Buffering and the Excretion of H+

BUFFERING AND THE EXCRETION OF H⁺

About 60 mmol of H⁺ are produced each day from the oxidation of sulfur-containing amino acid residues or from incomplete metabolic activities, such as anerobic glucose metabolism or ketone body formation . If all the H⁺ were released into the approximately 14 dm³ of ECF, the concentration of H⁺ would be 4 mmol dm^–3 or about 100 000 times more acidic than normal. In reality, the concentration of H⁺ is kept within the narrow limits of 40 p5 nmol dm^–3 to maintain the appropriate body physiological pH of 7.4 ± 0.05. This pH is necessary for normal physiological functions and is maintained by temporary buffering systems that resist changes to the pH of the plasma until the excessive H⁺ are excreted by the kidneys .

When H⁺are released by cells, the ECF is buffered by the hydrogen carbonate– carbonic acid buffer system:

Other buffering systems, such as hemoglobin in the erythrocytes, also make significant contributions as described. If the concentrations of H⁺ and HCO₃^– reach equilibrium, buffering would become ineffective. However, in the case of the hydrogen carbonate–carbonic acid system this is usually prevented from occurring by the breakdown of carbonic acid to CO₂ and water. The formation of carbonic acid from H⁺ and HCO₃^– is a rapid reaction. Its potentially slow breakdown to CO₂ and H₂O is accelerated by carbonic anhydrase in the erythrocytes and kidneys and the removal of carbon dioxide at the lungs prevents the system from reaching equilibrium.

Buffering by the hydrogen carbonate–carbonic acid system removes H⁺ from the ECF but at the expense of HCO₃^–. The ECF contains relatively large amounts of HCO₃^–, for example, its concentration is usually about 24 mmol dm^–3. If, for any reason, the amount of H⁺ produced increases, then the concentration of HCO₃^– will decrease as the hydrogen carbonate–carbonic acid buffering system operates. Any excess H⁺ must be excreted from the body by the kidneys

to keep the ECF and tissues at an appropriate pH. In addition, the HCO₃^– used in buffering must be regenerated to return its concentration in the plasma to normal values, otherwise the body will become depleted of HCO₃^– and buffering capacity. Two separate mechanisms operate in the kidneys to recover the HCO₃^– initially removed from the blood by filtration at the glomerulus and to regenerate that used in buffering. The first mechanism is the HCO₃^– recovery system while the second regenerates the HCO₃^– (Figures9.5 and 9.6).

In health, virtually all of the HCO₃^– is reabsorbed from the kidney tubule lumen. The operation of the system depends upon the tubule cells being polarized, that is, their luminal and basal surfaces differ in composition and permeability (Figure 9.5). In this manner, they resemble the enterocytes that line the absorptive surface of the gastroinstinal tract . Direct reabsorption of HCO₃^– from the renal tubular fluid cannot occur because the luminal surfaces of renal tubular cells are impermeable to HCO₃^–. However, the concentration of CO₂ within the tubular cells is maintained at a relatively high value and so carbonic anhydrase catalyzes the formation of carbonic acid. The acid dissociates to HCO₃^– and H⁺. The continuous formation of HCO₃^– and H⁺ within the tubule cells is promoted by their removal. The HCO₃^– is transported across the basal membrane of the cell into the interstitial fluid and then into the capillaries. In contrast, H⁺ is exchanged for Na⁺ across the luminal membrane and enters the lumen of the kidney tubule. A membrane protein called the sodium bicarbonate cotransporter 1 (NBC 1) present in the luminal cell membrane facilitates the exchange of ions. Within the lumen, the H⁺combine with HCO₃^– to form carbonic acid. The acid breaks down spontaneously to CO₂ and H₂O in the proximal tubule, but carbonic anhydrase activity on the luminal surfaces of the cells speeds up the reaction in the distal tubule. The CO₂ can enter the tubule cell across its luminal membrane and so the HCO₃^– is recovered, indirectly, as CO₂. Approximately 80% of the filtered HCO₃^– in the proximal tubule is recovered by this mechanism. However, there

has not been a net loss of H⁺ and the HCO₃^– used in buffering has not been regenerated. The HCO₃^– is regenerated when carbonic acid is formed in the luminal cell as described above (Figure 9.6). Again, H⁺are exchanged for Na⁺ and enter the lumen. Here the H⁺ react with phosphate (HPO₄^2–) and ammonia (NH₃) to give H₂PO₄^– and NH₄⁺ respectively. Ammonia is a significant urinary buffer produced by the deamination of glutamine in the renal tubular cells in a reaction catalyzed by glutaminase (Figure 9.7). The ammonia formed can readily diffuse across cell membranes but NH₄⁺ cannot enter the cells by passive reabsorption. Thus the NH₄⁺, and the H₂PO₄^–, are excreted in the urine. For every H⁺ excreted as NH ₄⁺ and H₂PO₄^–, a single HCO₃^– is formed in the tubule cell and secreted across the basal surface to the interstitial fluid and then into the blood. Hence the HCO₃^– concentration of the ECF is regenerated.

The synthesis of glutaminase is induced in states of chronic acidosis allowing an increase in the production of ammonia and an increasedexcretion of H⁺ as NH₄⁺.