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 int o the circulation and utilized in many tissues including the brain. Th e subsequent metabolism of acetate results in the production of adenos ine that has a number of effects in the central nervous system. The pu rpose of the present studies, therefore, was to investigate the contri bution of metabolically generated adenosine to the ethanol-induced pot entiation of the inhalational agents isoflurane and sevoflurane. Chang es in the anesthetic requirement for isoflurane and sevoflurane were d etermined in rats using the tail-clamp procedure. Both ethanol and sod ium acetate reduced anesthetic requirement for isoflurane and sevoflur ane in a dose-dependent fashion. The effect of acetate on anesthetic r equirement was completely blocked by the administration of the adenosi ne receptor blocker, 8-phenyltheophylline. The ethanol-induced reducti on in anesthetic requirement, however, was only partially blocked by 8 -phenyltheophylline. Direct intracerebroventricular (i.c.v.) administr ation of the water-soluble adenosine receptor blocker, 8-sulfophenylth eophylline, also completely blocked the effect of acetate and partiall y blocked the effect of ethanol. This i.c.v. administration demonstrat es that the actions of ethanol and acetate on anesthetic requirement a re a central nervous system effect. The i.c.v. administration of the a denosine A(1) receptor subtype agonist, R-phenylisopropyl adenosine, p otentiated the anesthetic effects of isoflurane and suggests that the A(1) receptor mediates the observed potentiation of anesthetic effect. This is further supported by the concomitant administration of 5-N-et hyIcarboxamido adenosine, a non-selective adenosine agonist, with the selective A(1) antagonist, 8-cyclopentyltheophylline, showing A(1) rec eptor potentiation of anesthetic requirements. The studies show that ( 1) acetate potentiates the anesthetic effects of the inhalational anes thetics, sevoflurane and isoflurane; (2) acetate contributes in part t o the effect of ethanol on anesthetic potency through metabolically ge nerated adenosine; (3) these effects are likely mediated via adenosine A(1) receptor subtypes. (C) 1997 Elsevier Science B.V.