IDENTIFICATION OF MECHANISMS FOR DUODENAL CONTRACTION INDUCED BY TACHYKININS IN THE RAT

Mechanisms for contractile effects of tachykinins on muscle strips of rat duodenum were studied using substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and neuropeptide K (NPK), and the tachykinin analog ues SP methyl ester (SPME), Nle10-NKA(4-10) (NleNYA) and senktide (SEN K) selective for neurokinin (NK)-1, NK-2 and NK-3 receptors, respectiv ely. NK receptors responsible for smooth muscle contraction were ident ified using selective ligands to protect NK receptors combined with in activation of residual receptors with N-ethylmaleimide. Tachykinins (1 0(-9) to 10(-5) m) caused dose-related contractions of the muscle stri ps. The order of potency of native tachykinins was NKA > NKB > SP > NP K in circular, and NKB > NKA > NPK > SP in longitudinal muscle, wherea s that of selective tachykinin analogues was SENK > NleNKA > SPME. NKA , NleNKA and SENK were equieffective as acetylcholine, whereas SP, SPM E, NKB and NPK were less effective. Spantide decreased the sensitivity to all tachykinin analogues. Atropine reduced the sensitivity to SENK only, whereas hexamethonium reduced the sensitivity to SENK and SPME, but not to NleNKA. Selective receptor protection with SPME, NleNKA or SENK protected contractions induced by SPME, NleNKA and SENK, respect ively. Responses to tachykinin analogues were reduced in Ca2+-free med ium. Thus, NKA is suggested to be the dominating tachykinin to stimula te contraction of the rat duodenum via NK receptors coupled to Ca2+-de pendent signal transduction pathways. Of the receptors available, the NK-1 subtype involves a nicotinic transmission step, and the NK-3 subt ype also a muscarinic step, whereas the NK-2 receptor subtype is not d ependent on cholinergic mechanisms.