INHIBITION OF ACETYLCHOLINE-RELEASE FROM CHOLINERGIC NERVES BY ADENOSINE, ADENINE-NUCLEOTIDES AND MORPHINE - ANTAGONISM BY THEOPHYLLINE

Abstract

Adenosine and adenine nucleotides [5''-AMP, 5''-ADP, ATP, cAMP [cyclic AMP] and dibutyryl cyclic AMP (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 from 1-500 .mu.M and was maximal within 1 min. For dbcAMP higher concentrations were required (10-fold increase) and inhibition was maximal after 20-30 min. Theophylline (0.05-0.5 mM) both reversed and prevented the inhibition produced by each of these agents. In higher concentrations (> 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. Adenosine and related nucleotides may act at a common receptor site at which theophylline acts as a competitive antagonist, and there is probably a link between morphine and adenine nucleotide action in this preparation.