Tachykinin NK 1 and NK 2 receptors mediate non-adrenergic noncholinergic excitatory neuromuscular transmission in the human ileum

Abstract

Tachykinin NK 1 and NK 2 receptor selective antagonists and agonists were used to study excitatory nonadrenergic non-cholinergic (NANC) transmission in circular muscle strips from human ileum by the sucrose-gap method. In the presence of atropine (1 μM), guanethidine (3 μM), indomethacin (3 μM), apamin (0.1 μM) and N ω-nitro-L-arginine (L-NOARG, 30 μM), electrical field simulation (EFS) produced a NANC inhibitory junction potential (i.j.p.) followed by NANC excitatory junction potential (e.j.p.) with superimposed action potentials and contraction of the circular muscle of human ileum. The selective tachykinin NK 1 receptor antagonist, GR 82334 (0.1–3 μM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC 50 = 0.21 μM) and contraction (IC 50 = 0.21 μM). The selective tachykinin NK 2 receptor antagonist, MEN 10627 (0.01–1 μM), likewise produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC 50 = 0.07 μM) and contraction (IC 50 = 0.03 μM). Either antagonist was more effective in inhibiting the mechanical than the electrical response to EFS. Neither GR 82334 nor MEN 10627 had any effect on the apamin- and L-NOARG-resistant NANC i.j.p. Activation of the NK 1 or NK 2 receptors by the selective receptor agonists, [Sar 9]substance P (SP) sulfone and [βAla 8]neurokinin A (NKA) (4–10), respectively (0.3 μM for 20 s each), produced depolarization with superimposed action potentials and contractions. GR 82334 selectively inhibited the responses to [Sar 9]]SP sulfone, without affecting the responses to [βAla 8]NKA (4–10). MEN 10627 inhibited the responses to [βAla 8]NKA (4–10), without affecting the responses to [Sar 9]SP sulfone. We conclude that both tachykinin NK 1 and NK 2 receptors co-operate in producing NANC excitation and contraction of the circular muscle in human ileum.