class="enumerated" style="list-style-type:decimal">The tachykinin receptors mediating contraction of isolated longitudinal strips of the guinea-pig oesophageal body were characterized with substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) as well as the analogues, [Sar9,Met(O2)11]SP, [Nle10]NKA(4–10) and [MePhe7]NKB, selective for NK1, NK2 and NK3, receptors, respectively. Experiments were performed both in the absence and presence of a cocktail of peptidase inhibitors, captopril (1 μM), thiorphan (1 μM) and amastatin (20 μM), in order to determine whether membrane bound proteases are important in the metabolism of tachykinins in this preparation.All agonists produced concentration-dependent contractile effects. The presence of the peptidase inhibitors shifted the concentration-response curves of SP, [Nle10]NKA(4–10) and [MePhe7]NKB significantly leftwards and the concentration-response curve of NKB was shifted significantly rightwards. However, the EC50 values were significantly different only for [Nle10]NKA(4–10) and NKB.In the presence of the peptidase inhibitors, the EC50 values of the selective agonists, [MePhe7]NKB (0.6 nM) and [Nle10]NKA(4–10) (66 nM) indicated the presence of both tachykinin NK3 and NK2 receptors. [MePhe7]NKB produced less than 50% of the maximal response obtained with the other agonists. Since [Sar9,Met(O2)11]SP produced a small response in the nanomolar concentration range in about 30% of the preparations tested, it is possible that some NK1 receptors were also present.Assuming competitive antagonism, the NK2-selective antagonist SR 48,968 (30 nM) gave apparent pKB values of 8.13 and 8.65 for [Nle10]NKA(4–10) in the absence and presence of peptidase inhibitors, respectively, supporting the presence of NK2 receptors.The NK3-selective antagonist SR 142,801 (0.1 μM), suppressed responses to low (0.1–10 nM) concentrations of [MePhe7]NKB. These contractile responses to [MePhe7]NKB were also abolished by atropine (0.6 μM) suggesting that this response was mediated via cholinergic nerves.It is concluded that the guinea-pig oesophagus is a complex system which has both NK2 and NK3 receptors and possibly some NK1 receptors as well.
展开▼
