Internal respiration is about ensuring the transport of oxygen in the blood from the lungs to the cells, and the transport of metabolic carbon dioxide from the tissue cells into the blood and to the lungs.

Once CO₂ and H₂O enter the interstitial fluid (around the cells) as a consequence of cellular respiration, they diffuse into the plasma of the blood. About 90 percent of the CO₂ then diffuses into the red blood cell. The balance of about 10 percent remains dissolved in the plasma, the dissolved PCO₂. The presence of CO₂ in the red blood cell is crucial to oxygen distribution.   Carbon dioxide is hydrated (combines with H₂O) to form carbonic acid: CO₂ + H₂O ↔ H₂CO₃. The carbonic acid dissociates (breaks down) into hydrogen and bicarbonate ions: H₂CO₃ ↔ H⁺ + HCO₃^̄. The increased presence of hydrogen ions, H⁺, means that the red blood cells become less alkaline, i.e. the pH of the fluid (cytosol) in red blood cells decreases. The bicarbonates, HCO₃^̄, diffuse into the blood where they buffer acids, e.g. lactic acid.

The amount of CO₂ generated by tissues determines precisely how much carbonic acid is formed, and thus the pH of the red blood cell, as well as the amount of bicarbonate entering the plasma. The presence of CO₂ gas and the drop in pH within red blood cells, independently and together, alter the spatial constitution (conformation) of the hemoglobin (Hb), which decreases its affinity for oxygen, i.e., it more readily gives up its oxygen and raises plasma PO₂ level; this change is known as the Bohr Effect. Thus, hemoglobin more readily distributes its O₂ to the tissues that need it, while simultaneously buffering the hydrogen ions generated by the dissociation of carbonic acid (H₂CO₃) to restore normal pH in red blood cells: HbO₂ + H⁺ ↔ HHb + O₂. Reduced pH and increased PCO₂ not only predisposes hemoglobin to release its oxygen, but also to release nitric oxide (a gas), a potent vasodilator. The result is increased blood volume and flow, which increases oxygen and glucose supply to cells that generate higher levels of CO₂, cells with elevated metabolism.

Increased plasma PCO₂ levels lead to increased (1) supply of oxygen (more blood), (2) supply of glucose (more blood), (3) levels of PO₂ (O₂/ml blood), and (4) supply of bicarbonates for buffering acids. Proper PCO₂ regulation means that red blood cell chemistry reflects surrounding tissue metabolism. Overbreathing reduces dissolved PCO₂, and thus decreases CO₂ and carbonic acid in red blood cells. This means reduced hydrogen ion concentration, increased pH in red blood cells. The effect on hemoglobin is twofold: (1) increased affinity for O₂ (Bohr Effect), reducing the likelihood of its release into the plasma, and (2) diminished release of nitric oxide, resulting in vasoconstriction. This translates into less oxygen (local hypoxia), less glucose (local hypoglycemia), and reduced buffering capacity for the tissues in need. Reduced nitric oxide also elevates plasma platelet level, their aggregation, and “adhering” propensity, thus increasing the likelihood of blood clotting.

Click here to learn about external respiration and cellular respiration.