Chloride shift (also known as the Hamburger's shift or Hamburger's 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).
Carbon dioxide (CO2) generated in tissues passively diffuses into capillaries via the interstitial fluid. Once in circulation, CO2 enters red blood cells (RBCs) to balance the intracellular and extracellular CO2 partial pressures. RBCs contain appreciable quantities of carbonic anhydrase, an enzyme which converts CO2 to carbonic acid and which is not highly expressed in interstitial fluid and plasma. RBC carbonic anhydrase converts dissolved CO2 and intracellular water to carbonic acid (H2CO3), which spontaneously dissociates to form bicarbonate (HCO-3) 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. A rise in intracellular bicarbonate causes chloride intake and bicarbonate export. The term "chloride shift" refers to this exchange. As a result, blood chloride concentration is lower in systemic venous blood than in systemic arterial blood or in pulmonary circulation because the levels of CO2 and therefore bicarbonate are higher in systemic venous blood, providing less of a driving force for exchange.
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. Inward movement of bicarbonate via the Band 3 exchanger allows carbonic anhydrase to convert it to CO2 for expiration.
Reaction (as it occurs in the lung)
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. Exchange of bicarbonate for chloride ions across the RBC membrane maintains the macroscopic electroneutrality of the 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.
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