Functional characterization of tachykinin NK 1 receptors in the mouse uterus

Abstract

1 Contractility studies were undertaken to determine the nature of the receptors mediating responses to tachykinins in uteri of oestrogen-treated mice. 2 In the presence of thiorphan, (3 μM), captopril (10 μM) and bestatin (10 μM), substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) produced concentration-related contractions of uterine preparations. The order of potency was SP ≥NKA>NKB. 3 Neither atropine (0.1 μM) nor 1-NOLA (100 μM), nor indomethacin (10 μM) alone or in combination with either ranitidine (10 μM) or mepyramine (10 μM), affected responses to SP. These findings indicate that SP actions are not mediated or modulated through the release of acetylcholine, nitric oxide, prostanoids or histamine. 4 In the presence of peptidase inhibitors, the tachykinin NK 1 receptor-selective agonist [Sar 9Met(O 2) 11]SP, produced a concentration-dependent contractile effect. The tachykinin NK 2 and NK 3 receptor-selective agonists [Lys 5MeLeu 9Nle 10]NKA(4-10) and [MePhe 7]NKB were relatively inactive. The potencies of SP analogues in which Glu replaced Gin 5 and/or Gin 6 were similar to that of SP. 5 The tachykinin NK 1 receptor-selective antagonist, SR140333 (10 nM), alone or combined with the tachykinin NK 2 receptor-selective antagonist, SR48968 (10 nM), shifted log concentration curves to SP, NKA and NKB to the right. SR140333 (10 nM) reduced the effect of [Sar 9Met(O 2) 11]SP. SR48968 did not affect responses to SP or [Sar 9Met(O 2) 11]SP, but reduced the effect of higher concentrations of NKA and shifted the log concentration-response curve to NKB to the right. The tachykinin NK 3 receptor-selective antagonist, SR 142801 (0.3 μM), had little effect on responses to SP and NKB. 6 We conclude that the tachykinin NK 1 receptor mediates contractile effects of SP, NKA and NKB and [Sar 9Met(O 2) 11]SP in myometrium from the oestrogen-primed mouse. The tachykinin NK 2 receptor may also participate in the responses to NKA and NKB.