Intracellular pH regulation and the acid delusion

The hydrogen ion concentration ([H⁺]) in intracellular cytoplasmic fluid (ICF) must be maintained in a narrow range in all species for normal protein functions. Thus, mechanisms regulating ICF are of fundamental biological importance. Studies on the regulation of ICF [H⁺] have been hampered by use of pH notation, failure to consider the roles played by differences in the concentration of strong ions (strong ion difference, SID), the conservation of mass, the principle of electrical neutrality, and that [H⁺] and bicarbonate ions [HCO₃^-] are dependent variables. This argument is based on the late Peter Stewart's physical-chemical analysis of [H⁺] regulation reported in this journal nearly forty years ago (Stewart. 1983. Can. J. Physiol. Pharmacol. 61: 1444-1461. Doi:10.1139/y83-207). We start by outlining the principles of Stewart's analysis and then provide a general understanding of its significance for regulation of ICF [H⁺]. The system may initially appear complex, but it becomes evident that changes in SID dominate regulation of [H⁺]. The primary strong ions are Na⁺, K⁺, and Cl^-, and a few organic strong anions. The second independent variable, partial pressure of carbon dioxide (PCO₂), can easily be assessed. The third independent variable, the activity of intracellular weak acids ([A_tot]), is much more complex but largely plays a modifying role. Attention to these principles will potentially provide new insights into ICF pH regulation.