Cellular pathways mediating tachykinin-evoked secretomotor responses in guinea pig ileum

This study characterized tachykinin-evoked secretomotor responses in in vitro submucosal and mucosal-submucosal preparations of the guinea pig ileum using combined intracellular and Ussing chamber recording techniques. Superfusion of endogenous tachykinins substance P (SP), neurokinin A (NKA), and neurokinin B depolarized single submucosal neurons and evoked increased short-circuit current (Isc) responses in Ussing chamber preparations. The NK1-receptor agonist [Sar9,Met(O2)11]SP [50% effective concentration (EC50) = 2 nM] depolarized all submucosal neurons examined. The NK3-receptor agonist senktide (EC50 = 20 nM) depolarized approximately 50% of neurons examined, whereas the NK2-receptor agonist [Ala5,beta-Ala8]NKA-(4-10) had no effect on membrane potential. [Sar9,Met(O2)11]SP and senktide evoked similar increases in Isc that were tetrodotoxin sensitive (91 and 100%, respectively) and were selectively blocked by the NK1 antagonist CP-99,994 and the NK3 antagonist SR-142,801, respectively. Capsaicin-evoked increases in Isc were significantly inhibited (54%, P < 0.05) by CP-99,994 but not by SR-142,801. Neither antagonist inhibited slow excitatory postsynaptic potentials. These findings suggest that tachykinin-evoked secretion in guinea pig ileum is mediated by NK1 and NK3 receptors on submucosal secretomotor neurons and that capsaicin-sensitive nerves release tachykinin(s) that activate the NK1 receptors.