Pre- and postjunctional modulation of cholinergic neuroeffector transmission by adenine nucleotides. Experiments with agonist and antagonist

Abstract

Adenosine, 2-chloroadenosine, AMP, AMPNH2, ADP, ATP, AMPPNP and beta, gamma meATP dose-dependently and reversibly inhibited contractile responses to nerve stimulation in longitudinal plexus-containing muscle preparations of guinea pig ileum. All the purines, except for 2-chloroadenosine, were virtually equipotent and elicited maximal inhibition within 2 min after application. Adenosine deaminase abolished inhibition by adenosine but did not block the effect of 2-chloroadenosine or the adenine nucleotides. During transmural nerve stimulation, the nucleotidase-resistant analogues alpha, beta meADP and AMPPNP significantly depressed acetylcholine release measured by gas chromatography-mass spectrometry. The inhibitory effect of all the purines was competitively, reversibly and at comparable pA2 values antagonized by 8-p-sulphophenyltheophylline. The results indicate that nucleotides per se can inhibit neurotransmission via a prejunctional receptor common to nucleosides and nucleotides. An excitatory effect by all the di- and triphosphate nucleotides was also observed. The excitation was unaltered by atropine, tetrodotoxin and 8-p-sulphophenyltheophylline, thus suggesting an action at postjunctional ADP- and ATP-like receptive sites.