Bicarbonate is the most significant buffer compound in human blood; other buffering agents, including proteins and organic acids, are present at much lower concentrations. The buffering capacity of blood depends primarily on two equilibria: (1) between gaseous CO 2 dissolved in the blood and carbonic acid formed by the reaction and (2) between carbonic acid and bicarbonate formed by the dissociation of H ⫹ The overall pK for these two sequential reactions is 6.35. (The further dissociation of to pK ⫽ 10.33, is not signifi- cant at physiological pH.) When the pH of the blood falls due to metabolic production of H ⫹ , the bicarbonate–carbonic acid equilibrium shifts toward more carbonic acid. At the same time, carbonic acid loses water to become CO 2 , which is then expired in the lungs as gaseous CO 2 . Conversely, when the blood pH rises, relatively more forms. Breathing is adjusted so that increased amounts of CO 2 in the lungs HCO ⫺ 3 CO 2⫺ 3 ,HCO ⫺ 3 H 2 CO 3 Δ H ⫹ ⫹ HCO ⫺ 3 CO 2 ⫹ H 2 O Δ H 2 CO 3 can be reintroduced into the blood for conversion to carbonic acid. In this manner, a near-constant hydrogen ion concentration can be maintained. The kidneys also play a role in acid–base balance by excreting and