Effects of acute administration of and tachyphylaxis to α,β-methylene ATP in the guinea-pig small intestine

Abstract

The aim of the present study was to assess the acute motility effects and desensitizing activity of the stable ATP analogue and P2X purinoceptor agonist α,β-methylene ATP (α,β-meATP) and the effect of α,β-meATP desensitization on nerve-mediated cholinergic responses in the guinea-pig ileum in vitro. It was confirmed that α,β-meATP (1-30 μM) causes neurally-mediated, cholinergic (tetrodotoxin- and atropine-sensitive) longitudinal contractions. These responses were not influenced by the ganglionic blocking drug hexamethonium (50 μM), or a combination of the adrenergic neurone blocking drug guanethidine (3 μM), the opioid receptor antagonist naloxone (0.5 μM) and the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NOARG; 100 μM), but were strongly reduced or abolished by the P2 purinoceptor antagonist PPADS (30 μM) or by tachyphylaxis evoked by 10 μM α,β-meATP. The contractile effect of α,β-meATP (3 μM) was moderately inhibited by 10 μM and strongly suppressed by 30 μM of NF 279, an antagonist predominantly affecting P2X1 purinoceptors, but left uninfluenced by the P2X5,7 receptor antagonist Brilliant blue G. No relaxant effect of α,β-meATP was detected in the concentration range of 1-30 μM. Tachyphylaxis to α,β-meATP (1-10 μM) caused a moderate inhibition of the cholinergic (atropine-sensitive) contractile response of the ileum to electrical field stimulation (5 Hz for 5 sec.). This reduction was unaltered in the presence of guanethidine, naloxone and L-NOARG. Responses to nicotine (1 or 2 μM) were not reduced by α,β-meATP tachyphylaxis. It is suggested that α,β-meATP-sensitive P 2X purinoceptors are involved in the prejunctional modulation of cholinergic neurotransmission between the myenteric plexus and longitudinal smooth muscle in the guinea-pig small intestine. © Basic & Clinical Pharmacology & Toxicology 2005.