The role of pH gradient in the distribution of ammonia between blood and cerebrospinal fluid, brain and muscle.

The role of ammonia toxicity in the production of the hepatic coma syndrome has not been clearly defined. No direct relationship has been demonstrated consistently between arterial or venous blood ammonia-nitrogen concentration or the arteriovenous ammonia-nitrogen difference and the state of cerebral dysfunction in hepatic disease. Recently a direct relationship between an increase in blood pH and the diffusion of ammonia from blood into tissues has been suggested (2). Other investigators have demonstrated greater toxicity of the more alkaline ammonium salts (3) and that an increase in blood pH enhanced passage of ammonia into the brain of mice (4). The diffusion of a weak electrolyte into a cell is determined by the pKa of the weak electrolyte, the pH within and without the cell, and the relative permeability of the cell membrane to the unionized species of the electrolyte (5, 6). It is proposed that ammonia, a weak base with pKa 9.3, should be distributed between blood and cerebrospinal fluid (CSF), brain and muscle according to existing pH gradients, in a manner analogous to that demonstrated in the studies of renal excretion (7, 8), gastrointestinal secretion (9) and absorption (10) of weak acids and bases, and in the studies of distribution of weak organic acids and bases from blood to CSF (11). This study was designed to evaluate in the dog the distribution of ammonia from blood to CSF, brain and muscle under conditions of experimentally induced pH gradients between blood and CSF, brain and muscle.