Regulation of Extra- and Intracellular pH in the Brain in Severe Hypoglycemia

Severe hypoglycemia is associated with a marked curtailment of cerebral glucose supply and with consumption of endogenous carbohydrate metabolites and amino acids, many of which exist as anions of acids. Since metabolic control of intracellular pH in acute hypo- and hypercapnia seems to be dependent on the production and consumption of metabolic acids, it must be suspected that intracellular pH in the brain is poorly regulated in hypoglycemic animals. We induced hypocapnia (P_aco₂ about 15 mm Hg) and hypercapnia (P_aco₂ about 90 mm Hg) in insulin-injected animals in “precoma” (EEG pattern of slow waves, polyspikes) and “coma” (cessation of EEG activity) and measured CSF and intracellular acid-base changes using the CO₂ method.

The induced hypoglycemia did not measurably alter CSF acid-base changes from the normal during hypercapnia, but it did impair CSF pH regulation in hypocapnia. Animals in precoma showed an unchanged cerebral energy state during both hypo- and hypercapnia. Regulation of intracellular pH was not measurably affected in hypercapnia but was reduced in hypocapnia. These results could be accounted for by a reduced ability of the hypoglycemic animals to produce metabolic acids in response to the decrease in Pco₂, while the capacity to “consume” acids was largely retained.

In comatose animals, cerebral energy state was held at normocapnic levels during hypercapnia but deteriorated during hypocapnia. In the latter condition, the reduction in adenylate energy charge correlated to a decrease in blood pressure. The capacity to alter metabolic acid levels was abolished. In spite of this, hypocapnia was associated with a marked rise in intracellular pH, in some animals to values of about 7.7 (control, 7.0), and hypercapnia caused only very moderate reduction in intracellular pH. It is proposed that the excessive increase in intracellular pH during hypocapnia was due to hypotension-induced energy failure with subsequent depolarization of cells and passive equilibration of HCO₃⁻ (or H⁺) across the cell membranes. In hypercapnia, the influx of HCO₃⁻ into cells was unrelated to further deterioration of cerebral energy state but could possibly have been caused by CO₂-induced depolarization and/or increased cell membrane permeability to HCO₃⁻/H⁺ ions.

It is concluded that severe hypoglycemia disrupts intracellular pH regulation in the brain and that hypocapnia combined with moderate hypotension leads to an excessive intracellular alkalosis of potential importance for the development of cell damage.