The chloride shift is the movement of Cl(-) from the plasma into erythrocytes as blood moves from the arterial to the venous end of systemic capillaries. The traditional explanation for the chloride shift emphasizes the causative roles of the rise in Pco(2) and the exclusive presence of carbonic anhydrase within the red blood cell. The purpose of this article is, first, to reexamine two aspects of the chloride shift that we feel are traditionally underemphasized. They are the role of hemoglobin in causing the chloride shift and the affect of the chloride shift on the acid-base status of the blood. Second, we wish to reconcile more recent work with the traditional understanding of the chloride shift. The chloride shift has never been modeled from the perspective of the Stewart strong ion approach. Similarly, the traditional understanding has generally treated Cl(-) as a passive participant in the chloride shift whose role was simply to replace the lost negative charge of the outward moving HCO-3. More recent work has suggested that the ingoing Cl(-) is important for both O(2) unloading and acid-base balance of the blood. We conclude this article with a model of the chloride shift that uses the Stewart approach and, though harmonious with the traditional understanding, highlights the importance of hemoglobin and Cl(-) in the chloride shift.

The PO(2)-dependent binding of chloride to Hb decreases the Cl(-) concentration of the red blood cell (RBC) intracellular fluid in venous blood to approximately 1-3 mmol/l less than that in arterial blood. This change is physiologically important because 1) Cl(-) is a negative heterotropic allosteric effector of Hb that competes for binding sites with 2,3-bisphosphoglycerate and CO(2) and decreases oxyhemoglobin affinity in several species; 2) it may help reconcile several longstanding problems with measured values of the Donnan ratios for Cl(-), HCO, and H(+) across the RBC membrane that are used to calculate total CO(2) carriage, ion flux rates, and membrane potentials; 3) it is a factor in the change in the dissociation constant for the combined nonvolatile weak acids of Hb associated with the Haldane effect; and 4) it diminishes the decrease in strong ion difference in the RBC intracellular fluid that would otherwise occur from the chloride shift and prevent the known increase of HCO concentration in that compartment.