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This Article Full Text Full Text (PDF) All Versions of this Article: 75/3/334    most recent biolreprod.106.051508v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pennefather, J. N. Articles by Candenas, M. L. Search for Related Content PubMed PubMed Citation Articles by Pennefather, J. N. Articles by Candenas, M. L. Agricola Articles by Pennefather, J. N. Articles by Candenas, M. L.

Regulation of the Stimulant Actions of Neurokinin A and Human Hemokinin-1 on the Human Uterus: A Comparison with Histamine¹

Department of Anaesthesia,⁴ Royal Women's Hospital, Carlton, Victoria 3053, Australia Department of Pharmaceutical Biology,⁵ Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia Instituto de Investigaciones Químicas,⁶ 41092 Sevilla, Spain School of Life Sciences,⁷ Kingston University London, Kingston-upon-Thames, Surrey KT1 1LQ, United Kingdom Department of Pharmacology,⁸ Monash University, Clayton, Victoria 3800, Australia Royal Children's Hospital and Mercy Hospital for Women,⁹ Parkville, Victoria 3052, Australia University of Melbourne Department of Obstetrics and Gynaecology,¹⁰ Royal Women's Hospital, Carlton, Victoria 3053, Australia

ABSTRACT

Regulation of the contractile effects of tachykinins and histamine on the human uterus was investigated with biopsy sections of the outer myometrial layer. The effects of neurokinin A (NKA) and human hemokinin-1 (hHK-1) in tissues from pregnant but not from nonpregnant women were enhanced by the inhibition of neprilysin. The effects of NKA 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 HK-1 acted as a 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 nonpregnant women. Mepyramine-sensitive maximal responses to histamine were similarly enhanced. The absolute maximum responses to NKA and its stable NK₂ receptor-selective analogue, [Lys⁵MeLeu⁹Nle¹⁰]NKA(4–10), were increased in pregnancy, but their efficacies relative to potassium responses were decreased. Tachykinin potencies were lower in tissues from pregnant women than in those from nonpregnant women. These data 1) show for the first time that hHK-1 is a uterine stimulant in the human, 2) confirm that the NK₂ receptor is predominant in mediating tachykinin actions on the human myometrium, and 3) 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 nonpregnant women undergoing hysterectomy are consistent with their possible role in menstrual and menopausal disorders.

eledoisin, endokinin, female reproductive tract, hemokinin, histamine, human myometrium, [Lys⁵MeLeu⁹Nle¹⁰]NKA(4–10), neprilysin, neurokinin A, neuropeptides, NK₁ and NK₂ receptors, pregnancy, signal transduction, tachykinins, uterine contractions, uterus

¹ Supported by grants from the National Health and Medical Research Council of Australia to J.N.P. and the Ministerio de Educación y Ciencia (BFU2005-04495-C02-01/BFI), Spain. J.N.P. and E.P. contributed equally to this work.

² Correspondence. FAX: 61 39 833 3754; jocelyn.oneil{at}vcp.monash.edu.au

³ Correspondence: M. Luz Candenas, Centro de Investigaciones Científicas Isla de La Cartuja, Instituto de Investigacones Químicas, Avda. Americo Vespucio 49, 41092 Sevilla, Spain. FAX: 34 95 446 0565; e-mail: luzcandenas{at}iiq.csic.es

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