Role of adenosine in the ethanol-induced potentiation of the effects of general anesthetics in rats.

Acetate, derived from ethanol metabolism in the liver, is released into the circulation and utilized in many tissues including the brain. The subsequent metabolism of acetate results in the production of adenosine that has a number of effects in the central nervous system. The purpose of the present studies, therefore, was to investigate the contribution of metabolically generated adenosine to the ethanol-induced potentiation of the inhalational agents isoflurane and sevoflurane. Changes in the anesthetic requirement for isoflurane and sevoflurane were determined in rats using the tail-clamp procedure. Both ethanol and sodium acetate reduced anesthetic requirement for isoflurane and sevoflurane in a dose-dependent fashion. The effect of acetate on anesthetic requirement was completely blocked by the administration of the adenosine receptor blocker, 8-phenyltheophylline. The ethanol-induced reduction in anesthetic requirement, however, was only partially blocked by 8-phenyltheophylline. Direct intracerebroventricular (i.c.v.) administration of the water-soluble adenosine receptor blocker, 8-sulfophenyltheophylline, also completely blocked the effect of acetate and partially blocked the effect of ethanol. This i.c.v. administration demonstrates that the actions of ethanol and acetate on anesthetic requirement are a central nervous system effect. The i.c.v. administration of the adenosine A1 receptor subtype agonist, R-phenylisopropyl adenosine, potentiated the anesthetic effects of isoflurane and suggests that the A receptor mediates the observed potentiation of anesthetic effect. This is further supported by the concomitant administration of 5-N-ethylcarboxamido adenosine, a non-selective adenosine agonist, with the selective A1 antagonist, 8-cyclopentyltheophylline, showing A1 receptor potentiation of anesthetic requirements. The studies show that (1) acetate potentiates the anesthetic effects of the inhalational anesthetics, sevoflurane and isoflurane; (2) acetate contributes in part to the effect of ethanol on anesthetic potency through metabolically generated adenosine; (3) these effects are likely mediated via adenosine A1 receptor subtypes.