TY - JOUR
T1 - Tachykinins mediate contraction of the human lower esophageal sphincter in vitro via activation of NK2 receptors
AU - Huber, Olivier
AU - Bertrand, Claude
AU - Bunnett, Nigel W.
AU - Pellegrini, Carlos A.
AU - Nadel, Jay A.
AU - Nakazato, Paul
AU - Debas, Haile T.
AU - Geppetti, Pierangelo
N1 - Funding Information:
This studyw as supportedin part by the NationalI nstituteo f Health,P rogramP rojectH L/24136.O .H. was supportedb y a grant of the Universityo f GenevaS, witzerlandP.. G. was supporteidn part by a grantf romCNR, Rome,I taly.
PY - 1993/8/3
Y1 - 1993/8/3
N2 - 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.
AB - 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.
KW - (Human)
KW - Lower esophageal sphincter
KW - NK receptors
KW - Neurokinin A
KW - Substance P
KW - Tachkinins
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U2 - 10.1016/0014-2999(93)90982-N
DO - 10.1016/0014-2999(93)90982-N
M3 - Article
C2 - 8223885
AN - SCOPUS:0027337914
SN - 0014-2999
VL - 239
SP - 103
EP - 109
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -