Role of adenosine A1 receptors in inhibition of receptor-stimulated cyclic AMP production by ethanol in hepatocytes.
Brief exposure of primary cultures of hepatocytes to ethanol had a biphasic effect on glucagon receptor-dependent cyclic AMP (cAMP) production: 25-50 mM ethanol decreased cAMP levels, whereas treatment with 100-200 mM ethanol increased cAMP. This biphasic effect was also observed after pretreatment with 10 microM 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Adenosine A1 and A2 receptors in primary cultures of rat hepatocytes are coupled to inhibition and stimulation of adenylyl cyclase, respectively. Since primary cultures of hepatocytes release adenosine into their extracellular media, we tested whether the acute effects of ethanol on cAMP were mediated by extracellular adenosine. Co-incubation with 2 U/mL adenosine deaminase prevented inhibition of cAMP production by 25-50 mM ethanol, but had no effect on stimulation by 100-200 mM ethanol. Pretreatment of hepatocytes with 110 nM 8-cyclopentyl-1,3-dimethylxanthine, an adenosine A1 receptor antagonist, also completely blocked the inhibitory effects of ethanol on cAMP production. Low concentrations of ethanol enhanced the inhibitory effects of R(-)N6-(2-phenylisopropyl)adenosine, an A1 receptor agonist, on cAMP production in cells pretreated with adenosine deaminase to remove endogenous adenosine. These data suggest that endogenously produced adenosine can be an important modulator of the effects of ethanol on receptor-stimulated cAMP production in primary cultures of rat hepatocytes.
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Department of Nutritional Sciences, University of Guelph, Ontario, Canada.
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005934:Glucagon / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D018047:Receptors, Purinergic P1; D010660:Phenylisopropyladenosine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D019830:Adenosine-5'-(N-ethylcarboxamide); D000431:Ethanol; D005934:Glucagon; D013806:Theophylline; D000242:Cyclic AMP; D000241:Adenosine