Effects of acute hyperosmolar NaCl or urea on brain H2O, Na+, K+, carbohydrate, and amino acid metabolism in weanling mice: NaCl induces insulin secretion and hypoglycemia.

This study compares early and late effects of the injection of hyperosmolar NaCl and urea of equal osmolarity on selected aspects of brain water, electrolyte, carbohydrate, amino acid, urea, and energy metabolism in normal suckling-weanling mice. One hour after treatment, salt-treated mice were critically ill, while the behavior of urea-treated animals could not be distinguished from that of controls. This clinical difference could not be explained on the basis of differences in plasma osmolality, the brain water content, or the degree of hemorrhagic encephalopathy. The injection of NaCl induced a 14-fold increase in plasma insulin and a progressive fall in the plasma glucose concentration (a reduction of 66% at 1 hr). In contrast, plasma glucose levels in urea-injected mice were unchanged. Prior to the fall in plasma glucose levels, metabolite changes in the brains of NaCl-injected mice were compatible with facilitation of transfer of glucose from the blood to the brain, increased metabolic flux in the Embden-Meyerhof and Krebs citric acid cycle pathways, and increased energy production. With the exception of the glucose content (unchanged), similar metabolite changes were seen in brain soon after urea injection. In the brains of the hypoglycemic NaCl-treated mice, glucose levels were reduced 80%, and glycogen 41%. Other metabolite changes were compatible with decreased glycolysis and metabolic flux through the Krebs citric acid cycle. In contrast, with few exceptions, at a similar time after injection, metabolite levels had returned to normal in the urea-treated mice. Permeability of the brain to urea was also examined. Brain urea reached high levels at 2 hr but returned to near baseline at 6 hr. Both hyperosmolar solutions increased the brain content of aspartic and glutamic acids 1 hr after injection. The failure of hypoglycemic mice with hypernatremia and elevated plasma osmolality (range, 416-434 mOsm/kg H2O) to respond to 1 M glucose (30 ml/kg) may have been due to the ill effects of the additional hyperosmolar load. The possibility remains that the encephalopathy induced by hyperosmolar NaCl, but not by hyperosmolar urea, is in some way related to the sudden elevation of brain Na+ and/or Cl- ions.

Mechanisms of increased brain glucose and glycogen after hydrocortisone: possible clinical significance.

We reported previously that chronic administration of hydrocortisone to normal developing mice increases the brain glucose content and cerebral energy reserve. The present report concerns possible mechanisms of this action. Increases in brain glucose (and glycogen) levels were not due to reduction of cerebral metabolic rate, and the effect of hydrocortisone in facilitating transport of hexose from blood to brain was not impressive. Chronic hydrocortisone treatment induced increases in the activities of brain glycerophosphate dehydrogenase and pyruvate carboxylase in vivo; there was no effect on eleven other enzymes of brain glucose and glycogen metabolism. In normal nursing mice, hydrocortisone produced consistent elevations in plasma beta-hydroxybutyrate (and glycerol) levels. Brain beta-hydroxybutyrate levels were also increased. Therefore, the brain glucose concentration may be elevated in these animals because of the availability of an increased supply of ketone bodies as alternative substrates for cerebral oxidative metabolism and biosynthesis. Ketonemia, elevated cerebral glucose and beta-hydroxybutyrate concentrations, and increased glycerophosphate dehydrogenase activity in brain suggest possible explanations for the beneficial action of adrenocorticotropic hormone and glucocorticoids in the treatment of infantile myoclonic epilepsy and other neurological disorders.

Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice.

In weanling mice treated with pharmacologic doses of aminophylline, the concentrations of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate in the brain increased 44 and 36 percent, respectively, and the cerebral metabolic rate was three times that in controls. In neonatal mice, therapeutic doses of aminophylline greatly decreased the rate of anoxic survival in vivo and the duration of gasping of the isolated head. The findings suggest caution in the use of this drug and other methylxanthines in hypoxic human newborns.

Hyperglycemia, hypoinsulinemia, and hyperglucagonemia in acute water intoxication.

When acute (four-hour) hyponatremia with clinical signs of water intoxication was produced in normal weanling mice by the use of hypotonic glucose or deionized water, there was a two-to-fourfold increase in plasma glucose concentration. Concomitantly, concentrations of plasma insulin fell 63 to 68 per cent, whereas plasma glucagon increased to 262 per cent of control. The findings are compatible with stress-induced catecholamine release.

Insulin and brain metabolism. Absence of direct action of insulin on K+ and Na+ transport in normal rabbit brain.

In fed, unanesthetized rabbits, regular zinc insulin, 50 U./kg. intravenously, decreased plasma glucose levels 52 per cent, p = 0.002, 35 minutes after injection. In 15-hour-fasted, unanesthetized animals, the same dose of insulin decreased plasma glucose levels 68 per cent, p less than 0.001. Plasma K+ concentration was not affected by insulin injection in the fed animals; in fasted rabbits, plasma K+ levels fell 26 per cent, p = 0.006. Despite this unequivocal evidence of insulin action in both sets of animals, there was no change in the K+, Na+, or H2O content in the brains of the same animals 35 minutes after insulin injection. These results, which give no evidence of a direct effect of insulin on electrolyte transport in brain, are in sharp contrast with those found in anesthetized rabbits, which suggested that insulin affects brain potassium and water content before any change in plasma glucose occurs.

Insulin and brain metabolism. Absence of direct action of insulin on K+ and Na+ transport in mouse brain.

This is a study of the effect of insulin on the transport of K+ and Na+ from the blood into the brains of normal mice. Despite profound reductions in plasma and brain glucose levels, reduction of plasma K+ concentration and progressive deterioration of neurologic function 30-120 minutes after insulin injection, in 20-22-day-old animals there was no increase in brain K+ and Na+ concentrations. In fact, at 120 minutes, when the brain water content increased 0.7 per cent, brain K+ concentration was significantly reduced, not elevated. The effect of insulin on brain electrolyte and water content in adult mice was also studied. Although brain water increased 0.5 per cent at 120 minutes, there was no changes in brain Na+ or K+ concentrations at any time after insulin injection. The data from mice do not support a role of insulin in electrolyte transport in brain.