Teleost red blood cells actively enhance the passive diffusion of oxygen that was discovered by August Krogh

In the early 20th century, August and Marie Krogh settled one of the most controversial questions in physiology, showing through elegant experiments that oxygen (O₂) uptake at the lung is driven by passive diffusion alone. Krogh's later work, on the regulation of local blood flow and capillary recruitment at the tissues, was awarded with the Nobel Prize in 1920. A century later it is still undisputed that O₂ moves across tissues by diffusion, however, animals use active mechanisms to regulate and facilitate the passive process. Teleost fishes have evolved a mechanism by which adrenergic sodium-proton-exchangers (β-NHEs) on the red blood cell (RBC) membrane actively create H⁺ gradients that are short-circuited in the presence of plasma-accessible carbonic anhydrase (CA) at the tissue capillaries. The rapid acidification of the RBC reduces the O₂ affinity of pH-sensitive haemoglobin, which increases the O₂ diffusion gradient to the tissues. When RBCs leave the site of plasma-accessible CA, β-NHE activity recovers RBC pH during venous transit, to promote renewed O₂ loading at the gills. This mechanism allows teleosts to unload more O₂ at their tissues without compromising O₂ diffusion gradients and therefore, to use the available O₂ carrying capacity of the blood to a greater degree. In Atlantic salmon, β-NHE short-circuiting reduces the requirements on the heart by up to 30% during moderate exercise and even at rest, with important ecological implications. Thus, in some teleosts, the RBCs participate in regulating the systemic O₂ flux by actively altering the passive diffusion of O₂ that Krogh discovered.