Tachykinin receptors in the circular muscle of the guinea‐pig ileum

1 We have studied the mechanical response of circular strips of the guinea‐pig ileum to tachykinins and characterized the receptors involved by means of receptor‐selective agonists. 2 The strips responded to both substance P (SP) and neurokinin A (NKA), as well as to [Pro 9 ]‐SP sulphone (selective NK 1 ‐receptor agonist), [βAla 8 ]‐NKA(4–10) (selective NK 2 ‐receptor agonist) and [MePhe 7 ]‐neurokinin B (selective NK 3 ‐receptor agonist). The ED 50 s of the various peptides (calculated as the concentration of agonist which produced 50% of the response to 10 μ m carbachol) were similar, in the range of 40–200 n m , i.e. no clearcut rank order of potency was evident. 3 The response to a submaximal (10 n m ) concentration of SP or NKA was unaffected in the presence of peptidase inhibitors (thiorphan, captopril and bestatin, 1 μ m each). 4 The response to the NK 1 ‐agonist was totally atropine‐resistant, but was reduced (about 30% inhibition) by tetrodotoxin. The response to the NK 3 ‐receptor agonist was halved by atropine and abolished by tetrodotoxin. The response to the NK 2 ‐agonist was unaffected by either atropine or tetrodotoxin. 5 The response to the selective NK 2 ‐agonist was unchanged after desensitization of NK 1 ‐ or NK 3 ‐receptors. 6 The response to the NK 2 ‐selective agonist was strongly inhibited by [Tyr 5 , d ‐Trp 6,8,9 , Arg 10 ]‐NKA(4–10) (MEN 10,207) a selective NK 2 ‐receptor antagonist which did not modify the response to the NK 1 ‐selective agonist. 7 Our findings indicate that all the three known types of tachykinin receptors mediate the contractile response of the circular muscle of the guinea‐pig ileum to peptides of this family. The response to activation of NK 3 ‐receptors is totally neurogenic and partially mediated by endogenous acetylcholine, the response to activation of NK 1 ‐receptors is partly neurogenic and largely myogenic and the response to activation of NK 2 ‐receptors is totally myogenic.