Table of Contents
Forms of Carbon Dioxide in Blood
After gas exchange in the tissues, carbon dioxide ($\mathrm{CO_2}$) enters the blood and is transported to the lungs. It does not travel only as dissolved gas. In humans and most vertebrates, approximately:
- 5–10%: physically dissolved in blood plasma
- 20–30%: bound (reversibly) to proteins, mainly hemoglobin (carbamino compounds)
- 60–70%: as bicarbonate ions ($\mathrm{HCO_3^-}$) in plasma and red blood cells
The distribution can vary slightly between species and with physiological state, but the dominance of bicarbonate is universal in vertebrates.
1. Physically Dissolved CO₂
CO₂ is more soluble in water than oxygen. A small portion:
- diffuses from tissues into blood
- remains as dissolved gas in plasma and in the fluid inside red blood cells (RBCs)
This fraction is in direct equilibrium with the partial pressure of CO₂ ($p\mathrm{CO_2}$) and is what is actually “sensed” by chemoreceptors that regulate breathing.
Despite being a small fraction of total CO₂ transport, this dissolved CO₂ is important for:
- setting $p\mathrm{CO_2}$ in blood
- determining acid–base status via the CO₂–bicarbonate buffer system
2. CO₂ Transport as Bicarbonate (HCO₃⁻)
Most CO₂ is converted to bicarbonate inside red blood cells. The key reaction:
$$
\mathrm{CO_2 + H_2O \rightleftharpoons H_2CO_3 \rightleftharpoons H^+ + HCO_3^-}
$$
In words: carbon dioxide + water ⇄ carbonic acid ⇄ hydrogen ion + bicarbonate ion.
Role of Carbonic Anhydrase
Inside RBCs, the enzyme carbonic anhydrase accelerates the first step:
$$
\mathrm{CO_2 + H_2O \xrightarrow[\text{carbonic anhydrase}]{} H_2CO_3}
$$
Without this enzyme, the reaction would be too slow to handle the large CO₂ fluxes occurring during active metabolism.
Steps in the Tissues (Loading CO₂)
At systemic capillaries (near tissues):
- CO₂ diffuses from tissue cells into the blood down its partial pressure gradient.
- CO₂ enters RBCs and, with water, is converted to carbonic acid ($\mathrm{H_2CO_3}$) via carbonic anhydrase.
- $ \mathrm{H_2CO_3} $ dissociates into $\mathrm{H^+}$ and $\mathrm{HCO_3^-}$.
- Bicarbonate ($\mathrm{HCO_3^-}$):
- is largely transported out of RBCs into plasma
- becomes the main transported form of CO₂ in blood
- Protons ($\mathrm{H^+}$) are mostly buffered by hemoglobin and other intracellular buffers (see below).
This process effectively removes CO₂ from solution in the RBC as fast as it enters, maintaining a diffusion gradient that favors continued CO₂ uptake.
Chloride Shift (Hamburger Effect)
As negatively charged bicarbonate ($\mathrm{HCO_3^-}$) leaves the RBC:
- To preserve electroneutrality, chloride ions ($\mathrm{Cl^-}$) move from the plasma into the RBC.
- This exchange is mediated by a specific anion exchanger protein in the RBC membrane.
This phenomenon is called the chloride shift. It:
- allows large amounts of bicarbonate to be stored in plasma
- prevents charge imbalance and osmotic problems in RBCs
In systemic capillaries (where CO₂ is taken up):
- $\mathrm{HCO_3^-}$ exits RBCs
- $\mathrm{Cl^-}$ enters RBCs
Reverse Reactions in the Lungs (Unloading CO₂)
At pulmonary capillaries (in the lungs), the process is reversed:
- Oxygen binds to hemoglobin (see chapter on gas exchange); this changes hemoglobin’s affinity for $\mathrm{H^+}$.
- $\mathrm{H^+}$ is released from hemoglobin.
- In RBCs, bicarbonate ($\mathrm{HCO_3^-}$) from the plasma re-enters via the anion exchanger, and chloride ($\mathrm{Cl^-}$) leaves the cell (reverse chloride shift).
- $\mathrm{H^+}$ and $\mathrm{HCO_3^-}$ recombine to form carbonic acid ($\mathrm{H_2CO_3}$).
- Carbonic anhydrase converts $\mathrm{H_2CO_3}$ back to CO₂ and water.
- CO₂ diffuses out of RBCs, across the alveolar membrane, and is exhaled.
Thus, the bicarbonate “form” of CO₂ in blood is converted back to gaseous CO₂ for elimination.
CO₂–Bicarbonate as a Buffer System
The $\mathrm{CO_2/HCO_3^-}$ pair serves as a major buffer system in blood:
- Increasing CO₂ (from metabolism or hypoventilation) pushes the equilibrium toward more $\mathrm{H^+}$ → lowers pH (respiratory acidosis).
- Decreasing CO₂ (through hyperventilation) removes $\mathrm{H^+}$ via formation and exhalation of CO₂ → raises pH (respiratory alkalosis).
The respiratory system therefore participates in acid–base regulation by controlling CO₂ removal.
(Details of systemic pH regulation and compensation by the kidneys are covered in other chapters.)
3. CO₂ Bound to Proteins (Carbamino Compounds)
A smaller, but physiologically important fraction of CO₂ is transported as carbamino compounds:
- CO₂ reacts reversibly with free amino groups ($-\mathrm{NH_2}$) on proteins to form carbamino groups:
$$
\mathrm{CO_2 + R{-}NH_2 \rightleftharpoons R{-}NH{-}COO^- + H^+}
$$
- In blood, the most important protein for this is hemoglobin in RBCs.
Carbaminohemoglobin
When CO₂ binds to hemoglobin:
- The compound is called carbaminohemoglobin.
- Binding occurs mainly at the terminal amino groups of the hemoglobin chains, not at the heme iron sites where oxygen binds.
This binding is influenced by:
- $p\mathrm{CO_2}$: more CO₂ → more carbamino formation.
- Oxygen saturation of hemoglobin (see Haldane effect, below).
Other plasma proteins can also carry small amounts of CO₂ as carbamino compounds, but their contribution is minor compared to hemoglobin.
Interaction With Acid–Base Balance
Note that carbamino formation releases protons:
- This contributes to the buffering role of hemoglobin within RBCs.
- Changes in carbamino formation thus affect both CO₂ transport and pH.
The Haldane Effect and the Bohr Effect
CO₂ transport is tightly linked to oxygen transport through two related phenomena: the Haldane effect and the Bohr effect. The detailed oxyhemoglobin dissociation curve is dealt with elsewhere; here, focus on how these effects favor effective CO₂ movement.
Haldane Effect: Influence of O₂ on CO₂ Transport
The Haldane effect describes:
- Deoxygenated hemoglobin (found in systemic venous blood) can:
- bind more CO₂ (as carbaminohemoglobin)
- buffer more $\mathrm{H^+}$ (thus favoring bicarbonate formation)
- Oxygenated hemoglobin (found in arterial blood in lungs) holds less CO₂ and fewer $\mathrm{H^+}$.
Consequences:
- In the tissues:
- Hemoglobin releases O₂ and becomes deoxygenated.
- Deoxygenated hemoglobin has a higher capacity to bind CO₂ and $\mathrm{H^+}$.
- This enhances CO₂ uptake and bicarbonate formation.
- In the lungs:
- Hemoglobin binds O₂, becoming oxygenated.
- Its capacity to hold CO₂ and $\mathrm{H^+}$ decreases.
- This promotes release of CO₂ and recombination of $\mathrm{H^+}$ with $\mathrm{HCO_3^-}$ to form CO₂, which is exhaled.
Thus, as blood picks up O₂ in the lungs, it tends to unload CO₂, and as it loses O₂ in the tissues, it tends to load CO₂. This makes gas exchange in both sites more efficient.
Bohr Effect: Influence of CO₂ and H⁺ on O₂ Transport
The Bohr effect is complementary, but from the oxygen perspective:
- Increased CO₂ and $\mathrm{H^+}$ (lower pH) in tissues reduce hemoglobin’s affinity for O₂.
- This promotes O₂ release where metabolism is active and CO₂ production is high.
Although the Bohr effect primarily concerns oxygen transport, it is driven by local CO₂ production and acidification, so it directly links to CO₂ handling. Where CO₂ is produced:
- O₂ is more readily released (Bohr effect),
- CO₂ and $\mathrm{H^+}$ are more readily taken up (Haldane effect and buffering).
Transport of CO₂: From Tissues to Lungs – A Summary Flow
To connect the processes:
In Systemic Capillaries (Near Tissues)
- Cells produce CO₂ via cellular respiration.
- CO₂ diffuses into blood:
- a small part remains dissolved.
- most enters RBCs.
- Inside RBCs:
- CO₂ + $\mathrm{H_2O}$ → $\mathrm{H_2CO_3}$ → $\mathrm{H^+} + \mathrm{HCO_3^-}$ (via carbonic anhydrase).
- Hemoglobin buffers $\mathrm{H^+}$.
- $\mathrm{HCO_3^-}$ leaves RBCs to plasma, $\mathrm{Cl^-}$ enters (chloride shift).
- Some CO₂ forms carbaminohemoglobin.
- Deoxygenated hemoglobin (due to O₂ delivery to tissues) increases the capacity of blood to carry CO₂ (Haldane effect).
Result: Venous blood carries most CO₂ as bicarbonate, some as carbaminohemoglobin, and a little dissolved.
In Pulmonary Capillaries (In the Lungs)
- Oxygen diffuses into blood and binds hemoglobin, making it more oxygenated.
- Oxygenated hemoglobin:
- releases $\mathrm{H^+}$ and CO₂ (Haldane effect).
- Inside RBCs:
- $\mathrm{HCO_3^-}$ enters from plasma, $\mathrm{Cl^-}$ leaves (reverse chloride shift).
- $\mathrm{H^+}$ + $\mathrm{HCO_3^-}$ → $\mathrm{H_2CO_3}$ → CO₂ + $\mathrm{H_2O}$ (via carbonic anhydrase).
- Carbaminohemoglobin releases CO₂.
- CO₂ (now dissolved) diffuses into alveoli and is exhaled.
Result: Arterial blood leaving the lungs has a lower CO₂ content and is closer to equilibrium with alveolar $p\mathrm{CO_2}$.
Additional Aspects and Variations
Differences Between Species
While the basic mechanisms are conserved among vertebrates, there are variations:
- Fish: CO₂ diffusion occurs across gill surfaces instead of lungs; different hemoglobin isoforms and buffering capacities adapt them to water $p\mathrm{CO_2}$ and pH conditions.
- Reptiles, amphibians, birds: show species-specific strengths of Haldane and Bohr effects, adapted to their metabolic rates and modes of respiration.
- Invertebrates:
- Some use hemocyanin or other respiratory pigments instead of hemoglobin.
- CO₂ is still mostly transported as bicarbonate, but the details of protein binding and buffering differ.
Pathophysiological Considerations
Disruption of CO₂ transport mechanisms can have major consequences:
- Respiratory diseases (e.g., chronic obstructive pulmonary disease) can impair CO₂ excretion, causing elevated $p\mathrm{CO_2}$ (hypercapnia) and acidosis.
- Anemia or hemoglobin disorders reduce not only O₂ transport but also CO₂ buffering and transport capacity.
- Circulatory failure (e.g., heart failure) reduces blood flow, impairing both O₂ delivery and CO₂ removal from tissues.
The heart and circulatory system thus play a key role in maintaining proper CO₂ transport, which is essential for both gas exchange and acid–base balance.