CO₂ Transport

Spec Mapping — OCR H420 Module 3.1.2 — Transport in animals, content statements covering the three forms in which CO₂ is transported in the blood (dissolved, carbaminohaemoglobin, hydrogencarbonate), the role of carbonic anhydrase, the chloride shift, and the link to the Bohr effect (refer to the official OCR H420 specification document for exact wording). This lesson develops the partner pathway to oxygen transport (Lesson 10) and shows how the two are coupled through haemoglobin.

Carbon dioxide is the main waste product of aerobic respiration, and at steady state it must be removed from tissues at the same rate as it is produced. Because CO₂ is much more soluble than oxygen and reacts chemically with water, the blood transports it in three distinct ways. The majority travels as hydrogencarbonate ions (HCO₃⁻) in the plasma, with smaller contributions from dissolved CO₂ and carbaminohaemoglobin. This lesson examines each pathway, the role of the enzyme carbonic anhydrase, the ingenious chloride shift that preserves electrical neutrality in red blood cells, and the mechanism by which CO₂ carriage is linked to the Bohr effect.

The chemistry was largely worked out by Joseph Barcroft and John Scott Haldane in the early 20th century. Haldane (after whom the Haldane effect — the reciprocal partner to the Bohr effect — is named) showed that deoxyhaemoglobin binds CO₂ more readily than oxyhaemoglobin, completing the coupled-transport picture. Mansfield Clarke's acid-base chemistry of plasma buffering and Henry Dakin's work on carbonic anhydrase (one of the fastest enzymes known) round out the molecular machinery.

Key Definitions:

Carbonic anhydrase — an enzyme in red blood cells that catalyses the reversible conversion of CO₂ + H₂O to H₂CO₃ (carbonic acid).

Hydrogencarbonate ion (HCO₃⁻) — the main form in which CO₂ is transported in the blood.

Carbaminohaemoglobin — haemoglobin with CO₂ bound (to free amine groups on the globin, not to the haem iron).

Chloride shift — the exchange of HCO₃⁻ out of the red blood cell for Cl⁻ into the cell, maintaining electrical neutrality.

Haemoglobinic acid (HHb) — haemoglobin that has accepted an H⁺ ion, acting as a buffer.

The Three Forms of CO₂ Transport

Form	Approximate percentage	Location
Dissolved CO₂ in plasma	~5%	Plasma
Carbaminohaemoglobin	~10%	Bound to globin chains in RBCs
Hydrogencarbonate ions (HCO₃⁻)	~85%	Plasma (after being made inside RBCs)

Only a small fraction is carried as dissolved gas, because CO₂ — while more soluble than O₂ — is still not sufficiently soluble to transport large amounts at body temperature. The majority is chemically converted to hydrogencarbonate ions for transport.

Pathway 1: Dissolved CO₂

About 5% of the CO₂ produced simply dissolves in the plasma and is carried in the free gaseous form. At the lungs, the same 5% diffuses straight back out along its gradient into the alveolar air.

Pathway 2: Carbaminohaemoglobin

Approximately 10% of CO₂ binds reversibly to free amine (–NH₂) groups on the globin polypeptides of haemoglobin, forming carbaminohaemoglobin:

$\text{Hb--NH}_2 + \text{CO}_2 \rightleftharpoons \text{Hb--NH--COOH}$

Note that the CO₂ binds to the globin chains, not to the haem iron. Deoxyhaemoglobin binds CO₂ more readily than oxyhaemoglobin does, which makes sense physiologically: haemoglobin that has just unloaded its oxygen in the tissues is in the best state to pick up CO₂ for the return journey. This is a key reason why venous blood carries more CO₂ than arterial blood.

Pathway 3: Hydrogencarbonate Ions (the Majority)

About 85% of the CO₂ carried in the blood travels as hydrogencarbonate ions (HCO₃⁻), produced inside the red blood cells and then exported into the plasma. The full sequence is:

Step 1: CO₂ Enters the RBC

CO₂ diffuses from respiring tissues → plasma → through the RBC membrane into the cytoplasm.

Step 2: Conversion to Carbonic Acid

Inside the RBC, carbonic anhydrase catalyses the hydration of CO₂:

$\text{CO}_2 + \text{H}_2\text{O} \xrightleftharpoons{\text{carbonic anhydrase}} \text{H}_2\text{CO}_3$

Without this enzyme the reaction would be far too slow; carbonic anhydrase is one of the fastest enzymes known, with a turnover number of up to 600,000 reactions per second.

Step 3: Dissociation

Carbonic acid is a weak acid and dissociates spontaneously:

$\text{H}_2\text{CO}_3 \rightleftharpoons \text{H}^+ + \text{HCO}_3^-$

This produces hydrogen ions (H⁺) and hydrogencarbonate ions (HCO₃⁻) inside the RBC.

Step 4: The H⁺ is Buffered by Haemoglobin

The hydrogen ions would rapidly lower the pH of the cytoplasm and disrupt haemoglobin function if left free. Instead, haemoglobin buffers the H⁺ by accepting them, forming haemoglobinic acid (HHb):

$\text{HbO}_2 + \text{H}^+ \rightleftharpoons \text{HHb} + \text{O}_2$

Crucially, binding H⁺ promotes the release of oxygen from haemoglobin — this is the molecular basis of the Bohr effect. The more CO₂ the tissues produce, the more H⁺ is generated inside the RBC, and the more oxygen is released to those same tissues.

Step 5: The Chloride Shift

The hydrogencarbonate ions now need to leave the red blood cell and travel in the plasma. They are exported across the RBC membrane by a band 3 antiporter protein, in exchange for chloride ions (Cl⁻) entering the cell. This exchange is called the chloride shift and is essential for maintaining electrical neutrality inside the red blood cell — otherwise the loss of negative HCO₃⁻ would leave the cell with an excess of positive charge.

flowchart LR
    subgraph Tissue
    T[Respiring cells]
    end
    subgraph RBC
    CO2[CO2] --> CA[Carbonic anhydrase]
    CA --> H2CO3[H2CO3]
    H2CO3 --> H[H plus]
    H2CO3 --> HCO3[HCO3 minus]
    H --> HB[Hb accepts H plus: HHb]
    HB --> RELO2[Releases O2]
    HCO3 --> OUT[Exits cell]
    end
    subgraph Plasma
    CL[Cl minus]
    end
    T --> CO2
    OUT -->|Chloride shift| CL
    CL --> RBCIn[Enters RBC]

CO₂ in physiology — partial pressures around the cycle

To put the chemistry in context, the key partial pressures are:

Location	pCO₂ (kPa)	pO₂ (kPa)
Inhaled atmospheric air	~0.04	~21
Alveolar air	~5.3	~13.3
Arterial blood (post-pulmonary)	~5.3	~13.3
Tissue capillary entry	~5.3	~13.3
Tissue capillary exit	~6.1	~5.3
Venous blood (post-tissue)	~6.1	~5.3

The pCO₂ rise across the tissue capillary is only ~0.8 kPa — but multiplied across the body's huge capillary surface area and 5 dm³ min⁻¹ blood flow, it represents the ~200 cm³ min⁻¹ of CO₂ that the body must remove at rest. During strenuous exercise, this can rise to >3000 cm³ min⁻¹ — a 15-fold increase in CO₂ flux that the transport system handles by raising both ventilation and cardiac output simultaneously.

The Henderson–Hasselbalch picture

The plasma equilibrium between CO₂, H₂CO₃ and HCO₃⁻ is governed by the Henderson–Hasselbalch equation:

$\text{pH} = \text{p}K_a + \log_{10}\frac{[\text{HCO}_3^-]}{[\text{CO}_2 \cdot 0.23]}$

where the constant 0.23 mmol L⁻¹ kPa⁻¹ converts pCO₂ in kPa to dissolved CO₂ concentration, and p $K_a$ = 6.1 for the CO₂/HCO₃⁻ pair. At normal arterial values ([HCO₃⁻] = 24 mmol L⁻¹, pCO₂ = 5.3 kPa):

$\text{pH} = 6.1 + \log_{10}\frac{24}{5.3 \times 0.23} = 6.1 + \log_{10}(19.7) \approx 6.1 + 1.29 = 7.39$

This sits comfortably within the physiological range 7.35–7.45. Disturbance of either numerator (HCO₃⁻, controlled by the kidney) or denominator (pCO₂, controlled by ventilation) shifts blood pH, defining the four primary acid-base disturbances (respiratory acidosis/alkalosis, metabolic acidosis/alkalosis). The Henderson–Hasselbalch equation is not directly assessed at A-Level, but it is the quantitative engine of clinical acid-base medicine.

Why three forms? An evolutionary perspective

If CO₂ were as poorly soluble as O₂, life would need a CO₂-carrying protein analogous to haemoglobin. Fortunately, CO₂ is much more soluble in water than O₂ (about 20-fold higher solubility at body temperature), and its reaction with water to form HCO₃⁻ provides an additional storage form that is essentially limitless in plasma. The "three forms" picture (dissolved + carbamino + HCO₃⁻) reflects the chemistry of CO₂ in water: at physiological pH, the equilibrium strongly favours HCO₃⁻, and so HCO₃⁻ dominates. The carbaminoHb contribution is the evolutionary bonus — haemoglobin happens to have free amine groups that bind CO₂ and helpfully couple CO₂ uptake to O₂ release (Haldane effect). Each pathway is an optimisation of the underlying chemistry, not a separate evolutionary invention.

At the Lungs — Reversal of Everything

When blood reaches the pulmonary capillaries, pO₂ in the alveolar air is high and pCO₂ is low. Each step of the tissue pathway runs in reverse:

Oxygen loads onto haemoglobin, displacing the H⁺ ions from haemoglobinic acid.
The released H⁺ combines with HCO₃⁻ (which has now entered the RBC back from the plasma via the reversed chloride shift) to reform carbonic acid: $\text{H}^+ + \text{HCO}_3^- \rightarrow \text{H}_2\text{CO}_3$
Carbonic anhydrase runs in the opposite direction, splitting carbonic acid into CO₂ and water: $\text{H}_2\text{CO}_3 \rightarrow \text{CO}_2 + \text{H}_2\text{O}$
CO₂ diffuses out of the RBC into the plasma and then into the alveolar air, where it is exhaled.
Carbaminohaemoglobin also releases its CO₂ as the equilibrium shifts.

The Buffering Role of Haemoglobin

Blood pH is normally held in the very narrow range 7.35–7.45. Large amounts of H⁺ are generated every second from dissolving CO₂, yet pH barely changes — this is because haemoglobin and plasma proteins act as buffers, absorbing H⁺ when it is produced and releasing it when it is removed. Without this buffering, even moderate exercise would cause severe acidosis.

Quantitatively, the blood-buffering capacity is dominated by three systems:

CO₂/HCO₃⁻ — by far the largest plasma buffer; controlled by ventilation (CO₂ side) and the kidney (HCO₃⁻ side).
Haemoglobin — buffers H⁺ inside the RBC via the imidazole groups of histidine residues; this also drives the Bohr effect.
Plasma proteins — albumin and globulins contribute a smaller amount of buffering via their dissociable side chains.

The genius of the CO₂/HCO₃⁻ system is its open-ended character: any disturbance can be corrected by physiological means (more ventilation removes CO₂; renal reabsorption changes HCO₃⁻), not just by chemical means. By contrast, an internal protein buffer can only absorb a finite amount of H⁺ before saturating; the CO₂/HCO₃⁻ system is essentially limitless because CO₂ can be vented to the atmosphere via the lungs.

Acidosis and alkalosis — disturbing the balance

Disturbance	Cause	Body's response
Respiratory acidosis	Hypoventilation (COPD, sleep apnoea, drug overdose) → CO₂ retention	Kidney increases HCO₃⁻ reabsorption (slow, days)
Respiratory alkalosis	Hyperventilation (anxiety, altitude, pulmonary embolism) → CO₂ loss	Kidney decreases HCO₃⁻ reabsorption
Metabolic acidosis	Diabetic ketoacidosis, lactic acidosis, kidney failure, diarrhoea (HCO₃⁻ loss)	Increased ventilation (Kussmaul breathing) blows off CO₂
Metabolic alkalosis	Vomiting (loss of stomach acid → loss of H⁺), diuretics	Decreased ventilation (CO₂ retention)

Each disturbance has both an immediate (respiratory) compensation and a delayed (renal) compensation. Clinical practice routinely measures arterial blood gases (pH, pCO₂, HCO₃⁻) and uses the Henderson–Hasselbalch framework to identify the primary disturbance and the compensation.

Coupled Transport of O₂ and CO₂

The interplay between O₂ and CO₂ transport is elegantly coupled:

In active tissues (high CO₂, low O₂), H⁺ generation promotes O₂ release (Bohr effect) and deoxyhaemoglobin binds CO₂ more readily.
In the lungs (high O₂, low CO₂), O₂ loading displaces H⁺ from haemoglobinic acid, which drives the HCO₃⁻ back to CO₂ for exhalation. This is sometimes called the Haldane effect, although OCR rarely uses that name at A-Level.

CO2 Transport