Inhibition of acetylcholine release from cholinergic nerves by adenosine, adenine nucleotides and morphine: antagonism by theophylline

Abstract

Adenosine and adenine nucleotides [adenosine-5'-monophosphate, adenosine-5'-diphosphate, adenosine triphosphate (ATP), cyclic adenosine 3',5'-monophosphate (dbcAMP)], but not (cAMP) and dibutyryl cyclic adenosine 3',5'-monosphosphate (dbcAMP)], but not adenine or inosine, inhibited the twitch response of the electrically stimulated guinea-pig myenteric plexus-longitudinal muscle preparation. With each agent except dbcAMP, inhibition was manifest muscle preparation. With each agent except dbcAMP, inhibition was manifest from 1 to 500 muM was maximal within 1 minute. For dbcAMP, higher concentrations were required (10-fold increase) and inhibition was maximal after 20 to 30 minutes. Theophylline (0.05-0.5 mM) both reversed and prevented the inhibition produced by each of these agents. In higher concentrations (greater than 1 mM), theophylline itself depressed the twitch response. Neither propranolol nor phenoxybenzamine altered theophylline-induced depression, whereas phenoxybenzamine did not alter adenosine-induced inhibition. Adenosine, ATP, cAMP and theophylline (0.25 mM) did not alter acetylcholine-induced contractions, whereas a higher concentration of theophylline (2.5 mM) inhibited contractions. Theophylline (up to 0.5 mM) did not antagonize epinephrine- or dopamine-induced inhibition of the twitch response, but did antagonize morphine-induced inhibition. These findings suggest that adenosine and related nucleotides act at a common receptor site at which theophylline acts as a competitive antagonist and that there is a link between morphine and adenine nucleotide action in this preparation.