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.
MacNaughton
W
W
Gastrointestinal Research Group, University of Calgary, Alberta, Canada.
Moore
B
B
Vanner
S
S
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D015287:Neurokinin B / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology*
D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; D015320:Tachykinins; C054724:senktide; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D015288:Neurokinin A; D015287:Neurokinin B; C091554:SR 142801; D002211:Capsaicin