13.10 Carbon Dioxide Transport, the Chloride Shift & Acid-Base Control of Breathing

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:

1. Dissolved Gas in Plasma (7-10%): Readily measured as $PCO_2$.
2. Carbaminohemoglobin (20-23%): $CO_2$ reacts reversibly with uncharged terminal amino groups of deoxyhemoglobin globin chains, forming carbamate adducts: $\text{Hb-NH}_2 + CO_2 \rightleftharpoons \text{Hb-NH-COO}^- + H^+$. Deoxygenated hemoglobin binds $CO_2$ with far greater affinity than oxygenated hemoglobin—a phenomenon known as the Haldane Effect.
3. Bicarbonate Ions ($HCO_3^-$) in Plasma (70%): The primary physiological transport mechanism.

The Bicarbonate Buffer and Chloride Shift Cascade

• In Systemic Capillaries: Metabolically generated $CO_2$ 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 $CO_2$: $$CO_2 + H_2O \rightleftharpoons H_2CO_3 \rightleftharpoons H^+ + HCO_3^-$$
  • The generated protons ($H^+$) are buffered by deoxyhemoglobin, driving the Bohr effect to release $O_2$.
  • As intracellular $[HCO_3^-]$ 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 ($Cl^-$). 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 $O_2$ binds hemoglobin, releasing buffered $H^+$ (Haldane effect). Bicarbonate ($HCO_3^-$) moves back into the RBC while chloride ($Cl^-$) is transported out (Reverse Chloride Shift). Carbonic anhydrase converts $H^+ + HCO_3^-$ back into $CO_2 + H_2O$. The newly formed $CO_2$ 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

1. 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 $PCO_2$:
   • Charged hydrogen ions ($H^+$) and bicarbonate cannot cross the lipophilic blood-brain barrier (BBB).
   • However, molecular $CO_2$ 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), $CO_2$ hydrates via carbonic anhydrase: $CO_2 + H_2O \rightleftharpoons H^+ + HCO_3^-$.
   • The liberated $H^+$ directly stimulates central chemoreceptors, signaling the DRG to increase minute ventilation (hyperventilation) to blow off excess $CO_2$.
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 $PO_2$ (hypoxemia), increases in arterial $PCO_2$, and increases in arterial $[H^+]$ (metabolic acidosis).
   • The Hypoxic Drive: Peripheral chemoreceptors are relatively insensitive to modest drops in $PO_2$, but fire exponentially when arterial $PO_2$ 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:

• Metabolic Acidosis (Primary Decreased $[HCO_3^-]$): Diabetic ketoacidosis or lactic acidosis lowers plasma pH. Peripheral chemoreceptors detect elevated $[H^+]$, signaling the brainstem to induce rapid, deep respirations (Kussmaul breathing). Hyperventilation "blows off" $CO_2$, lowering arterial $PCO_2$ and restoring the $[HCO_3^-]/PCO_2$ ratio toward 20:1, bringing blood pH back toward 7.40.
• Metabolic Alkalosis (Primary Increased $[HCO_3^-]$): Severe vomiting (loss of HCl) elevates plasma pH. Chemoreceptors trigger hypoventilation, retaining $CO_2$ (elevating $PCO_2$) to shift pH downward toward baseline.
• Respiratory Acidosis (Primary Increased $PCO_2$): Hypoventilation from COPD or opioid overdose retains $CO_2$. Chronic compensation relies on the kidneys (taking 48-72 hours) to upregulate apical $H^+$ excretion and retain/generate new $HCO_3^-$.
• Respiratory Alkalosis (Primary Decreased $PCO_2$): Hyperventilation from panic attacks or high altitude blows off excess $CO_2$. Compensated by renal excretion of $HCO_3^-$.