APPS November 2002 Meeting Abstract 2420

The tachykinins (TKs) are potent uterotonic agents in the human.¹Recently the preproTK-B gene, which encodes neurokinin (NK) B, was reported to be expressed in human uterus and placenta.^{2, 3} Although NKB typically exhibits preference for the NK₃receptor, the uterotonic effects of the mammalian TK peptides on the human uterus appear to be mediated primarily by NK₂receptors.¹We have now employed the non-mammalian TK undecapeptide, eledoisin, which is believed to act at NKB-preferring NK₃receptors in the rodent central nervous system, as a tool in investigation of the receptor mediating TK-induced contractions of human pregnant uterus. Myometrium was obtained from six pregnant women (31-38 yrs, 37-39 weeks gestation), who gave written informed consent. Log concentration-response curves to eledoisin were constructed in the absence and presence of the peptidase inhibitors thiorphan (3 然), captopril (10然) and bestatin (10然), and in the combined presence of these inhibitors plus the NK₁ receptor antagonist, SR 140333 (1nM) or the NK₂receptor antagonist SR48968 (1nM). The peptidase inhibitors enhanced eledoisin-induced uterine contractions. Its potency was less than that of NKA but greater than that of NKB and substance P, indicating activation of NK₂ receptors. The NK₁receptor antagonist, SR 140333 (1nM), did not antagonise its actions but the NK₂ receptor antagonist SR48968 (1nM) produced an 8.5-fold rightward shift in the log concentration-response curve to this peptide, yielding a pA₂ value of ≈10. These data indicate that in pregnant human uterus eledoisin activates a receptor with properties similar to the prototypical NK₂receptor, and are consistent with this being the major TK receptor subtype regulating myometrial contractility.