caa a22 4500 46907826X CHVBK 20180323132941.0 cr unu---uuuuu 170328e19920901xx s 000 0 eng 10.1007/BF00173545 doi (NATIONALLICENCE)springer-10.1007/BF00173545 CP-96,345, a non-peptide antagonist of substance P: I. Effects on the actions mediated by substance P and related tachykinins on the guinea-pig ileum and rabbit jejunum [Elektronische Daten] [F. Legat, T. Griesbacher, F. Lembeck] Summary: The effects of a non-peptide antagonist of substance P, CP 96,345, were investigated, in vitro, on the guinea-pig ileum and the rabbit jejunum. Contractions of the guinea-pig ileum, induced by substance P and neurokinin A, were specifically inhibited by the racemate (±)CP-96,345 (pIC50 7.8 and 7.3, respectively). The inhibition by (±)CP-96,345 of contractions evoked by neurokinin B and by bradykinin (pIC50 6.1 and 4.9, respectively) was attributed to unspecific effects of the antagonist. The inhibition of substance P-induced contractions of the rabbit jejunum required a 10 times higher concentration of (±)CP-96,345 (pIC50 = 6.8) than was required with the guinea-pig ileum. The plateau phase of contraction of the guinea-pig ileum induced by high concentrations of substance P, neurokinin A or neurokinin B, which is known to be mediated through tachykinin receptors on intrinsic cholinergic neurones, was inhibited by 200 nM (±)CP-96,345 but not by the inactive enantiomer, CP-96,344. This indicates a specific inhibition of these neuronal tachykinin receptors by (±)CP-96,345 Contractions known to be mediated by the release of substance P, such as those evoked by capsaicin and by mesenteric nerve or field stimulation, were partially inhibited by (±)CP-96,345 at concentrations of 200 to 600 nM. Unspecific inhibitory effects of CP-96,345, in concentrations of 1 µM or higher, were observed on histamine-induced contractions, and on the cholinergic twitch response to electrical stimulation, of the guinea-pig ileum. Therefore, an inhibition by CP-96,345 of substance P-related effects can only be regarded as specific if the concentration of the antagonist is below 1 µM. No effect of CP-96,345 (1 µM) was seen on peristalsis in vitro. The peristaltic reflex, in situ, was also not affected by CP-96,345 (1.6 µmolkg−1, i.v.). The present results demonstrate that, although inhibitory actions of CP-96,345 can be observed on certain motor responses in the guinea-pig small intestine, peristalsis, a physiologically relevant function, remains intact. Springer-Verlag, 1992 Guinea-pig ileum nationallicence Rabbit jejunum nationallicence Nonpeptide antagonist of substance P nationallicence CP-96,345 nationallicence Tachykinins nationallicence Legat F. Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Universitätsplatz 4, A-8010, Graz, Austria aut Griesbacher T. Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Universitätsplatz 4, A-8010, Graz, Austria aut Lembeck F. Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Universitätsplatz 4, A-8010, Graz, Austria aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/3(1992-09-01), 315-322 0028-1298 346:3<315 1992 346 210 https://doi.org/10.1007/BF00173545 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00173545 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Legat F. Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Universitätsplatz 4, A-8010, Graz, Austria aut NATIONALLICENCE 700 1- Griesbacher T. Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Universitätsplatz 4, A-8010, Graz, Austria aut NATIONALLICENCE 700 1- Lembeck F. Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Universitätsplatz 4, A-8010, Graz, Austria aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/3(1992-09-01), 315-322 0028-1298 346:3<315 1992 346 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer