Elevated blood ketone and glucagon levels cannot account for 1,3-butanediol induced cerebral protection in the levine rat

Abstract

1,3-Butanediol is an ethanol dimer that induces systemic ketosis. It has previously been shown to increase hypoxic survival time and reduce neurologic deficit in several experimental preparations. The aim of this study was to determine if the mechanism of 1,3- butanediol-induced cerebral protection was elevation of blood ketone levels, blood glucagon levels, or both. Blood β-hydroxybutyrate levels, glucagon levels, or both produced by a previously reported protective dose of 1,3-butanediol (47 mmol/kg) were simulated by direct i.v. infusion of the ketone β-hydroxybutyrate and glucagon separately and in combination, and the effect on hypoxic survival time in instrumented Levine rats (unilateral carotid ligation and hypoxic exposure) was determined. To test if the mechanism was a direct or osmotic effect of the alcohol, an equimolar dose of ethanol (47 mmol/kg) was administered and the effect on hypoxic survival time was compared with that produced by 1,3-butanediol. As in previous studies, 1,3-butanediol significantly increased hypoxic survival time (241% of control, Scheffe p < 0.05). Various doses of β-hydroxybutyrate and glucagon were infused to approximate the blood levels of β-hydroxybutyrate and glucagon produced by a protective dose of 1,3-butanediol. Although β-hydroxybutyrate or glucagon infusions produced blood levels of these substances that were comparable with those produced by administering butanediol, they failed to prolong hypoxic survival time as long as 1,3-butanediol. No correlation was detected between hypoxic survival time and blood levels of β-hydroxybutyrate, glucagon, insulin, or glucose. An equimolar dose of ethanol did not significantly increase hypoxic survival time. Neither simple elevation of blood ketones or glucagon nor a direct or osmotic effect of the alcohol can explain the protective effects of 1,3-butanediol. © 1987 American Heart Association, Inc.