After studying this chapter, you should be able to:

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  Describe the manner in which O₂ flows “downhill” from the lungs to the tissues and CO₂ flows “downhill” from the tissues to the lungs.

  
  
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  List the important factors affecting the affinity of hemoglobin for O₂ and the physiologic significance of each.

  
  
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  List the reactions that increase the amount of CO₂ in the blood, and draw the CO₂ dissociation curve for arterial and venous blood.

  
  
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  Define alkalosis and acidosis and list typical causes and compensatory responses to each.

  
  
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  Define hypoxia and describe differences in subtypes of hypoxia.

  
  
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  Describe the effects of hypercapnia and hypocapnia, and give examples of conditions that can cause them.

The concentrations for O₂ and CO₂ (measured as partial pressures, or P_o2 and P_co2) change within each region of the lung, allowing for these gases to flow “downhill” or from higher partial pressures to lower partial pressures. For example, P_o2 is highest in the alveoli upon inspiration and lowest in the deoxygenated blood, whereas, P_co2 is exactly opposite. This allows for O₂ to cross the alveoli and re-oxygenate the blood in the pulmonary vasculature, while CO₂ leaves the bloodstream and enters the alveoli where it is expired. However, the amount of both of these gases transported to and from the tissues would be grossly inadequate if it were not for the fact that about 99% of the O₂ that dissolves in the blood combines with the O₂-carrying protein hemoglobin and that about 94.5% of the CO₂ that dissolves enters into a series of reversible chemical reactions that convert it into other compounds. Thus, the presence of hemoglobin increases the O₂-carrying capacity of the blood 70-fold, and the reactions of CO₂ increase the blood CO₂ content 17-fold. In this chapter, physiologic details that underlie O₂ and CO₂ movement under various conditions are discussed.

OXYGEN DELIVERY TO THE TISSUES

Oxygen delivery, or by definition, the volume of oxygen delivered to the systemic vascular bed per minute, is the product of the cardiac output and the arterial oxygen concentration. The ability to deliver O₂ in the body depends on both the respiratory and the cardiovascular systems. O₂ delivery to a particular tissue depends on the amount of O₂ entering the lungs, the adequacy of pulmonary gas exchange, the blood flow to the tissue, and the capacity of the blood to carry O₂. Blood flow to an individual tissue depends on cardiac output and the degree of constriction of the vascular bed in the tissue. The amount of O₂ in the blood is determined by the amount of dissolved O₂, the amount of hemoglobin in the blood, and the affinity of the hemoglobin for O₂.

REACTION OF HEMOGLOBIN & OXYGEN

The dynamics of the reaction of hemoglobin with O₂ make it a particularly suitable O₂ carrier. Hemoglobin is a protein made up of four subunits, each of which contains a heme moiety attached to a polypeptide chain. In normal adults, most of the hemoglobin molecules contain two α and two β chains. Heme (see Figure 31–7) is a porphyrin ring complex that includes one atom of ferrous iron. Each of the four iron atoms in hemoglobin can reversibly bind one O₂ molecule. The iron stays in the ferrous state, so that the reaction is oxygenation (not oxidation). It has been customary to write the reaction of hemoglobin with O₂ as Hb + O₂ HbO₂. Because it contains four deoxyhemoglobin (Hb) units, the hemoglobin molecule can also be represented as Hb₄, and it actually reacts with four molecules of O₂ to form Hb₄O₈.

The reaction is rapid, requiring less than 0.01 s. The deoxygenation of Hb₄O₈ is also very rapid.

The quaternary structure of hemoglobin determines its affinity for O₂. In deoxyhemoglobin, the globin units are tightly bound in a tense (T) configuration, which reduces the affinity of the molecule for O₂. When O₂ is first bound, the bonds holding the globin units are released, producing a relaxed (R) configuration, which exposes more O₂ binding sites. The net result is a 500-fold increase in O₂ affinity. In tissues, these reactions are reversed, resulting in O₂ release. The transition from one state to another has been calculated to occur about 10⁸ times in the life of a red blood cell.

The oxygen-hemoglobin dissociation curve relates percentage saturation of the O₂ carrying power of hemoglobin (abbreviated as SaO₂) to the Po₂ (Figure 35–1). This curve has a characteristic sigmoid shape due to the T–R configuration interconversion. Combination of the first heme in the Hb molecule with O₂ increases the affinity of the second heme for O₂, and oxygenation of the second increases the affinity of the third, and so on, so that the affinity of Hb for the fourth O₂ molecule is many times that for the first. Especially note that small changes at low Po₂ lead to large changes in SaO₂.

When blood is equilibrated with 100% O₂, the normal hemoglobin becomes 100% saturated. When fully saturated, each gram of normal hemoglobin contains 1.39 mL of O₂. However, blood normally contains small quantities of inactive hemoglobin derivatives, and the measured value in vivo is thus slightly lower. Using the traditional estimate of saturated hemoglobin in vivo, 1.34 mL of O₂, the hemoglobin concentration in normal blood is about 15 g/dL (14 g/dL in women and 16 g/dL in men). Therefore, 1 dL of blood contains 20.1 mL (1.34 mL × 15) of O₂ bound to hemoglobin when the hemoglobin is 100% saturated. The amount of dissolved O₂ is a linear function of the Po₂ (0.003 mL/dL blood/mm Hg Po₂).

In vivo, the hemoglobin in the blood at the ends of the pulmonary capillaries is about 97.5% saturated with O₂ (Po₂ = 100 mm Hg). Because of a slight admixture with venous blood that bypasses the pulmonary capillaries (ie, physiologic shunt), the hemoglobin in systemic arterial blood is only 97% saturated. The arterial blood therefore contains a total of about 19.8 mL of O₂ per dL: 0.29 mL in solution and 19.5 mL bound to hemoglobin. In venous blood at rest, the hemoglobin is 75% saturated and the total O₂ content is about 15.2 mL/dL: 0.12 mL in solution and 15.1 mL bound to hemoglobin. Thus, at rest the tissues remove about 4.6 mL of O₂ from each deciliter of blood passing through them (Table 35–1); 0.17 mL of this total represents O₂ that was in solution in the blood, and the remainder represents O₂ that was liberated from hemoglobin. In this way, 250 mL of O₂ per minute is transported from the blood to the tissues at rest.

FACTORS AFFECTING THE AFFINITY OF HEMOGLOBIN FOR OXYGEN

Three important conditions affect the oxygen-hemoglobin dissociation curve: the pH, the temperature, and the concentration of 2,3-diphosphoglycerate (DPG; 2,3-DPG). A rise in temperature or a fall in pH shifts the curve to the right (Figure 35–2). When the curve is shifted in this direction, a higher Po₂ is required for hemoglobin to bind a given amount of O₂. Conversely, a fall in temperature or a rise in pH shifts the curve to the left, and a lower Po₂ is required to bind a given amount of O₂. A convenient index for comparison of such shifts is the P₅₀, the Po₂ at which hemoglobin is half saturated with O₂. The higher the P₅₀, the lower the affinity of hemoglobin for O₂.

The decrease in O₂ affinity of hemoglobin when the pH of blood falls is called the Bohr effect and is closely related to the fact that deoxygenated hemoglobin (deoxyhemoglobin) binds H⁺ more actively than does oxygenated hemoglobin (oxyhemoglobin). The pH of blood falls as its CO₂ content increases, so that when the Pco₂ rises, the curve shifts to the right and the P₅₀ rises. Most of the unsaturation of hemoglobin that occurs in the tissues is secondary to the decline in the Po₂, but an extra 1–2% unsaturation is due to the rise in Pco₂ and consequent shift of the dissociation curve to the right.

2,3-DPG is very plentiful in red cells. It is formed from 3-phosphoglyceraldehyde, which is a product of glycolysis via the Embden-Meyerhof pathway. It is a highly charged anion that binds to the β chains of deoxyhemoglobin. One mole of deoxyhemoglobin binds 1 mol of 2,3-DPG. In effect,

In this equilibrium, an increase in the concentration of 2,3-DPG shifts the reaction to the right, causing more O₂ to be liberated.

Because acidosis inhibits red cell glycolysis, the 2,3-DPG concentration falls when the pH is low. Conversely, thyroid hormones, growth hormones, and androgens can all increase the concentration of 2,3-DPG and the P₅₀.

Exercise has been reported to produce an increase in 2,3-DPG within 60 min (although the rise may not occur in trained athletes). The P₅₀ is also increased during exercise, because the temperature rises in active tissues and CO₂ and metabolites accumulate, lowering the pH. In addition, much more O₂ is removed from each unit of blood flowing through active tissues because the tissue Po₂ declines. Finally, at low Po₂ values, the oxygen-hemoglobin dissociation curve is steep, and large amounts of O₂ are liberated per unit drop in Po₂. Some clinical features of hemoglobin are discussed in Clinical Box 35–1.

An interesting contrast to hemoglobin is myoglobin, an iron-containing pigment found in skeletal muscle. Myoglobin resembles hemoglobin but binds 1 rather than 4 mol of O₂ per mole protein. The lack of cooperative binding is reflected in the myoglobin dissociation curve, a rectangular hyperbola rather than the sigmoid curve observed for hemoglobin (Figure 35–3). Additionally, the leftward shift of the myoglobin O₂ binding curve when compared with hemoglobin demonstrates a higher affinity for O₂, and thus promotes a favorable transfer of O₂ from hemoglobin in the blood. The steepness of the myoglobin curve also shows that O₂ is released only at low Po₂ values (eg, during exercise). The myoglobin content is greatest in muscles specialized for sustained contraction. The muscle blood supply is compressed during such contractions, and myoglobin can continue to provide O₂ under reduced blood flow and/or reduced Po₂ in the blood.

MOLECULAR FATE OF CARBON DIOXIDE IN BLOOD

The solubility of CO₂ in blood is about 20 times that of O₂; therefore, considerably more CO₂ than O₂ is present in simple solution at equal partial pressures. The CO₂ that diffuses into red blood cells is rapidly hydrated to H₂CO₃ because of the presence of carbonic anhydrase (Figure 35–4). The H₂CO₃ dissociates to H⁺ and HCO₃⁻, and the H⁺ is buffered, primarily by hemoglobin, while the HCO₃⁻ enters the plasma. Some of the CO₂ in the red cells reacts with the amino groups of hemoglobin and other proteins (R), forming carbamino compounds.

Because deoxyhemoglobin binds more H⁺ than oxyhemoglobin and forms carbamino compounds more readily, binding of O₂ to hemoglobin reduces its affinity for CO₂. The Haldane effect refers to the increased capacity of deoxygenated hemoglobin to bind and carry CO₂. Consequently, venous blood carries more CO₂ than arterial blood, CO₂ uptake is facilitated in the tissues, and CO₂ release is facilitated in the lungs. About 11% of the CO₂ added to the blood in the systemic capillaries is carried to the lungs as carbamino-CO₂.

CHLORIDE SHIFT

Because the rise in the HCO₃⁻ content of red cells is much greater than that in plasma as the blood passes through the capillaries, about 70% of the HCO₃⁻ formed in the red cells enters the plasma. The excess HCO₃⁻ leaves the red cells in exchange for Cl⁻ (Figure 35–4). This process is mediated by anion exchanger 1 (AE1; also called Band 3), a major membrane protein in the red blood cell. Because of this chloride shift, the Cl⁻ content of the red cells in venous blood is significantly greater than that in arterial blood. The chloride shift occurs rapidly and is essentially complete within 1 s.

Note that for each CO₂ molecule added to a red cell, there is an increase of one osmotically active particle in the cell—either an HCO₃⁻ or a Cl⁻ (Figure 35–4). Consequently, the red cells take up water and increase in size. For this reason, plus the fact that a small amount of fluid in the arterial blood returns via the lymphatics rather than the veins, the hematocrit of venous blood is normally 3% greater than that of the arterial blood. In the lungs, the Cl⁻ moves back out of the cells and they shrink.

SPATIAL DISTRIBUTION OF CARBON DIOXIDE IN BLOOD

For convenience, the various fates of CO₂ in the plasma and red cells are summarized in Table 35–2. The extent to which they increase the capacity of the blood to carry CO₂ is indicated by the difference between the lines indicating the dissolved CO₂ and the total CO₂ in the dissociation curves for CO₂ shown in Figure 35–5.

Of the approximately 49 mL of CO₂ in each deciliter of arterial blood (Table 35–1), 2.6 mL is dissolved, 2.6 mL is in carbamino compounds, and 43.8 mL is in HCO₃⁻. In the tissues, 3.7 mL of CO₂

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