The generation of HCO3 − in red blood cells is mainly facilitated by the reaction of CO2 with H2O, resulting in the formation of carbonic acid (H2CO3) (Equation 24.3). This reaction is typically slow, but it is expedited within red blood cells by the enzyme carbonic anhydrase. The chloride shift occurs, allowing HCO3 − to diffuse out of the red blood cell in exchange for Cl−, thus helping the cell maintain its osmotic balance. This reversible chemical reaction (Fig. 24.8) can be shifted to the right, producing more HCO3 − when there is an increase in CO2 from the tissues entering the blood. Conversely, it can be shifted to the left when CO2 is exhaled in the lungs, leading to a reduction in HCO3 − levels. H+ ions are rapidly buffered within the red blood cell by binding to Hgb. Buffering H+ is crucial for driving the reaction towards the synthesis of HCO3 −, as high levels of free H+ (low pH) cause the reaction to shift to the left.

Maintenance of pH is essential for normal homeostasis as it significantly affects numerous metabolic processes within cells. Blood pH is measured in the clinical setting to assess H+ concentration. The lungs, kidneys, and chemical buffer systems work together to maintain a normal pH range of 7.35 to 7.45. The conversion of CO2 to HCO3 − (Equation 24.4) plays a significant role in buffering and regulating H+ concentration (pH). Changes in PACO2 result in corresponding alterations in the concentrations of HCO3 −, H2CO3, and PaCO2. The Henderson-Hasselbalch equation (Equation 24.5) is used to calculate the impact of CO2 and HCO3 − changes on pH. The solubility of CO2 (α) in solution determines its amount, with α having a value of 0.03 for plasma at 37°C. The negative logarithm of the overall dissociation constant for the reaction (pK′) has a logarithmic value of 6.1 for plasma at 37°C. The CO2 dissociation curve in blood is linear and directly related to PCO2 (Fig. 24.9). Hgb saturation with O2 significantly affects the CO2 dissociation curve. The transport of O2 in blood primarily occurs within red blood cells bound to Hgb, while CO2 is predominantly carried in the form of HCO3 − within red blood cells.

Acute hyperventilation due to exercise or anxiety leads to a reduction in PCO2, resulting in an increase in pH (respiratory alkalosis). On the other hand, an overdose of a respiratory depressant causing hypoventilation and an increase in PCO2 leads to a decrease in pH (respiratory acidosis). Metabolic disorders such as lactic acidosis, ketoacidosis, renal failure, hypokalemia, hypochloremia, and high doses of steroids can also cause acid-base imbalances. Gases with a rapid rate of air-to-blood equilibration (nitrous oxide, ether, helium) are considered perfusion limited, while gases with a slower rate (CO) are diffusion limited. Under normal conditions, O2 and CO2 exchange are perfusion limited, but in certain situations, they can become diffusion limited.
Fig. 24.8 ). Once CO2 diffuses through the tissue and enters plasma, it quickly dissolves. The reaction of CO2 with H2O to form carbonic acid (H2CO3) is the major mechanism for the generation of HCO3 − in red blood cells:
Equation 24.3
The reaction normally proceeds quite slowly; however, it is catalyzed within red blood cells by the enzyme carbonic anhydrase. The HCO3 − diffuses out of the red blood cell in exchange for Cl−, in a process known as the chloride shift, which helps the cell maintain its osmotic equilibrium. This chemical reaction (see
Fig. 24.8 ) is reversible and can be shifted to the right to generate more HCO3 − in response to more CO2 entering the blood from tissues, or it can be shifted to the left as CO2 is exhaled in the lungs, which reduces HCO3 − levels. The free H+ is quickly buffered within the red blood cell by binding to Hgb. Buffering of H+ is critical for keeping the reaction moving toward the synthesis of HCO3; high levels of free H+ (low pH) cause the reaction to shift to the left.
Regulation of Hydrogen Ion Concentration and Acid-Base Balance
The H+ concentration (pH) has a dramatic effect on many metabolic processes within cells, and regulation of pH is essential for normal homeostasis. In the clinical setting, blood pH is measured to assess the concentration of H+ . The normal pH range for adults is 7.35 to 7.45 and is maintained by the lungs, kidneys, and chemical buffer systems. In the respiratory system, conversion of CO2 to HCO3 − , illustrated as follows, is a major mechanism of buffering and regulating the H+ concentration (pH):
Equation 24.4
As PACO2 changes, so does the concentration of HCO3 − and H2CO3, as well as PaCO2. The Henderson-Hasselbalch equation is used to calculate how changes in CO2 and HCO3 − affect pH:
Equation 24.5 where α= solubility. Thus
Equation 24.6 log[HCO3 − ]pH = 6 1. + 0 03 × PCO2
In these equations, the amount of CO2 is determined from the PCO2 and its solubility (α) in solution. For plasma at 37°C, α has a value of 0.03. Also, pK′ is the negative logarithm of the overall dissociation constant for the reaction and has a logarithmic value of 6.1 for plasma at 37°C.
Acute hyperventilation secondary to exercise or anxiety reduces PCO2 and thereby causes an increase in pH (respiratory alkalosis). Conversely, if PCO2 increases because of hypoventilation secondary to an overdose of a respiratory depressant, the pH decreases (respiratory acidosis). Acid-base imbalances are also caused by metabolic disorders such as metabolic acidosis (e.g., lactic acidosis, ketoacidosis, and renal failure) and metabolic alkalosis (e.g., hypokalemia, hypochloremia, vomiting, high doses of steroids).
In contrast to O2, the dissociation curve for CO2 in blood is linear and directly related to PCO2 (
Fig. 24.9). The degree of Hgb saturation with O2 has a major effect on the CO2 dissociation curve. Although O2 and CO2 bind to Hgb 1.
Gases (nitrous oxide, ether, helium) that have a rapid rate of air-to-blood equilibration are perfusion limited. Gases (CO) that have a slow air-to-blood equilibration rate are diffusion limited. Under normal conditions, O2 and CO2 exchange are perfusion limited but can be diffusion limited in some situations.
2.
The major transport mechanism of O2 in blood is within the red blood cell bound to Hgb, and for CO2, it is within red blood cells in the form of HCO3 − .
3.