Chloride shift

Chloride shift (also known as the Hamburger shift or Hamburger phenomenon, named after Hartog Jakob Hamburger) is a process which occurs in a cardiovascular system and refers to the exchange of bicarbonate (HCO₃⁻) and chloride (Cl⁻) across the membrane of red blood cells (RBCs).^[1]

Mechanism

Carbon dioxide (CO₂) generated in tissues carbonic acid and which is not highly expressed in interstitial fluid and plasma. RBC carbonic anhydrase catalyzes the conversion of dissolved CO₂ and intracellular water to carbonic acid (H₂CO₃), which spontaneously dissociates to form bicarbonate (HCO₃⁻) and a hydrogen ion (H⁺). In response to the fall of intracellular pCO₂, more CO₂ passively diffuses into the cell.

Red blood cell membranes are impermeable to hydrogen ions but are able to exchange bicarbonate ions for chloride ions using the anion exchanger protein Band 3. The rise in intracellular bicarbonate leads to bicarbonate export and chloride intake. The term "chloride shift" refers to this exchange. As a result, plasma chloride concentration is lower^[2] in systemic venous blood than in systemic arterial blood: high venous pCO₂ leads to bicarbonate production in RBCs, which then leaves the RBC in exchange for chloride coming in.

The opposite process occurs in the pulmonary capillaries of the lungs when the PO₂ rises and PCO₂ falls, and the Haldane effect occurs (release of CO₂ from hemoglobin during oxygenation). This releases hydrogen ions from hemoglobin, increases H⁺ concentration within RBCs, and shifts the equilibrium towards CO₂ and water formation from bicarbonate. The subsequent decrease in intracellular bicarbonate concentration reverses chloride-bicarbonate exchange: bicarbonate moves into the cell in exchange for chloride moving out. Inward movement of bicarbonate via the Band 3 exchanger allows carbonic anhydrase to convert it to CO₂ for expiration.^[3]

The chloride shift may also regulate the affinity of hemoglobin for oxygen through the chloride ion acting as an allosteric effector.^[4]

Reaction

Reaction (as it occurs in the lung)

   PLASMA                RBC

   HCO3− --> --> -->    HCO3−
 
   Na+                   K+

   Cl− <-- <-- <-- <--   Cl−

Bicarbonate in the red blood cell (RBC) exchanging with chloride from plasma.

The underlying properties creating the chloride shift are the presence of carbonic anhydrase within the RBCs but not the plasma, and the permeability of the RBC membrane to carbon dioxide and bicarbonate ion but not to hydrogen ion. Continuous process of carbonic acid dissociation and outflow of bicarbonate ions would eventually lead to a change of intracellular electric potential because of lasting H+ ions. Inflow of chloride ions maintains electrical neutrality of a cell. The net direction of bicarbonate-chloride exchange (bicarbonate out of RBCs in the systemic capillaries, bicarbonate into RBCs at pulmonary capillaries) proceeds in the direction that decreases the sum of the electrochemical potentials for the chloride and bicarbonate ions being transported.

References