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Hemokinin-1 acts at the tachykinin NK1 receptor in the oestrogen-treated mouse uterus

M. Gozali1, E. Patak1, J.N. Pennefather2, 1Dept of Anaesthesia, Royal Women's Hospital, Carlton, VIC, Australia, 2Dept of Pharmaceutical Biology and Pharmacology, Monash University, Parkville, VIC, Australia

We have previously established that the mammalian tachykinins (TKs) substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) induce uterine contractions in the oestrogen-primed mouse uterus by acting at an NK1 receptor1. Recently a new TK termed hemokinin-1 (HK-1) has been discovered2 which exhibits remarkable selectivity for the NK1 receptor3. In the periphery HK-1 appears to be expressed in non-neuronal cells in contrast to the largely neuronal expression of the other mammalian TKs. Our aim was to investigate the effects of HK-1 and the SP analogue, septide, in mediating uterine contractility in the oestrogen-primed mouse uterus. Myometrium was obtained from oestrogen-treated (20 μg/kg s.c.) BalbC mice which had been humanely killed. Preparations were set up in organ baths to record force produced by the longitudinal muscle layer. Discrete log concentration-response curves (LCRCs) were constructed to SP, NKA, HK-1 and septide (0.1nM - 1μM) in the absence (n=9-10) and presence (n=5) of the NK1 receptor-selective antagonist SR 140333 (10nM). In the presence of phosphoramidon (10μM) and captopril (10μM) all four agonists produced concentration-related responses with the LCRC to SP lying to the left of those for the other agonists. SP and HK-1 produced significantly lower maximum responses than NKA and septide (one-way ANOVA, P<0.05). The NK1 receptor antagonist SR 140333 (10nM) reduced responses to all four agonists. These results are consistent with a role for TKs acting at the NK1 receptor in regulating uterine function in the oestrogen-primed mouse. However we propose that HK-1 and SP may act differently at the NK1 receptor than do NKA and septide.

1. Patak E et al (2002) Brit. J. Pharmacol., 137, 1247-1254.

2. Camarda V et al (2002) Life Sci., 71, 363-370.

3. Zhang Y et al (2000) Nat. Immunol., 1, 392-397.