Tachykinin receptors in the guinea‐pig isolated oesophagus: a complex system

Abstract

1 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, [Sar 9 ,Met (O 2 ) 11 ]SP, [Nle 10 ]NKA(4 ± 10) and [MePhe 7 ]NKB, selective for NK 1 , NK 2 and NK 3 , receptors, respectively. Experiments were performed both in the absence and presence of a cocktail of peptidase inhibitors, captopril (1 mM), thiorphan (1 mM) and amastatin (20 mM), in order to determine whether membrane bound proteases are important in the metabolism of tachykinins in this preparation. 2 All agonists produced concentration-dependent contractile eects. The presence of the peptidase inhibitors shifted the concentration-response curves of SP, [Nle 10 ]NKA(4 ± 10) and [MePhe 7 ]NKB signi®cantly leftwards and the concentration-response curve of NKB was shifted signi®cantly rightwards. However, the EC 50 values were signi®cantly dierent only for [Nle 10 ]NKA(4 ± 10) and NKB. ]SP produced a small response in the nanomolar concentration range in about 30% of the preparations tested, it is possible that some NK 1 receptors were also present. 4 Assuming competitive antagonism, the NK 2 -selective antagonist SR 48,968 (30 nM) gave apparent pK B values of 8.13 and 8.65 for [Nle 10 ]NKA(4 ± 10) in the absence and presence of peptidase inhibitors, respectively, supporting the presence of NK 2 receptors. 5 The NK 3 -selective antagonist SR 142,801 (0.1 mM), suppressed responses to low (0.1 ± 10 nM) concentrations of [MePhe 7 ]NKB. These contractile responses to [MePhe 7 ]NKB were also abolished by atropine (0.6 mM) suggesting that this response was mediated via cholinergic nerves. 6 It is concluded that the guinea-pig oesophagus is a complex system which has both NK 2 and NK 3 receptors and possibly some NK 1 receptors as well.

Tachykinin‐induced contraction of the guinea‐pig isolated oesophageal mucosa is mediated by NK2 receptors

“…Kerr et al (1997) found a pD 2 value of 7.2 for [Nle 10 ]-NKA(4 ± 10) in the guinea-pig whole oesophagus. It is suggested that this lower value, compared to that of 8.2 obtained in the current study may have resulted from the 10 fold lower concentrations of the peptidase inhibitors, thiorphan and captopril, used in that study.…”

“…The e ect of NKA was tested in the absence of peptidase inhibitors, because it has been shown that these enzyme inhibitors do not signi®cantly a ect the response to this peptide in the guinea-pig whole oesophagus preparation (Kerr et al, 1997). The e ects of senktide, which is protected from peptidases by the succinyl moiety, were also tested in the absence of peptidase inhibitors.…”

“…In the isolated muscularis mucosae, a single maximum concentration of [Sar 9 ,Met(O 2 ) 11 ]-SP (10 nM, n=3) and a single maximum concentration of [MePhe 7 ]-NKB (10 nM, n=4) gave no response. The concentration of 10 nM was chosen for the maximal concentration as the work of Kerr et al (1997) showed that the maximal response to both of these agonists at selective concentrations in the whole oesophagus occurred at 10 nM. A single near-maximal concentration of senktide (3 nM, n=3), based on the concentration-response curve obtained in the whole oesophagus gave no response in the isolated muscularis mucosae.…”

“…Although contractile responses did occur in response to [MePhe 7 ]-NKB at concentrations greater than 3 mM, it has been found that [MePhe 7 ]-NKB stimulates NK 2 receptors in micromolar concentrations (Maggi, 1995;Kerr et al, 1997). While the NK 3 receptor-selective agonist, senktide, elicited contractile responses over the nanomolar concentration range in the whole oesophageal preparation, these responses were absent in the isolated mucosal preparation.…”

“…NKA, NPK and NPg are relatively more selective for NK 2 receptors. Tachykinin receptors in the body of the guinea-pig oesophagus have been characterized as predominantly NK 2 and NK 3 receptors (Kerr et al, 1997). Atropine was shown to abolish the contractile responses to the NK 3 receptor selective agonist, [MePhe 7 ]-NKB, suggesting that the NK 3 receptors are present on cholinergic neurones, possibly in the myenteric plexus.…”