Hypoxic tolerance enhanced by beta-hydroxybutyrate-glucagon in the mouse.

Abstract

A coorelation has been observed between increased blood ketones and the tolerance of mice to hypoxia (4-5% oxygen). In previous studies fasted mice, alloxan diabetic mice and mice given 1,3-butanediol were found to be ketotic and to have increased tolerance to hypoxia. We attempted to induce a similar increased hypoxic tolerance by direct elevation of blood ketones with IV and IP beta-hydroxybutyrate (BHB). No increase in hypoxic tolerance was observed with BHB alone. Inasmuch as fasting and alloxan diabetes are both associated with elevated blood glucagon (G), hypoxic tolerance tests were made 30 min after G alone or a combination of G plus BHB. The mice given G alone or BHB alone had hypoxic survival times not different from saline controls. The mice given G plus BHB had increased survival times that could not be explained on the basis of a G mediated alteration in blood BHB.

Increased Plasma Beta-Hydroxybutyrate, Preserved Cerebral Energy Metabolism, and Amelioration of Brain Damage During Neonatal Hypoxia Ischemia with Dexamethasone Pretreatment

“…The administration of exogenous BHB has been shown to increase the survival time of immature mice exposed to hypoxic or anoxic conditions (33). In a study in adult animals, the administration of BHB alone was not significantly beneficial but the combination of BHB and glucagon increased hypoxic tolerance (34). In adult animals exposed to ischemia, the administration of 1,3-butanediol induces ketosis and results in reduction of metabolic alterations associated with HI, a reduction in cerebral water content, and improvement in neurologic function, and an increase in blood BHB levels (34 -37).…”

Glucagon stimulates ketone utilization by rat brain slices.

“…3 Briefly, mice weighing 20-40 g received both an intravenous (0.25 ml in lateral tail vein) and intraperitoneal (0.5 ml) injection 30 minutes prior to the onset of hypoxic gas exposure. Seven groups of mice were tested: (1) normal saline iv and ip; (2) 62.5 mg glucose iv and saline ip; (3) normal saline iv and 60 mg BHB ip; (4) 62.5 mg glucose iv and 60 mg BHB ip; (5) 125 mg glucose iv and 60 mg BHB ip; (6) 4.0 ug glucagon iv and 60 mg BHB ip; (7) 62.5 mg glucose and 4.0 ug glucagon iv and 60 mg BHB ip.…”

“…3 The concentration of glucagon in the brain slice medium was chosen on the basis of our experiments demonstrating the stimulatory effects of glucagon on isolated brain mitochondria 8 and from experiments of isolated hepatocytes showing similar stimulation of subsequently isolated mitochondria. 7 …”

“…1 -2 Furthermore, this enhanced hypoxic tolerance was potentiated by exogenous glucagon (GG). 3 Before such manipulations of blood glucose, ketones or GG can be considered for clinical applicability, some basic understanding of the mechanism by which these procedures increase tolerance for hypoxia would be desirable.…”

“…4 For example, it has been reported that acute GG treatment of intact animals alters liver mitochondrial calcium flux and respiration. 3 Furthermore, Suzuki 6 reported that the intravenous injection of GG increases oxygen consumption of subsequently prepared liver slices. In order to discriminate between a direct cellular effect and an indirect systemic effect of GG, Siess and Wieland 7 first isolated hepatocytes and then treated them with GG.…”