TACHYKININS MEDIATE CONTRACTION OF THE HUMAN LOWER ESOPHAGEAL SPHINCTER IN-VITRO VIA ACTIVATION OF NK(2) RECEPTORS

The contractile response to natural tachykinins and selective peptide agonists for tachykinin receptors was studied in strips of circular sm ooth 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 selec tively block NK1 and NK2 receptors, respectively, were also investigat ed. Substance P, neurokinin A and neurokinin B produced a concentratio n-dependent contractile response. The rank order of potency was neurok inin A > neurokinin B > substance P. Phosphoramidon (1 muM) potentiate d the response to substance P without changing the order of potency of natural tachykinins. The NK2-selective agonist, ([betaAla8]neurokinin A-(4-10)), produced a concentration-dependent contraction. The NK1 ([ Sar9,Met(O2)11]substance P, 1 muM) and NK3 ([MePhe7]neurokinin B, 1 mu M) selective agonists, however, did not exert any contractile effect. The selective NK2 antagonist, SR 48968, potently inhibited in a concen tration-dependent (10 nM-1 muM) manner the response to neurokinin A, w ithout affecting the response to carbachol. The selective NK1 antagoni st, CP-96,345 (1 muM), did not affect the response to neurokinin A. Th ese results indicate that tachykinins contract the circular muscle of human lower esophageal sphincter, and that this effect is mediated by NK2 receptor stimulation. Moreover, a phosphoramidon-sensitive mechani sm plays a role in the regulation of the response to substance P.