Tachykinins and tachykinin receptors in human uterus

1 Studies were undertaken to determine the nature of the receptors mediating contractile effects of tachykinins in the uteri of nonpregnant women, and to analyse the expression of preprotachykinins ( PPT), tachykinin receptors and the cell-surface peptidase, neprilysin (NEP), in the myometrium from pregnant and nonpregnant women. 2 The neurokinin B (NKB) precursor PPT-B was expressed in higher levels in the myometrium from nonpregnant than from pregnant women. Faint expression of PPT-A mRNA was detectable in the myometrium from nonpregnant but not pregnant women. PPT-C, the gene encoding the novel tachykinin peptide hemokinin-1 (HK-1), was present in trace amounts in the uteri from both pregnant and nonpregnant women. 3 Tachykinin NK2 receptors were more strongly expressed in tissues from nonpregnant than from pregnant women. NK1 receptor mRNA was present in low levels in tissues from both pregnant and nonpregnant women. A low abundance transcript corresponding to the NK3 receptor was present only in tissues from nonpregnant women. 4 The mRNA expression of the tachykinin-degrading enzyme NEP was lower in tissues from nonpregnant than from pregnant women. 5 Substance P (SP), neurokinin A (NKA) and NKB, in the presence of the peptidase inhibitors thiorphan, captopril and bestatin, produced contractions of myometrium from nonpregnant women. The order of potency was NKA>>SPgreater than or equal toNKB. The potency of NKA was unchanged in the absence of peptidase inhibitors. 6 The tachykinin NK2 receptor-selective agonist [ Lys(5)MeLeu(9)Nle(10)] NKA( 4 - 10) was approximately equipotent with NKA, but the tachykinin NK1 and NK3 receptor-selective agonists [Sar(9)Met(O-2)(11)] SP and[ MePhe 7] NKB were ineffective in the myometrium from nonpregnant women. 7 The uterotonic effects of [Lys(5) MeLeu(9) Nle(10)] NKA(4 - 10) were antagonizedby the tachykinin NK2 receptor-selective antagonist SR48968. Neither atropine, nor phentolamine nor tetrodotoxin affected responses to [Lys(5)MeLeu(9)Nle(10)] NKA( 4 - 10). 8 These data are consistent with a role of tachykinins in the regulation of human uterine function, and reinforce the importance of NK2 receptors in the regulation of myometrial contraction.