METABOLIC-ACIDOSIS IS A POTENT STIMULUS FOR CELLULAR INORGANIC-PHOSPHATE GENERATION IN UREMIA

1. During metabolic acidosis, significant fluxes of inorganic phosphate (P-i) may occur from cellular to extracellular fluid. In this study P-i was measured in erythrocytes of uraemic patients before and after haemodialysis and was related to their plasma pH (acidosis), plasma P-i (hyperphosphataemia) and cellular organic phosphate concentrations. 2. Before dialysis, the ratio of cellular to extracellular P-i concentration correlated inversely with plasma pH, increasing 2.5-fold as pH fell from 7.4 to 7.2. 3. An increase in cellular P-i similar to that seen in the patients was observed within 90 min of adding acid to normal erythrocytes in vitro. 4. The total P-i content of the cell suspension increased 25% on decreasing plasma pH from 7.4 to 7.2, largely as a result of generation of P-i from 2,3-bisphosphoglycerate in the cells. This was accompanied by net efflux of P-i into plasma. 5. In addition, the increase in the steady-state cellular P-i concentration on adding a constant extracellular P-i load was 50% greater at pH 7.2 than at 7.4, implying that alterations in the regulation of the transmembrane P-i gradient also contribute to the rise in cellular P-i observed at low pH. 6. At normal plasma P-i concentration (1 mM), glycolytic flux (lactate production) was inhibited by 20% when pH was lowered from 7.4 to 7.2. However, this inhibition was blocked when cellular P-i was increased by adding P-i to the plasma in vitro. 7. Metabolic acidosis is therefore a potent stimulus for P-i generation in erythrocytes, and this P-i may serve to stimulate glycolysis which is normally inhibited by low pH.