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13.10 Carbon Dioxide Transport, the Chloride Shift & Acid-Base Control of Breathing
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13.10 Carbon Dioxide Transport, the Chloride Shift & Acid-Base Control of Breathing
Key Takeaways Explain This Topic AI
Carbon dioxide is transported primarily (70%) as bicarbonate ions (HCO3-) in plasma, generated by erythrocyte carbonic anhydrase and extruded via the Band 3 anion exchanger in reciprocal exchange for chloride (the Chloride Shift).
Respiratory ventilation is continuously fine-tuned by central chemoreceptors in the medulla oblongata, which respond to arterial PCO2 via changes in cerebrospinal fluid [H+], providing rapid respiratory compensation for metabolic acid-base disorders.
The bicarbonate buffer system links ventilation directly to blood pH, so a metabolic acidosis such as diabetic ketoacidosis triggers compensatory hyperventilation (Kussmaul breathing) that blows off carbon dioxide and raises pH, while hypoventilation retains carbon dioxide and produces a respiratory acidosis.
Last updated: September 2026
- 13.10 Carbon Dioxide Transport, the Chloride Shift & Acid-Base Control of Breathing
- Carbon Dioxide Transport & The Erythrocyte Chloride Shift
Carbon dioxide generated by mitochondrial Krebs cycle decarboxylation is transported in blood in three forms:
Dissolved Gas in Plasma (7-10%) : Readily measured as P C O 2 PCO_2 PC O 2 .
Carbaminohemoglobin (20-23%) : C O 2 CO_2 C O 2 reacts reversibly with uncharged terminal amino groups of deoxyhemoglobin globin chains, forming carbamate adducts: Hb-NH 2 + C O 2 ⇌ Hb-NH-COO − + H + \text{Hb-NH}_2 + CO_2 \rightleftharpoons \text{Hb-NH-COO}^- + H^+ Hb-NH 2 + C O 2 ⇌ Hb-NH-COO − + H + . Deoxygenated hemoglobin binds C O 2 CO_2 C O 2 with far greater affinity than oxygenated hemoglobin—a phenomenon known as the Haldane Effect .
Bicarbonate Ions ( H C O 3 − HCO_3^- H C O 3 − ) in Plasma (70%) : The primary physiological transport mechanism.
The Bicarbonate Buffer and Chloride Shift Cascade
In Systemic Capillaries : Metabolically generated C O 2 CO_2 C O 2 diffuses down its partial pressure gradient out of tissues into erythrocytes. Inside the RBC, the zinc metalloenzyme carbonic anhydrase catalyzes the rapid reversible hydration of C O 2 CO_2 C O 2 : C O 2 + H 2 O ⇌ H 2 C O 3 ⇌ H + + H C O 3 − CO_2 + H_2O \rightleftharpoons H_2CO_3 \rightleftharpoons H^+ + HCO_3^- C O 2 + H 2 O ⇌ H 2 C O 3 ⇌ H + + H C O 3 −
The generated protons ( H + H^+ H + ) are buffered by deoxyhemoglobin, driving the Bohr effect to release O 2 O_2 O 2 .
As intracellular [ H C O 3 − ] [HCO_3^-] [ H C O 3 − ] accumulates, it is extruded into the plasma down its concentration gradient via the electroneutral anion exchanger 1 (AE1 / Band 3) antiporter in exchange for an incoming chloride ion ( C l − Cl^- C l − ) . This movement of chloride into the erythrocyte to preserve electrical neutrality is the Chloride Shift (Hamburger Phenomenon) .
In Pulmonary Capillaries : The reverse sequence occurs. Deoxygenation is reversed as O 2 O_2 O 2 binds hemoglobin, releasing buffered H + H^+ H + (Haldane effect). Bicarbonate ( H C O 3 − HCO_3^- H C O 3 − ) moves back into the RBC while chloride ( C l − Cl^- C l − ) is transported out ( Reverse Chloride Shift ). Carbonic anhydrase converts H + + H C O 3 − H^+ + HCO_3^- H + + H C O 3 − back into C O 2 + H 2 O CO_2 + H_2O C O 2 + H 2 O . The newly formed C O 2 CO_2 C O 2 gas rapidly diffuses across the alveolar-capillary membrane into the alveolar air space to be exhaled.
Neural Control of Ventilation & Respiratory Acid-Base Compensation
Ventilation is driven automatically by respiratory rhythm generators in the brainstem, dynamically fine-tuned by chemical feedback:
Medullary Respiratory Center :
Dorsal Respiratory Group (DRG) : Located in the nucleus tractus solitarius; generates the baseline rhythmic drive for inspiration, projecting via the phrenic and intercostal nerves.
Ventral Respiratory Group (VRG) : Contains the Pre-Bötzinger complex (the primary pacemaker for respiratory rhythm) and neurons controlling forced active exhalation.
Pontine Respiratory Centers : The pneumotaxic center limits the duration of inspiration, controlling tidal volume and respiratory rate; the apneustic center prevents inspiratory shutoff, promoting prolonged deep gasps.
Chemoreceptor Regulation
Central Chemoreceptors : Located on the ventrolateral surface of the medulla oblongata, directly bathed in brain extracellular fluid (ECF). They are the primary regulators of resting ventilation , responding to changes in arterial P C O 2 PCO_2 PC O 2 :
Charged hydrogen ions ( H + H^+ H + ) and bicarbonate cannot cross the lipophilic blood-brain barrier (BBB) .
However, molecular C O 2 CO_2 C O 2 is highly lipid-soluble and diffuses instantaneously across the BBB into the cerebrospinal fluid (CSF) and brain ECF.
In the CSF (which has virtually no protein buffering capacity), C O 2 CO_2 C O 2 hydrates via carbonic anhydrase: C O 2 + H 2 O ⇌ H + + H C O 3 − CO_2 + H_2O \rightleftharpoons H^+ + HCO_3^- C O 2 + H 2 O ⇌ H + + H C O 3 − .
The liberated H + H^+ H + directly stimulates central chemoreceptors, signaling the DRG to increase minute ventilation (hyperventilation) to blow off excess C O 2 CO_2 C O 2 .
Peripheral Chemoreceptors : Specialized glomus cells located in the carotid bodies (at the bifurcation of common carotid arteries; innervated by the glossopharyngeal nerve [CN IX] ) and aortic bodies (along the aortic arch; innervated by the vagus nerve [CN X] ):
Senses decreases in arterial P O 2 PO_2 P O 2 (hypoxemia) , increases in arterial P C O 2 PCO_2 PC O 2 , and increases in arterial [ H + ] [H^+] [ H + ] (metabolic acidosis).
The Hypoxic Drive : Peripheral chemoreceptors are relatively insensitive to modest drops in P O 2 PO_2 P O 2 , but fire exponentially when arterial P O 2 PO_2 P O 2 drops below 60 mmHg (the steep portion of the Hb curve), stimulating vigorous ventilation.
Respiratory Compensation for Acid-Base Disturbances
Blood pH is governed by the Henderson-Hasselbalch Equation for the bicarbonate buffer system: p H = 6.1 + log 10 ( [ H C O 3 − ] 0.03 × P C O 2 ) pH = 6.1 + \log_{10}\left(\frac{[HCO_3^-]}{0.03 \times PCO_2}\right) p H = 6.1 + lo g 10 ( 0.03 × PC O 2 [ H C O 3 − ] )
Metabolic Acidosis (Primary Decreased [ H C O 3 − ] [HCO_3^-] [ H C O 3 − ] ) : Diabetic ketoacidosis or lactic acidosis lowers plasma pH. Peripheral chemoreceptors detect elevated [ H + ] [H^+] [ H + ] , signaling the brainstem to induce rapid, deep respirations ( Kussmaul breathing ). Hyperventilation "blows off" C O 2 CO_2 C O 2 , lowering arterial P C O 2 PCO_2 PC O 2 and restoring the [ H C O 3 − ] / P C O 2 [HCO_3^-]/PCO_2 [ H C O 3 − ] / PC O 2 ratio toward 20:1, bringing blood pH back toward 7.40.
Metabolic Alkalosis (Primary Increased [ H C O 3 − ] [HCO_3^-] [ H C O 3 − ] ) : Severe vomiting (loss of HCl) elevates plasma pH. Chemoreceptors trigger hypoventilation, retaining C O 2 CO_2 C O 2 (elevating P C O 2 PCO_2 PC O 2 ) to shift pH downward toward baseline.
Respiratory Acidosis (Primary Increased P C O 2 PCO_2 PC O 2 ) : Hypoventilation from COPD or opioid overdose retains C O 2 CO_2 C O 2 . Chronic compensation relies on the kidneys (taking 48-72 hours) to upregulate apical H + H^+ H + excretion and retain/generate new H C O 3 − HCO_3^- H C O 3 − .
Respiratory Alkalosis (Primary Decreased P C O 2 PCO_2 PC O 2 ) : Hyperventilation from panic attacks or high altitude blows off excess C O 2 CO_2 C O 2 . Compensated by renal excretion of H C O 3 − HCO_3^- H C O 3 − .