Which of the following compounds binds to hemoglobin in the blood blocking the hemoglobins ability to carry oxygen throughout the body?

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.

Oxygen is transported both physically dissolved in blood and chemically combined to the hemoglobin in the erythrocytes. Much more oxygen is normally transported combined with hemoglobin than is physically dissolved in the blood. Without hemoglobin, the cardiovascular system could not supply sufficient oxygen to meet tissue demands.

Physically Dissolved

At a temperature of 37°C, 1 mL of plasma contains 0.00003 mL O2/mm Hg

. This corresponds to Henry’s law, as discussed in Chapter 6. Whole blood contains a similar amount of dissolved oxygen per milliliter because oxygen dissolves in the fluid of the erythrocytes in about the same amount. Therefore, normal arterial blood with a

of approximately 100 mm Hg contains only about 0.003 mL O2/mL of blood, or 0.3 mL O2/100 mL of blood. (Blood oxygen content is conventionally expressed in milliliters of oxygen per 100 mL of blood, or volumes percent.)

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.

This corresponds directly to the partial pressure of oxygen in the plasma under the conditions in the body. Thus, the

of the plasma determines the amount of oxygen that binds to the hemoglobin in the erythrocytes.

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

). Both content and capacity are expressed as milliliters of oxygen per 100 mL of blood. On the other hand, the percent hemoglobin saturation expresses only a percentage and not an amount or volume of oxygen. Therefore, “percent saturation” is not interchangeable with “oxygen content.” For example, 2 patients might have the same percent of hemoglobin saturation, but if one has a lower blood hemoglobin concentration because of anemia, he or she will have a lower blood oxygen content.

The relationship between the

of the plasma and the percent of hemoglobin saturation is demonstrated graphically as the oxyhemoglobin dissociation curve. An oxyhemoglobin dissociation curve for normal blood is shown in Figure 7–1.

Figure 7–1.

A typical “normal” adult oxyhemoglobin dissociation curve for blood at 37°C with a pH of 7.40 and a

of 40 mm Hg. The P50 is the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen.

The oxyhemoglobin dissociation curve is really a plot of how the availability of one of the reactants, oxygen (expressed as the

of the plasma), affects the reversible chemical reaction of oxygen and hemoglobin. The product, oxyhemoglobin, is expressed as percent saturation—really a percentage of the maximum for any given amount of hemoglobin.

As can be seen in Figure 7–1, the relationship between

and HbO2 is not linear; it is an S-shaped curve, steep at the lower

and nearly flat when the

is above 70 mm Hg.

It is this S shape that is responsible for several very important physiologic properties of the reaction of oxygen and hemoglobin. The reason that the curve is S-shaped and not linear is that it is actually a plot of 4 reactions rather than 1. That is, each of the 4 subunits of hemoglobin can combine with 1 molecule of oxygen. Indeed, it may be more correct to write the following equation:

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

of about 40 mm Hg, as discussed in Chapter 5. At a

of 40 mm Hg, hemoglobin is about 75% saturated with oxygen, as seen in Figure 7–1. Assuming a blood hemoglobin concentration of 15 g Hb/100 mL of blood, this corresponds to 15.08 mL O2/100 mL of blood bound to hemoglobin plus an additional 0.12 mL O2/100 mL of blood physically dissolved, or a total oxygen content of approximately 15.2 mL O2/100 mL of blood.

Oxygen-carrying capacity is

Oxygen bound to hemoglobin at a

of 40 mm Hg (37°C, pH 7.4) is

Oxygen physically dissolved at a

of 40 mm Hg is

Total blood oxygen content at a

of 40 mm Hg (37°C, pH 7.4) is

As the blood passes through the pulmonary capillaries, it equilibrates with the alveolar

of about 100 mm Hg. At a

of 100 mm Hg, hemoglobin is about 97.4% saturated with oxygen, as seen in Figure 7–1. This corresponds to 19.58 mL O2/100 mL of blood bound to hemoglobin plus 0.3 mL O2/100 mL of blood physically dissolved, or a total oxygen content of 19.88 mL O2/100 mL of blood.

Oxygen bound to hemoglobin at a

of 100 mm Hg (37°C, pH 7.4) is

Oxygen physically dissolved at a

of 100 mm Hg is

Total blood oxygen content at a

of 100 mm Hg (37°C, pH 7.4) is

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

is greater than approximately 70 mm Hg. This is very important physiologically because it means that there is only a small decrease in the oxygen content of blood equilibrated with a

of 70 mm Hg instead of 100 mm Hg. In fact, the curve shows that at a

of 70 mm Hg, hemoglobin is still approximately 94.1% saturated with oxygen. This constitutes an important safety factor because a patient with a relatively low alveolar or arterial

of 70 mm Hg (owing to hypoventilation or intrapulmonary shunting, for example) is still able to load oxygen into the blood with little difficulty. A quick calculation shows that at 70 mm Hg the total blood oxygen content is approximately 19.12 mL O2/100 mL of blood compared with the 19.88 mL O2/100 mL of blood at a

of 100 mm Hg. These calculations show that

is often a more sensitive diagnostic indicator of the status of a patient’s respiratory system than is the arterial oxygen content. Of course, the oxygen content is more important physiologically to the patient.

It should also be noted that since hemoglobin is approximately 97.4% saturated at a

of 100 mm Hg, raising the alveolar

above 100 mm Hg can combine little additional oxygen with hemoglobin (only about 0.52 mL O2/100 mL of blood at a hemoglobin concentration of 15 g/100 mL of blood). Hemoglobin is fully saturated with oxygen at a

of about 250 mm Hg.

Unloading Oxygen at the Tissues

As blood passes from the arteries into the systemic capillaries, it is exposed to lower

, and oxygen is released by the hemoglobin. The

in the capillaries varies from tissue to tissue, being very low in some (eg, myocardium) and relatively higher in others (eg, kidney). As can be seen in Figure 7–1, the oxyhemoglobin dissociation curve is very steep in the range of 40 to 10 mm Hg. This means that a small decrease in

can result in a substantial further dissociation of oxygen and hemoglobin, unloading more oxygen for use by the tissues. At a

of 40 mm Hg, hemoglobin is about 75% saturated with oxygen, with a total blood oxygen content of 15.2 mL O2/100 mL of blood (at 15 g Hb/100 mL of blood). At a

of 20 mm Hg, hemoglobin is only 32% saturated with oxygen. The total blood oxygen content is only 6.49 mL O2/100 mL of blood, a decrease of 8.71 mL O2/100 mL of blood for only a 20-mm Hg decrease in

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,

, temperature of the blood, and concentration of 2,3-BPG (2,3 bisphosphoglycerate) in the erythrocytes.

Figure 7–2 shows the influence of alterations in temperature, pH,

, and 2,3-BPG on the oxyhemoglobin dissociation curve.

High temperature, low pH, high

, and elevated levels of 2,3-BPG all “shift the oxyhemoglobin dissociation curve to the right.” That is, for any particular

there is less oxygen chemically combined with hemoglobin at higher temperatures, lower pHs, higher

, and elevated levels of 2,3-BPG.

Figure 7–2.

The effects of pH (A),

(B), temperature (C), and 2,3-BPG (D) on the oxyhemoglobin dissociation curve.

Effects of pH and

The effects of blood pH and

on the oxyhemoglobin dissociation curve are shown in Figure 7–2A and B. Low pHs and high

both shift the curve to the right. High pHs and low

both shift the curve to the left. Because high

in blood are often associated with low pHs, these 2 effects often occur together (see below and Chapter 8 for details). The influence of pH (and

) on the oxyhemoglobin dissociation curve is referred to as the Bohr effect. The Bohr effect will be discussed in greater detail at the end of this chapter.

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

. It should also be noted that oxygen is more soluble in water or plasma at lower temperatures than it is at normal body temperature. At 20°C about 50% more oxygen will dissolve in plasma.

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

. Very low levels of 2,3-BPG shift the curve far to the left, as shown in the figure. This means that blood deficient in 2,3-BPG does not unload much oxygen except at very low

. It is important to note that blood stored at blood banks for as little as 1 week has been shown to have very low levels of 2,3-BPG. Use of banked blood in patients may result in greatly decreased oxygen unloading to the tissues unless steps are taken to restore the normal levels of 2,3-BPG. In summary, 2,3-BPG is an important regulating mechanism in the release of oxygen by hemoglobin. Without its presence, hemoglobin’s high affinity for oxygen would impair the oxygen supply of the tissues.

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

is higher, the pH is lower, and the temperature is also higher than that of the arterial blood. It is evident, then, that in our original discussion of and calculations based on the oxyhemoglobin dissociation curve, shown in Figure 7–1, we were neglecting some important factors. The curve shown in Figure 7–1 is for blood at 37°C, with a pH of 7.4 and a

of 40 mm Hg. Blood in metabolically active tissues and therefore the venous blood draining them are no longer subject to these conditions because they have been exposed to a different environment. Because low pH, high

, and higher temperature all shift the oxyhemoglobin dissociation curve to the right, they all can help unload oxygen from hemoglobin at the tissues. On the other hand, as the venous blood returns to the lung and CO2 leaves the blood (which increases the pH), the affinity of hemoglobin for oxygen increases as the curve shifts back to the left, as shown in Figure 7–3.

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

(and possibly the temperature) is higher. The rightward shift results in a higher P50 for venous blood. a = arterial point (

= 100 mm Hg);

= mixed venous point (

= 40 mm Hg).

Note that the effects of pH,

, and temperature shown in Figure 7–2 are all more pronounced at lower

than at greater

. That is, they have a more profound effect on enhancing the unloading of oxygen at the tissues than they do interfering with its loading at the lungs.

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

at which 50% of the hemoglobin present in the blood is in the deoxyhemoglobin state and 50% is in the oxyhemoglobin state. At a temperature of 37°C, a pH of 7.4, and a

of 40 mm Hg, normal human blood has a P50 of 26 or 27 mm Hg. If the oxyhemoglobin dissociation curve is shifted to the right, the P50 increases. If it is shifted to the left, the P50 decreases.

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

. The arterial content of oxygen, however, in milliliters of oxygen per 100 mL of blood, is reduced, as shown in Figure 7–4A, because the decreased amount of hemoglobin per 100 mL of blood decreases the oxygen-carrying capacity of the blood. Anemia severe enough to increase tissue anaerobic metabolism causes metabolic acidosis and a rightward shift of the oxyhemoglobin dissociation curve.

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

is low, NO—a potent vasodilator—could be released. Some researchers have proposed that this mechanism plays an important role in hypoxia-induced vasodilation or that NO scavenging by hemoglobin plays a role in hypoxic pulmonary vasoconstriction, but this has not been established.

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

are much lower than those of an adult. The curve is located properly for its operating range. Furthermore, HbF’s greater affinity for oxygen relative to the maternal hemoglobin promotes transport of oxygen across the placenta by maintaining the diffusion difference. The shape of the HbF curve in blood appears to be a result of the fact that 2,3-BPG has little effect on the affinity of HbF for oxygen. The curve is similar to that of HbA without 2,3-BPG (Figure 7–2D). Abnormal hemoglobins may have either increased or decreased affinities for oxygen. For example, Hb Seattle and Hb Kansas have lower affinities for oxygen than does HbA; Hb Rainier has a higher affinity for oxygen.

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

, much more oxygen remains bound to Mb. Mb can therefore act to transport and store oxygen in skeletal muscle. As blood passes through the muscle, oxygen leaves hemoglobin and binds to Mb. It can be released from the Mb when conditions cause 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

, they can carry significantly more oxygen than plasma can. At very high

(eg, around 660 mm Hg, which would be attained in the pulmonary capillaries of alveoli ventilated with 100% O2), these fluorocarbon emulsions can carry nearly as much oxygen as hemoglobin can. Fluorocarbons may become useful as emergency blood substitutes, for transfusions, and to augment blood transport in anemic patients or during surgery. They may also be used for partial or total liquid ventilation in the future.

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.

Carbon dioxide is carried in the blood in physical solution, chemically combined to amino acids in blood proteins, and as bicarbonate ions. About 200 to 250 mL of carbon dioxide is produced by the tissue metabolism each minute in a resting 70-kg person and must be carried by the venous blood to the lung for removal from the body. At a cardiac output of 5 L/min, each 100 mL of blood passing through the lungs must therefore unload 4 to 5 mL of carbon dioxide.

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

will dissolve in 1 mL of plasma at 37°C. One hundred milliliters of plasma or whole blood at a

of 40 mm Hg, therefore, contains about 2.4 mL CO2 in physical solution. Figure 7–5 shows that the total CO2 content of whole blood is about 48 mL CO2/100 mL of blood at 40 mm Hg, and so approximately 5% of the carbon dioxide carried in the arterial blood is in physical solution. Similarly, multiplying 0.06 mL CO2/100 mL of blood/mm Hg

times a venous

of 45 mm Hg shows that about 2.7 mL CO2 is physically dissolved in the mixed venous blood. The total carbon dioxide content of venous blood is about 52.5 mL CO2/100 mL of blood; a little more than 5% of the total carbon dioxide content of venous blood is in physical solution.

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;

= mixed venous 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”).

Deoxyhemoglobin can bind more carbon dioxide as carbamino groups than can oxyhemoglobin. Therefore, as the hemoglobin in the venous blood enters the lung and combines with oxygen, it releases carbon dioxide from its terminal amine groups. About 5% to 10% of the total carbon dioxide content of blood is in the form of carbamino compounds.

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 curve is nearly a straight line, with no steep or flat portions. If it is plotted on axes similar to those for oxygen, the carbon dioxide dissociation curve for whole blood is steeper than the oxygen dissociation curve for whole blood. That is, there is a greater change in CO2 content per mm Hg change in

than there is in oxygen content per mm Hg change in

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.

That is, deoxyhemoglobin more readily accepts the hydrogen ion liberated by the dissociation of carbonic acid, thus permitting more carbon dioxide to be transported in the form of bicarbonate ion. This is referred to as the isohydric shift. Conversely, the association of hydrogen ions with the amino acids of hemoglobin lowers the affinity of hemoglobin for oxygen, thus shifting the oxyhemoglobin dissociation curve to the right at low pHs or high

. The following “equation” can therefore be written

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

is low and the

is high. Carbon dioxide dissolves in the plasma, and some diffuses into the erythrocyte. Some of this carbon dioxide dissolves in the cytosol, some forms carbamino compounds with hemoglobin, and some is hydrated by carbonic anhydrase to form carbonic acid. At low

, there are substantial amounts of deoxyhemoglobin in the erythrocytes and the deoxy hemoglobin is able to accept the hydrogen ions liberated by the dissociation of carbonic acid and the formation of carbamino compounds. The hydrogen ions released by the dissociation of carbonic acid and the formation of carbamino compounds bind to specific amino acid residues on the globin chains and facilitate the release of oxygen from hemoglobin (the Bohr effect). Bicarbonate ions diffuse out of the erythrocyte through the cell membrane much more readily than do hydrogen ions. Because more bicarbonate ions than hydrogen ions leave the erythrocyte, electrical neutrality is maintained by the exchange of chloride ions for bicarbonate ions by the bicarbonate-chloride carrier protein. This is the “chloride shift.” Small amounts of water also move into the cell to maintain the osmotic equilibrium.

At the lung, the

is high and the

is low. As oxygen combines with hemoglobin, the hydrogen ions that were taken up when it was in the deoxyhemoglobin state are released. They combine with bicarbonate ions, forming carbonic acid. This breaks down into carbon dioxide and water. At the same time, carbon dioxide is also released from the carbamino compounds. Carbon dioxide then diffuses out of the red blood cells and plasma and into the alveoli. A chloride shift opposite in direction to that in the tissues also occurs to maintain electrical neutrality.

Blood normally carries a small amount of oxygen physically dissolved in the plasma and a large amount chemically combined to hemoglobin: only the physically dissolved oxygen contributes to the partial pressure, but the partial pressure of oxygen determines how much combines chemically with hemoglobin.

The oxyhemoglobin dissociation curve describes the reversible reaction of oxygen and hemoglobin to form oxyhemoglobin; it is relatively flat at a

above approximately 70 mm Hg and is very steep at a

in the range of 20 to 40 mm Hg.

Decreased pH, increased

, increased temperature, and increased 2,3-BPG concentration of the blood all shift the oxyhemoglobin dissociation curve to the right.

Blood normally carries small amounts of carbon dioxide physically dissolved in the plasma and chemically combined to blood proteins as carbamino compounds and a large amount in the form of bicarbonate ions.

Deoxyhemoglobin favors the formation of carbamino compounds, and it promotes the transport of carbon dioxide as bicarbonate ions by buffering hydrogen ions formed by the dissociation of carbonic acid.

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

of 100 mm Hg. What is the patient’s arterial oxygen content, including physically dissolved oxygen (37°C, pH 7.40,

of 40 mm Hg)?

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

of 95 mm Hg, a

of 28 mm Hg (normal range 35–45 mm Hg), and an arterial pH of 7.30 (normal range 7.35–7.45) despite the hypocapnia. He becomes agitated and loses consciousness. He is intubated (a tube inserted into trachea) and mechanically ventilated via the endotracheal tube.

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

would decrease as tissues extracted as much oxygen as possible from the arterial blood. Renal and endocrine responses to hemorrhage also would occur.

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).

Comroe JH. Physiology of Respiration. 2nd ed. Chicago, Ill: Year Book; 1974:183–196.

Hsia CCW. Respiratory function of hemoglobin. N Engl J Med. 1998;338:239–247. [PubMed: 9435331]

Miller AC, Gladwin MT. Pulmonary complications of sickle cell disease. Am J Respir Crit Care Med. 2012;185:1154–1165. [PubMed: 22447965]

Orkin SH, Higgs DR. Sickle cell disease at 100 years. Science. 2010;329:291–292. [PubMed: 20647458]

Robinson JM, Lancaster JR. Hemoglobin-mediated hypoxia-induced vasodilation via nitric oxide. Am J Respir Cell Mol Biol. 2005;32:257–261. [PubMed: 15778415]

Roughton FJW. Transport of oxygen and carbon dioxide. In: Fenn WO, Rahn H, eds. Handbook of Physiology, sec 3: Respiration. Washington, DC: American Physiological Society; 1964:767–825.

Veeramachaneni NK, Harken AH, Cairns CB. Clinical implications of hemoglobin as a nitric oxide carrier. Arch Surg. 1999;134:434–437. [PubMed: 10199319]

What does hemoglobin bind to to be able to carry oxygen?

[6] Hemoglobin is a metalloprotein with four subunits composed of an iron-containing heme group attached to a globin polypeptide chain. [7] One molecule of oxygen can bind to the iron atom of a heme group, giving each hemoglobin the ability to transport four oxygen molecules.

What substance binds with hemoglobin?

Oxygen from the lungs binds to hemoglobin molecules and is carried through blood vessels to the rest of the body.

What prevents hemoglobin from binding oxygen?

Hemoglobin binds carbon monoxide (CO) 200 to 300 times more than with oxygen, resulting in the formation of carboxyhemoglobin and preventing the binding of oxygen to hemoglobin due to the competition of the same binding sites.

Which of the following compounds binds to hemoglobin in the blood blocking the hemoglobins ability to carry oxygen throughout the body?

Physically Dissolved

Chemically Combined with Hemoglobin

The Structure of Hemoglobin

Chemical Reaction of Oxygen and Hemoglobin

The Oxyhemoglobin Dissociation Curve

Loading Oxygen in the Lung

Unloading Oxygen at the Tissues

Effects of pH and

Effects of Temperature

Effects of 2,3-BPG

Physiologic Consequences of the Effects of Temperature, pH, , and 2,3-BPG

Other Factors Affecting Oxygen Transport

Anemia

Carbon Monoxide

Nitric Oxide

Methemoglobin

Hemoglobins Other Than Adult Hemoglobin

Myoglobin

Artificial Blood

Cyanosis

Physically Dissolved

Carbamino Compounds

Bicarbonate

What does hemoglobin bind to to be able to carry oxygen?

What substance binds with hemoglobin?

What prevents hemoglobin from binding oxygen?

zusammenhängende Posts

Werbung

NEUESTEN NACHRICHTEN

Werbung

Populer

Werbung

Um

Legal

Hilfe

Sozial