Tachykinins mediate contraction of the human lower esophageal sphincter in vitro via activation of NK2 receptors

Olivier Huber, Claude Bertrand, Nigel W. Bunnett, Carlos A. Pellegrini, Jay A. Nadel, Paul Nakazato, Haile T. Debas, Pierangelo Geppetti

Research output: Contribution to journalArticle

Abstract

The contractile response to natural tachykinins and selective peptide agonists for tachykinin receptors was studied in strips of circular smooth muscle of human lower esophageal sphincter in vitro. The effects of phosphoramidon, which inhibits neutral endopeptidase (EC.3.4.24.11) and of the non-peptide compounds, SR 48968 and CP-96,345, which selectively block NK1 and NK2 receptors, respectively, were also investigated. Substance P, neurokinin A and neurokinin B produced a concentration-dependent contractile response. The rank order of potency was neurokinin A > neurokin B > substance P. Phosphoramidon (1 μM) potentiated the response to substance P without changing the order of potency of natural tachykinins. The NK2-selective agonist, ([βAla8]neurokinin A-(4-10)), produced a concentration-dependent contraction. The NK1 ([Sar9, Met(O2)11]substance P, 1 μM) and NK3 ([MePhe7]neurokinin B, 1 μM) selective agonists, however, did not exert any contractile effect. The selective NK2 antagonist, SR 48968, potently inhibited in a concentration-dependent (10 nM-1 μM) manner the response to neurokinin A, without affecting the response to carbachol. The selective NK1 antagonist, CP-96,345 (1 μM), did not affect the response to neurokinin A. These results indicate that tachykinins contract muscle of human lower esophageal sphincter, and that this effect is mediated by NK2 receptor stimulation. Moreover, a phosphoramidon-sensitive mechanism plays a role in the regulation of the response to substance P.

Original languageEnglish (US)
Pages (from-to)103-109
Number of pages7
JournalEuropean Journal of Pharmacology
Volume239
Issue number1-3
DOIs
StatePublished - Aug 3 1993

Keywords

  • (Human)
  • Lower esophageal sphincter
  • NK receptors
  • Neurokinin A
  • Substance P
  • Tachkinins

ASJC Scopus subject areas

  • Pharmacology

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