Multiple Motor Effects of ATP and their Inhibition by P2 Purinoceptor Antagonist, Pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic Acid in the Small Intestine of the Guinea‐Pig

: Adenosine 5′‐triphosphate (ATP) may be an important neurotransmitter in the gastrointestinal tract. The present study examined the motor effects of exogenous ATP on longitudinally‐oriented preparations of the guinea‐pig isolated ileum and the influence of drugs on the ATP‐induced responses. High micromolar concentrations of ATP caused two types of contraction, a phasic, cholinergic response and a tonic, tetrodotoxin‐resistant contraction. The phasic contraction was reduced by hexamethonium (5×10−5 M), but left uninfluenced by capsaicin tachyphylaxis or tachyphylaxis to α,β‐methylene ATP. The tonic response was resistant to atropine, hexamethonium, capsaicin, ω‐conotoxin GVIA, or pretreatment with α,β‐methylene ATP. Both types of ATP‐induced contraction were diminished or abolished by the P2 purinoceptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS, 3×10−6 and 3×10−5 M, respectively). In the precontracted, atropine‐treated ileum ATP (10−6–10−4 M) caused guanethidine‐resistant relaxation. This response was not influenced by tetrodotoxin, ω‐conotoxin GVIA, or NG‐nitro‐L‐arginine, but was abolished by apamin (10−7 M), and inhibited by PPADS (3×10−5 M) or reactive blue 2 (10−5 M), in a surmountable manner. A high degree of tachyphylaxis was observed with the relaxant effect of ATP (10−5–10−4 M). A high concentration (3×10−4 M) of PPADS failed to influence ileum contractions to exogenous acetylcholine or histamine. It is concluded that, in addition to its direct contractile action in the guinea‐pig ileum, ATP can activate (partly preganglionic) cholinergic neurones, an effect whose mechanism is largely different from that of α,β‐methylene ATP. ATP also causes relaxation by a direct, probably P2Y‐receptor‐mediated effect on the smooth muscle. All motor effects of ATP are inhibited by the antagonist PPADS.