Definition

Carbon dioxide migration

At the mitochondrial level the metabolism of carbohydrate, fat or protein leads to the generation of CO₂. As CO₂ is very soluble (x 25 that of O₂) in biological fluids and across cellular membranes, it migrates very readily from the peripheral tissue cytoplasm to the capillaries and thence to the red blood cells (RBCs).

Despite CO₂‘s high plasma solubility the majority of this gas is transported as HCO₃– and its relationship to dissolved CO₂ is provided by the Henderson-Hasselbalch equation:
pH = pK_a + log [HCO₃^–]/[CO₂]

As hydrogen ion concentration ([H⁺]) is inversely related to pH it is thus directly related to the [CO₂].

Carbonic anhydrase

Carbon dioxide moves from the peripheral tissue where it is relatively abundant to the RBCs which are replete with oxygen (O₂). This gradient is in part generated by the facilitated reaction between CO₂ and H₂O where the enzyme carbonic anhydrase (CA) plays an important role. The inter conversion between CO₂ and HCO₃^– within RBCs requires only 2ms for 95% completion.

Within the cell the reaction between CO₂ and water that produces H₂CO₃ moves further to the right as the carbonic acid dissociates into bicarbonate (HCO₃^–) and a proton (H⁺). Hypercarbia therefore leads to acidosis and, in situations where CO₂ cannot be adequately excreted at the lungs, respiratory acidosis ensues. The transport of CO₂ as bicarbonate in this fashion is referred to as facilitated CO₂ diffusion.

Inhibitors of carbonic anhydrase like the drug Acetazolamide are useful as a diuretic agent as they prevent this reaction occurring in renal tubular cells and thus allow more H₂O to be excreted.

Haldane effect

In peripheral tissues, deoxygenated haemoglobin has a higher affinity for carbon dioxide which helps with the removal of CO2 from tissues. This is called the Haldane effect, and it occurs because deoxyHB has a greater affinity for protons which drives the CA-catalysed reaction to the right in the presense of deoxyHb

It may thus be appreciated that the increase in CO₂ leads to a rise in H⁺ since the HCO₃^– is mobilised to the extracellular spaces in exchange for Chloride (Cl^–) by a membrane bound ion exchange mechanism. This trade between intracellular HCO₃^– and extracellular Cl^– is the Chloride Shift or Hamburger Shift which maintains electrical neutrality within the RBC.

The Chloride Shift is rapid and is complete before the cells exit the capillary and the osmotic effect of the extra HCO₃^– and Cl^– in venous RBCs causes them to swell slightly. Consequently, venous hematocrit slightly surpasses the arterial hematocrit.