In vitro characterizat of the non-peptide tachykinin NK 1 and NK 2-receptor antagonists, SR140333 and SR48968 in different rat and guinea-pig intestinal segments

Abstract

We investigated the potent non-peptide tachykinin receptor antagonists SR140333 and SR48968 for their ability to prevent the contraction of isolated intestinal tissues elicited by the non-selective agonists substance P (SP) and neurokinin A (NKA), or by [Sar 9,Met(O 2) 11]SP and [β-Ala 8]NKA-(4–10) that are selective agonist for NK 1 and NK 2 receptors,respectively. In guinea-pig ileum, containing mainly NK 1-receptors: SR140333 caused a pseudo-irreversible blockade of contractions induced by either SP (K B, 0.01 nM) or [Sar 9, Met(O 2) 11]SP (K B, 0.03 nM); SR140333 but not SR48968, dose-dependently (IC 50, 0.06 nM) antagonized the contractions elicited by capsaicin. In rat duodenum, containing mainly NK 2 receptors, SR48968 caused a parallel rightward shift of the concentration-response curves of [β-Ala 8]NKA-(4–10) (pA 2, 9.5), but not of NKA. In rat esophageal tunica muscularis mucosae, SR48968 and non-competitively antagonized [β-Ala 8]NKA-(4–10) and NKA. SR48968 and SR140333 thus appear to be potent tachykinin receptor antagonists, selective for intestinal receptors respectively of the NK 2 and NK 1 type. The results also suggest that rat esophagus might contain a NK 2-receptor subtype different from that of rat duodenum.