APPS November 2002 Meeting Abstract 2420


UTEROTONIC EFFECTS OF ELEDOISIN ON PREGNANT HUMAN UTERUS ARE MEDIATED BY NK2 RECEPTORS

Eva Patak1, Sebastian Ziccone1, Jocelyn N. Pennefather1, Margot E. Story2, Alison Lilley1, 1 Dept of Anaesthetics, RWH, Carlton, Vic., 2 Dept of Pharmacology, Monash University, Clayton, Vic.

The tachykinins (TKs) are potent uterotonic agents in the human.1 Recently 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 NK3 receptor, the uterotonic effects of the mammalian TK peptides on the human uterus appear to be mediated primarily by NK2 receptors.1 We have now employed the non-mammalian TK undecapeptide, eledoisin, which is believed to act at NKB-preferring NK3 receptors 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 ÁM), captopril (10ÁM) and bestatin (10ÁM), and in the combined presence of these inhibitors plus the NK1 receptor antagonist, SR 140333 (1nM) or the NK2 receptor 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 NK1 receptor 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 NK2 receptor, and are consistent with this being the major TK receptor subtype regulating myometrial contractility.

(1) Patak EN, Ziccone S, Story ME, Fleming AJ, Lilley A, Pennefather JN. Human Reproduction. 2000;6:549-554.

(2) Pinto, FM, Candenas M, Ventura S, Ziccone, S, Patak E, Lilley A, Pennefather, JN. Proceedings of International Federations of Placenta Associations. 2002,8th meeting.

(3) Page NM, Woods RJ, Gardiner SM, Lomthaisong K, Gladwell RT, Butlin DJ, Manyonda IT, Lowry PJ. Nature. 2000;405:(6788) 797-800.

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