Tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitatory neuromuscular transmission in the human ileum.

Tachykinin NK1 and NK2 receptor selective antagonists and agonists were used to study excitatory non-adrenergic non-cholinergic (NANC) transmission in circular muscle strips from human ileum by the sucrose-gap method. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), apamin (0.1 microM), and N omega-nitro-L-arginine (L-NOARG, 30 microM), 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 NK1 receptor antagonist, GR 82334 (0.1-3 microM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC50 = 0.21 microM) and contraction (IC50 = 0.21 microM). The selective tachykinin NK2 receptor antagonist, MEN 10627 (0.01-1 microM), likewise produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC50 = 0.07 microM) and contraction (IC50 = 0.03 microM). 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 NK1 or NK2 receptors by the selective receptor agonists, [Sar9]substance P (SP) sulfone and [beta Ala8]neurokinin A (NKA) (4-10), respectively (0.3 microM for 20 s each), produced depolarization with superimposed action potentials and contractions. GR 82334 selectively inhibited the responses to [Sar9]]SP sulfone, without affecting the responses to [beta Ala8]NKA (4-10). MEN 10627 inhibited the responses to [beta Ala8]NKA (4-10), without affecting the responses to [Sar9]SP sulfone. We conclude that both tachykinin NK1 and NK2 receptors co-operate in producing NANC excitation and contraction of the circular muscle in human ileum.