min or more. Under such conditions, the cardiac output would have to be greater than 1000 L/min if physically dissolved oxygen were to supply all the oxygen required by the tissues. The maximum cardiac outputs attainable by normal adults during strenuous exercise are in the range of 25 L/min. Clearly, the physically dissolved oxygen in the blood cannot meet the metabolic demand for oxygen, even at rest.
Chemically Combined with Hemoglobin
The Structure of Hemoglobin
Hemoglobin is a complex molecule with a molecular weight of about 64,500. The protein portion (globin) has a tetrameric structure consisting of 4 linked polypeptide chains, each of which is attached to a protoporphyrin (heme) group. Each heme group consists of 4 symmetrically arranged pyrroles with a ferrous (Fe2+) iron atom at its center. The iron atom is bound to each of the pyrrole groups and to 1 of the 4 polypeptide chains. A sixth binding site on the ferrous iron atom is freely available to bind with oxygen (or carbon monoxide). Therefore each of the 4 polypeptide chains can bind a molecule of oxygen (or carbon monoxide) to the iron atom in its own heme group, and so the tetrameric hemoglobin molecule can combine chemically with 4 oxygen molecules (or 8 oxygen atoms). Both the globin component and the heme component (with its iron atom in the ferrous state), in their proper spatial orientation to each other, are necessary for the chemical reaction with oxygen to take place—neither heme nor globin alone will combine with oxygen. Each of the tetrameric hemoglobin subunits can combine with oxygen by itself (see Figure 7–4C).
Variations in the amino acid sequences of the 4 globin subunits may have important physiologic consequences. Normal adult hemoglobin (HbA) consists of 2 alpha (α) chains, each of which has 141 amino acids, and 2 beta (β) chains, each of which has 146 amino acids. Fetal hemoglobin (HbF), which consists of 2 α chains and 2 gamma (γ) chains, has a higher affinity for oxygen than does HbA. Synthesis of β chains normally begins about 6 weeks before birth, and HbA usually replaces almost all the HbF by the time an infant is 4 months old. Other, abnormal hemoglobin molecules may be produced by genetic substitution of a single amino acid for the normal one in an α or β chain or (rarely) by alterations in the structure of heme groups. These alterations may produce changes in the affinity of the hemoglobin for oxygen, change the physical properties of hemoglobin, or alter the interaction of hemoglobin and other substances that affect its combination with oxygen, such as 2,3-bisphosphoglycerate (2,3-BPG) (discussed later in this chapter). More than 1000 abnormal variants of normal HbA have been demonstrated in patients. The best known of these, hemoglobin S, is present in sickle cell disease, an autosomal recessive genetic disorder caused by a single point mutation in the β chain. Hemoglobin S tends to polymerize and crystallize in the cytosol of the erythrocyte when it is not combined with oxygen. This polymerization and crystallization decreases the solubility of hemoglobin S within the erythrocyte and changes the shape of the cell from the normal biconcave disk to a crescent or “sickle” shape. A sickled cell is more fragile than a normal cell, causing hemolytic anemia. In addition, the cells have a tendency to stick to one another, which increases blood viscosity and also favors thrombosis or blockage of blood vessels.
Chemical Reaction of Oxygen and Hemoglobin
Hemoglobin rapidly combines reversibly with oxygen. It is the reversibility of the reaction that allows oxygen to be released to the tissues; if the reaction did not proceed easily in both directions, hemoglobin would be of little use in delivering oxygen to satisfy metabolic needs. The reaction is very fast, with a half-time of 0.01 of a second or less. Each gram of hemoglobin is capable of combining with about 1.39 mL of oxygen under optimal conditions, but under normal circumstances some hemoglobin exists in forms such as methemoglobin (in which the iron atom is in the ferric state) or is combined with carbon monoxide, in which case the hemoglobin does not bind oxygen. For this reason, the oxygen-carrying capacity of hemoglobin is conventionally considered to be 1.34 mL O2/g Hb. That is, each gram of hemoglobin, when fully saturated with oxygen, binds 1.34 mL of oxygen. Therefore, a person with 15 g Hb/100 mL of blood has an oxygen-carrying capacity of 20.1 mL O2/100 mL of blood:
The reaction of hemoglobin and oxygen is conventionally written
The equilibrium point of the reversible reaction of hemoglobin and oxygen is, of course, dependent on how much oxygen the hemoglobin in blood is exposed to.
The Oxyhemoglobin Dissociation Curve
One way to express the proportion of hemoglobin that is bound to oxygen is as percent saturation. This is equal to the content of oxygen in the blood (minus that part physically dissolved) divided by the oxygen-carrying capacity of the hemoglobin in the blood times 100%:
Note that the oxygen-carrying capacity of an individual depends on the amount of hemoglobin in that person’s blood. The blood oxygen content also depends on the amount of hemoglobin present (as well as on the
The relationship between the
Figure 7–1.
A typical “normal” adult oxyhemoglobin dissociation curve for blood at 37°C with a pH of 7.40 and a
The oxyhemoglobin dissociation curve is really a plot of how the availability of one of the reactants, oxygen (expressed as the
As can be seen in Figure 7–1, the relationship between
The reactions of the 4 subunits of hemoglobin with oxygen do not appear to occur simultaneously. Instead they are believed to occur sequentially in 4 steps, with an interaction between the subunits occurring in such a way that during the successive combinations of the subunits with oxygen, each combination facilitates the next (“positive cooperativity”). Similarly, dissociation of oxygen from hemoglobin subunits facilitates further dissociations. The dissociation curve for a single monomer of hemoglobin is far different from that for the tetramer (see Figure 7–4C).
As already stated, for hemoglobin to participate in the transport of oxygen from the lungs to the tissues, it must combine with oxygen in the pulmonary capillaries and then release oxygen to the metabolizing tissues in the systemic capillaries. The oxyhemoglobin dissociation curve in Figure 7–1 shows how this is accomplished.
Loading Oxygen in the Lung
Mixed venous blood entering the pulmonary capillaries normally has a
Oxygen-carrying capacity is
Oxygen bound to hemoglobin at a
Oxygen physically dissolved at a
Total blood oxygen content at a
As the blood passes through the pulmonary capillaries, it equilibrates with the alveolar
Oxygen bound to hemoglobin at a
Oxygen physically dissolved at a
Total blood oxygen content at a
Thus, in passing through the lungs, each 100 mL of blood has loaded (19.88 – 15.20) mL O2, or 4.68 mL O2. Assuming a cardiac output of 5 L/min, this means that approximately 234 mL O2 is loaded into the blood per minute:
Note that the oxyhemoglobin dissociation curve is relatively flat when
It should also be noted that since hemoglobin is approximately 97.4% saturated at a
Unloading Oxygen at the Tissues
As blood passes from the arteries into the systemic capillaries, it is exposed to lower
The unloading of oxygen at the tissues is also facilitated by other physiologic factors that can alter the shape and position of the oxyhemoglobin dissociation curve. These include the pH,
Figure 7–2 shows the influence of alterations in temperature, pH,
Figure 7–2.
The effects of pH (A),
Effects of pH and
The effects of blood pH and
Effects of Temperature
Figure 7–2C shows the effects of blood temperature on the oxyhemoglobin dissociation curve. High temperatures shift the curve to the right; low temperatures shift the curve to the left. At very low blood temperatures, hemoglobin has such a high affinity for oxygen that it does not release the oxygen, even at very low
Effects of 2,3-BPG
2,3-BPG (also called 2,3-diphosphoglycerate, or 2,3-DPG) is produced by erythrocytes during their normal glycolysis and is present in fairly high concentrations within red blood cells (about 15 mmol/g Hb). 2,3-BPG binds to the hemoglobin in erythrocytes, which decreases the affinity of hemoglobin for oxygen. Higher concentrations of 2,3-BPG therefore shift the oxyhemoglobin dissociation curve to the right, as shown in Figure 7–2D. More 2,3-BPG is produced during chronic hypoxic conditions, shifting the dissociation curve to the right and allowing more oxygen to be released from hemoglobin at a particular
Physiologic Consequences of the Effects of Temperature, pH, , and 2,3-BPG
As blood enters metabolically active tissues, it is exposed to an environment different from that found in the arterial tree. The
Figure 7–3.
Oxyhemoglobin dissociation curves for arterial and venous blood. The venous curve is shifted to the right because the pH is lower and the
Note that the effects of pH,
A convenient way to discuss shifts in the oxyhemoglobin dissociation curve is the P50, shown in Figures 7–1 and 7–3. The P50 is the
Other Factors Affecting Oxygen Transport
Anemia
Most forms of anemia do not affect the oxyhemoglobin dissociation curve if the association of oxygen and hemoglobin is expressed as percent saturation. For example, anemia secondary to blood loss does not affect the combination of oxygen and hemoglobin for the remaining erythrocytes. It is the amount of hemoglobin that decreases, not the percent saturation or even the arterial
Figure 7–4.
A: The effects of carbon monoxide and anemia on the carriage of oxygen by hemoglobin. Note that the ordinate is expressed as the volume of oxygen bound to hemoglobin in milliliters of oxygen per 100 mL of blood. B: A comparison of the oxyhemoglobin dissociation curves for normal adult hemoglobin (HbA) and fetal hemoglobin (HbF). C: Dissociation curves for normal HbA, a single monomeric subunit of hemoglobin (Hb subunit), and myoglobin (Mb).
Carbon Monoxide
Carbon monoxide has a much greater affinity for hemoglobin than does oxygen, as discussed in Chapter 6. It can therefore effectively block the combination of oxygen with hemoglobin because oxygen does not bind to iron atoms already combined with carbon monoxide. Carbon monoxide has a second deleterious effect: It shifts the oxyhemoglobin dissociation curve to the left. Thus, carbon monoxide can prevent the loading of oxygen into the blood in the lungs and can also interfere with the unloading of oxygen at the tissues. This can be seen in Figure 7–4A.
Carbon monoxide is dangerous for several reasons. A person breathing very low concentrations of carbon monoxide can slowly reach life-threatening levels of carboxyhemoglobin (COHb) in the blood because carbon monoxide has such a high affinity for hemoglobin. The effect is cumulative. What is worse is that a person breathing carbon monoxide is not aware of doing so—the gas is colorless, odorless, and tasteless, and does not elicit any reflex coughing or sneezing, increase in ventilation, or feeling of difficulty in breathing.
Smoking and living in urban areas cause small amounts of COHb to be present in the blood of healthy adults. A nonsmoker who lives in a rural area may have only about 1% COHb; a smoker who lives in an urban area may have 5% to 8% COHb in the blood.
Nitric Oxide
Hemoglobin within erythrocytes can rapidly scavenge nitric oxide (NO). NO can react with oxyhemoglobin to form methemoglobin and nitrate or react with deoxy hemoglobin to form a hemoglobin–NO complex. In addition, hemoglobin may act as a carrier for NO, in the form of S-nitrosothiol, on the cysteine residues on the β-globin chain. This is called s-nitrosohemoglobin (SNO-Hb). When hemoglobin binds oxygen, the formation of this S-nitrosothiol is enhanced; when hemoglobin releases oxygen, NO could be released. Thus, in regions where the
Methemoglobin
Methemoglobin is hemoglobin with iron in the ferric (Fe3+) state. It can be caused by nitrite poisoning or by toxic reactions to oxidant drugs, or it can be found congenitally in patients with hemoglobin M. Iron atoms in the Fe3+ state will not combine with oxygen.
Hemoglobins Other Than Adult Hemoglobin
As already discussed in this chapter, variants of the normal HbA may have different affinities for oxygen. HbF in red blood cells has a dissociation curve to the left of that for HbA, as shown in Figure 7–4B. This is perfectly reasonable because fetal
Myoglobin
Myoglobin (Mb), a heme protein that occurs naturally in muscle cells, consists of a single polypeptide chain attached to a heme group. It can therefore combine chemically with a single molecule of oxygen and is similar structurally to a single subunit of hemoglobin. As can be seen in Figure 7–4C, the hyperbolic dissociation curve of Mb (which is similar to that of a single hemoglobin subunit) is far to the left of that of normal HbA. That is, at lower
Artificial Blood
Oxygen can bind reversibly to emulsions of fluorocarbons. Although these fluorocarbon emulsions do not have nearly as much oxygen-carrying capacity as does hemoglobin at normal
Cyanosis
Cyanosis is not really an influence on the transport of oxygen but rather is a sign of poor transport of oxygen. Cyanosis occurs when more than 5 g Hb/100 mL of arterial blood is in the deoxy state. It is a bluish purple discoloration of the skin, nail beds, and mucous membranes, and its presence is indicative of an abnormally high concentration of deoxyhemoglobin in the arterial blood. Its absence, however, does not exclude hypoxemia because an anemic patient with hypoxemia may not have sufficient hemoglobin to appear cyanotic. Patients with abnormally high levels of hemoglobin in their arterial blood, such as those with polycythemia, may appear cyanotic without being hypoxemic.
Physically Dissolved
Carbon dioxide is about 20 times as soluble in the plasma (and inside the erythrocytes) as is oxygen. About 5% to 10% of the total carbon dioxide transported by the blood is carried in physical solution.
About 0.0006 mL CO2/mm Hg
Figure 7–5.
Carbon dioxide dissociation curves for whole blood (37°C) at different oxyhemoglobin saturations. Note that the ordinate is whole blood CO2 content in milliliters of CO2 per 100 mL of blood. a = arterial point;
Carbamino Compounds
Carbon dioxide can combine chemically with the terminal amine groups in blood proteins, forming carbamino compounds.
The reaction occurs rapidly; no enzymes are necessary. Note that a hydrogen ion is released when a carbamino compound is formed.
Because the protein found in greatest concentration in the blood is the globin of hemoglobin, most of the carbon dioxide transported in this manner is bound to amino acids of hemoglobin (“carbaminohemoglobin”).
Bicarbonate
The remaining 80% to 90% of the carbon dioxide transported by the blood is carried as bicarbonate ions. Carbon dioxide can combine with water to form carbonic acid, which then dissociates into a hydrogen ion and a bicarbonate ion.
Very little carbonic acid is formed by the association of water and carbon dioxide without the presence of the enzyme carbonic anhydrase because the reaction occurs so slowly. Carbonic anhydrase, which is present in high concentration in erythrocytes (but not in plasma), makes the reaction proceed about 13,000 times faster. When carbonic anhydrase is present, carbon dioxide and water form a hydrogen ion and a bicarbonate ion directly, skipping the carbonic acid step:
Hemoglobin also plays an integral role in the transport of carbon dioxide because it can accept the hydrogen ion liberated by the dissociation of carbonic acid, thus allowing the reaction to continue. This will be discussed in detail in the last section of this chapter.
The carbon dioxide dissociation curve for whole blood is shown in Figure 7–5. Note that the Y-axis is total CO2: dissolved CO2 plus CO2 as carbamino compounds, and as bicarbonate. Within the normal physiologic range of
The carbon dioxide dissociation curve for whole blood is shifted to the right at greater levels of oxyhemoglobin and shifted to the left at greater levels of deoxyhemoglobin. This is known as the Haldane effect, which will be explained in the next section. The Haldane effect allows the blood to load more carbon dioxide at the tissues, where there is more deoxyhemoglobin, and unload more carbon dioxide in the lungs, where there is more oxyhemoglobin.
The Bohr and Haldane effects are both explained by the fact that deoxyhemoglobin is a weaker acid than oxyhemoglobin.
These effects can be seen in the schematic diagrams of oxygen and carbon dioxide transport shown in Figure 7–6.
Figure 7–6.
Representation of uptake and release of carbon dioxide and oxygen at the tissues (A) and in the lung (B). Note that small amounts of carbon dioxide can form carbamino compounds with blood proteins other than hemoglobin and may also be hydrated in trivial amounts in the plasma to form carbonic acid and then bicarbonate (not shown in diagram). The circles represent the bicarbonate-chloride exchange carrier protein. Note that the carbonic acid step is included for clarity, even though it is skipped in the presence of carbonic anhydrase.
At the tissues, the
At the lung, the
Results of tests on a patient’s blood show the hemoglobin concentration to be 10 g/100 mL of blood. The blood is 97.4% saturated with oxygen at a
Total: 13.35 mL O2/100 mL of blood
What is the approximate hemoglobin oxygen saturation (SO2) of a blood sample that contains 10 g Hb/100 mL blood and has an oxygen content of 10 mL O2 /100 mL blood (ignore physically dissolved O2)?
From Raff H, Levitzky MG, eds. Medical Physiology: A Systems Approach. New York: McGraw-Hill; 2011:372.
An 18 year-old man is brought by ambulance to the emergency department about 35 minutes after being shot in the leg. He is conscious, although disoriented and in pain, and appears pale. Heart rate is 150/min, and his arterial blood pressure is 80/60 mm Hg. He is breathing spontaneously with a respiratory rate of 26/min. During the trip to hospital, the wound was stabilized and he received 2 liters of normal saline (0.9% NaCl in water) solution intravenously.
In the emergency department he continues to lose blood while the physicians attempt to stop the hemorrhage. As his arterial blood pressure continues to fall to 60/45 mm Hg, he is given 2 additional liters of saline. His hematocrit falls to 21% (normal range 40%–50%), corresponding to a hemoglobin concentration of 7 grams/100 ml of blood (normal range 13–18 grams/ 100 ml blood). His respiratory rate increases to 40/min.
Results of blood gas analysis (see Chapter 8) from an arterial blood sample shows a
The patient’s decreased blood volume led to decreased venous return, decreased cardiac output, and decreased systemic blood pressure. Decreased firing of the baroreceptors in the carotid sinuses and aortic arch decreased parasympathetic stimulation of the heart and increased sympathetic stimulation of the heart, arterioles, and the veins. This resulted in increased heart rate and myocardial contractility; increased arteriolar tone; and decreased venous compliance to enhance venous return, cardiac output, and blood pressure. However, all of these responses were not sufficient to increase his blood pressure or his cardiac output to normal levels, as he continued to lose blood. The decreased cardiac output and increased vascular resistance to most vascular beds resulted in decreased tissue perfusion (including his skin, explaining his pale appearance). This ischemia resulted in production of lactic acid causing hydrogen ion stimulation of the arterial chemoreceptors see Chapters 8 and 9), which explains his tachypnea (high respiratory rate). He was hyperventilating in compensation as demonstrated by the hypocapnia. As he continued to lose blood, his blood pressure was no longer sufficient to provide adequate cerebral blood flow and he lost consciousness and showed signs of circulatory shock.
Administration of normal saline temporarily increased blood volume, but diluted his erythrocytes, decreasing his hematocrit, hemoglobin concentration, oxygen carrying capacity, and arterial oxygen content, even if his alveolar and arterial partial pressures of oxygen were normal. Mixed venous
In the emergency department, his treatment would be aimed at stopping blood loss and restoring cardiac output and blood pressure with matched packed red blood cells (red blood cells after most of the plasma and other cells have been removed from whole blood).
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