Biol Reprod 2006 May 17; (Read article online)

Pennefather JN, Patak E, Ziccone S, Lilley A, Pinto FM, Page NM, Story ME, Grover S, Candenas ML

Regulation of the contractile effects of tachykinins and histamine on human uterus was investigated using biopsy sections of the outer myometrial layer. The effects of neurokinin A and human hemokinin-1 in tissues from pregnant but not from non-pregnant women were enhanced by inhibition of neprilysin. The effects of neurokinin A and eledoisin were blocked by the NK2 receptor antagonist, SR 48968 but not by the NK1 receptor antagonist SR 140333 in tissues from both groups of women. Human hemokinin-1 acted as partial agonist blocked by SR 48968 and to a lesser extent by SR 140333; endokinin D was inactive. In tissues from pregnant women, responses to high potassium-containing Krebs solution were 2-3 fold higher than those from non-pregnant women. Mepyramine-sensitive maximal responses to histamine were similarly enhanced. The absolute maximum responses to neurokinin A and its stable NK2 receptor selective analogue, [Lys(5)MeLeu(9)Nle(10)]NKA(4-10) were increased in pregnancy, but their efficacies relative to potassium responses were decreased. Tachykinin potencies were lower in tissues from pregnant compared to non-pregnant women. These data (a) show for the first time that human hemokinin-1 is a uterine stimulant in the human, (b) confirm that the NK2 receptor is predominant in mediating tachykinin actions on human myometrium, and (c) indicate that mammalian tachykinin effects are tightly regulated during pregnancy in a manner that would negate an inappropriate uterotonic effect. The potencies of these peptides in tissues from non-pregnant women undergoing hysterectomy are consistent with a possible role in menstrual and menopausal disorders.