Molecular Human Reproduction, Vol. 6, No. 6, 549-554,
June 2000
© 2000 European Society of Human Reproduction and Embryology
Pregnancy |
Activation of neurokinin NK2 receptors by tachykinin peptides causes contraction of uterus in pregnant women near term
1 Department of Pharmacology, Monash University, Clayton, Victoria, 3168 and 2 Department of Anaesthetics, Royal Women's Hospital, Carlton, Victoria, 3053, Australia
Abstract
The aim of this study was firstly to elucidate whether the mammalian tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)-regulated contractility of myometrium obtained from near-term pregnant women, and secondly to investigate the receptor subtype(s) responsible. In the presence of peptidase inhibitors, i.e. thiorphan (3 µmol/l; endopeptidase 24.11 inhibitor), captopril (10 µmol/l; angiotensin converting enzyme inhibitor) and bestatin (10 µmol/l; aminopeptidase inhibitor); all three mammalian tachykinins elicited concentration-related contractions of isolated myometrial preparations. The rank order of agonist potency of the mammalian tachykinins in the presence of the peptidase inhibitors was NKA > SP = NKB, indicating that the contractile effects were mediated by activation of an NK2 receptor. The NK2 receptor-selective agonist, [Lys5, MeLeu9, Nle10]NKA(4–10), produced concentration-related contractile responses, while the respective NK1 and NK3 receptor-selective agonists, [Sar9,Met(O2)11]SP and [N-MePhe7]NKB, had no effect either in the absence or presence of the peptidase inhibitors. The NK2 receptor-selective antagonist, SR48968, produced concentration-related rightward shift in the log concentration curve to [Lys5, MeLeu9, Nle10]NKA(4–10). This study shows that tachykinins elicit contractile effects on human myometrium obtained from pregnant women near term, and that these effects are mediated by an NK2 receptor. An excitatory effect of the tachykinins on these preparations could indicate a physiological role for these peptides in enhancing contractility of the uterus in women at term.
human uterus/NK2 receptors/peptidase inhibitors/pregnancy/tachykinins
Introduction
Tachykinins are a family of regulatory peptides that share a common amidated terminal sequence Phe-X-Gly-Leu-Met-NH2. They are widely distributed throughout the mammalian body where they are known to act as neurotransmitters in both the central and peripheral nervous systems. In the periphery they are mostly found in capsaicin-sensitive sensory nerves which are now accepted not only to relay information to the central nervous system, but also to release peptide neurotransmitters from their efferent terminals; this release can bring about effects in surrounding tissues (Lembeck and Holzer, 1979
; Maggi and Meli, 1988). The mammalian tachykinins include substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) which preferentially act at three G-protein-linked receptors termed NK1, NK2 and NK3 respectively, though at high concentrations they can act at all three receptors (Henry, 1987; Burcher et al., 1991; Maggi et al., 1993; Mussap et al., 1993). Activation of the tachykinin receptors can lead to a wide variety of biological actions such as smooth muscle contraction, vasodilation, secretion, neurogenic inflammation and activation of the immune system (for review, see Otsuka and Yoshioka, 1993).
Substance P-immunoreactive (IR) and NKA-IR nerve fibres have been detected in the uteri of various species including the mouse, rat, guinea-pig and human (Alm et al., 1978; Huang et al., 1984; Traurig et al., 1984; Papka et al., 1985; Samuelson et al., 1985; Heinrich et al., 1986; Alm and Lundberg, 1988; Reinecke et al., 1989; Traurig et al., 1991). The association of these nerves with smooth muscle cells suggests the possibility that tachykinins released from their peripheral terminals may influence myometrial contractility.
Enhancement of uterine smooth muscle activity by tachykinins has previously been shown in the rat uterus. These effects have been mediated predominantly through NK2 and possibly NK1 (Fisher et al., 1993; Pennefather et al., 1993b; Fisher and Pennefather, 1997; Magraner et al., 1998) and NK3 receptors (Barr et al., 1991). However, a role of tachykinins in regulating myometrial contractility in humans remains unclear. While both SP and the non-mammalian tachykinin eledoisin have been reported to elicit contractions of uterine preparations from non-pregnant women (Molina and Zappia, 1976; Ottesen et al., 1983), the respective NK1, NK2 and NK3 neurokinin receptor-selective agonists, substance P methyl ester (SPOMe), [ß-Ala8]NKA(4–10) and senktide, have been reported to have no effect on uterine preparations from pregnant women (Barr et al., 1991), although in the report no data were given.
The aims of the present study were two-fold. The first aim was to establish whether the mammalian tachykinins SP, NKA and NKB elicited contractions of near-term gravid human myometrium preparations. If these tachykinins did exert uterotonic effects on such preparations, the second aim was to determine the tachykinin receptor subtype(s) responsible using the neurokinin receptor selective agonists [Sar9,Met(O2)11]SP, [Lys5,MeLeu9,Nle10]NKA(4–10) and [N-MePhe7]NKB which are selective for the NK1, NK2 and NK3 receptors respectively (Drapeau et al., 1987; Regoli et al., 1987; Chassaing et al., 1991) together with an appropriate antagonist study.
Materials and methods
Ethical approval for this study was obtained from the Royal Women's Hospital Human Ethics Committee. Human myometrium was obtained from 27 women (23–41 years old), undergoing elective lower uterine segment Caesarean section at 33 weeks (n = 1) or 36–40 weeks (n = 26) following informed written patient consent. All women received ranitidine as a preanaesthetic medication. This was followed by either spinal or epidural anaesthesia induced by a combination of bupivicaine and fentanyl or marcain and fentanyl. Two women underwent general anaesthesia induced by thiopentone. Specimens were excised from the upper edge of the incision.
Isometric tension recording
The methods used to examine myometrial contractility have been described previously (Story et al., 1988; Pennefather et al., 1993a). Up to four samples of outer myometrium were obtained from each specimen. Preparations (2x2x10 mm) were mounted in 5 ml organ baths containing a modified Krebs–Henseleit solution of the following composition (mmol/l): NaCl, 118; KCl, 4.7; MgSO4, 1.1; KH2PO4, 1.18; NaHCO3, 25; glucose, 11.66; CaCl2, 1.9) maintained at 37°C and continuously bubbled with carbogen (5% CO2 in O2). Preparations were set up under an initial resting force of 100–150 mN. Isometric force produced by the longitudinally-arranged smooth muscle was measured using a Grass FT03 force transducer connected to a MacLab data acquisition system. To prevent peptides from adhering to the glass, organ baths were coated with silicon (Coatasil, dimethyldichlorosilane; Ajax Chemicals, Auburn, N.S.W., Australia).
After 30 min equilibration the peptidase inhibitors captopril (10 µmol/l, angiotensin converting enzyme inhibitor), thiorphan (3 µmol/l, endopeptidase 24.11 inhibitor) and bestatin (10 µmol/l, aminopeptidase inhibitor) were added to the baths and the tissues allowed to equilibrate for a further 30 min. Discrete log concentration-response curves (0.1 nmol/l–3 µmol/l, increasing in 0.5 log increments) were then constructed for SP, NKA and NKB. A single concentration-response curve to one peptide was constructed on any one tissue. Each agonist concentration remained in contact with a tissue for 5 min, the tissue was then washed and 15 min allowed to elapse before the next agonist addition. Inhibitors were replaced each time the tissue was washed. Peptidase inhibitors were not included when the stable NK2-receptor selective agonist [Lys5, MeLeu9,Nle10]NKA(4–10) was tested and inhibitors were present only for three of six experiments using [Sar9,Met(O2)11]SP and [N-MePhe7]NKB. A solution in which 40 mmol/l KCl was present (composition in mmol/l: NaCl, 82.7; KCl, 40.0; CaCl2.2H2O, 2.5; MgSO4.7H2O, 0.5; KH2PO4, 1.2; NaHCO3, 25.0; glucose, 11.7) was applied to the tissues at the conclusion of construction of the log concentration curves to the peptides.
An initial series of experiments was conducted in which discrete concentration-response curves were established for SP and NKA in the absence and presence of the endopeptidase 24.11 inhibitor, thiorphan (10 µmol/l). After 30 min equilibration thiorphan was added to half the tissues and a further 30 min equilibration was allowed, thiorphan was then replaced each time the tissues were washed. A single concentration–response curve to either SP or NKA was constructed on any one tissue. Agonists were added in increasing log unit increments (0.1 nmol/l–1 µmol/l) and then a half log increment (3 µmol/l).
An additional series of experiments was conducted in which discrete concentration-response curves were constructed to [Lys5, MeLeu9, Nle10]NKA(4–10) in the absence and presence of increasing concentrations of the NK2 receptor-selective antagonist SR48968 (Emonds-Alt et al., 1992) (1, 3 and 10 nmol/l). Tissues were incubated with the antagonist for 60 min prior to construction of log concentration–response curves. Antagonists were replaced each time the tissue was washed.
Data analysis
Data analysis was undertaken by measuring the area under the force-time curve (AUC, in g.s) over the 5 min period the agonist was in contact with the tissue. A measurement of AUC for a 5 min period of spontaneous activity was then made from the 15 min period prior to the agonist addition and subtracted from AUC. In this way the possibility that spontaneous contractions could be misconstrued as an agonist-induced response was avoided. Responses were expressed as a percentage of the corresponding response to the KCl containing solution and presented as mean ± SEM.
Reagents
The compounds used were: bestatin (Sigma, St Louis, MO, USA); captopril (D-3-mercapto-2-methyl propanoyl-L-proline) (Bristol-Myers Squibb, Noble Park, Vic., Australia); DL-thiorphan (DL -3-mercapto-2-benzylpropanoylglycine, Sigma); [Lys5, MeLeu9, Nle10] NKA(4–10) (a gift from S.Lavielle, Lab De Chimie Organique Biologique, Paris, France or purchased from Research Biochemicals International; Natick, MA, USA); NKA (Auspep, Parkville, Victoria, Australia); NKB (Auspep); [N-MePhe7]NKB (Auspep, Parkville, Victoria, Australia); [Sar9,Met(O2)11]SP (Auspep); SR48968 (((S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide), a gift from Sanofi Recherche, Montpellier, France; and SP (Auspep). All other reagents used were of analytical grade. Captopril and thiorphan were dissolved in distilled water. [N-MePhe7]NKB and NKB were dissolved in ammonia (0.01 mol/l) and diluted in distilled water. SR48968 was dissolved in absolute ethanol at 1 mmol/l and diluted in distilled water. All remaining compounds were dissolved in hydrochloric acid (0.01 mol/l) and diluted in distilled water. Bestatin and SR48968 stock solutions (1 mmol/l) were stored at 4°C, while standard solutions (1 mmol/l) of other peptides were stored at –70°C.
Statistical analysis
All data are expressed as the mean ± SEM for n experimental observations. Mean log concentration-response curves were constructed by pooling data from individual log concentration-response curves. When mean log concentration-response curves for an agonist reached a clear maximum, negative log EC50 values were determined using non-linear regression analysis in the GraphPad Prism (Version 2.0) program. When log concentration-response curves did not reach a plateau these estimates could not be made but agonist potency ratios were determined. When there was significant regression of response with agonist concentration, least squares regression lines were fitted to the linear portions (typically 15–85% of the maximum response to the reference agonist, NKA or [Lys5, MeLeu9, Nle10]NKA(4–10)) of the log concentration-response curves and analysis of variance undertaken to determine deviation from parallelism and coincidence as outlined in Geigy Scientific Tables (Lentner, 1982). When lines so obtained were parallel to those for NKA, estimates of potency ratio, together with 95% confidence limits, were determined for each agonist. A significant difference in apparent potency of the agonist was indicated when the 95% confidence limits of the potency ratio did not include one. Two-way repeated measures analyses of variance were conducted to compare log concentration-response curves; Dunnett's or the Student Newman–Keuls test were used for multiple comparisons, depending upon the presence or otherwise of a control log concentration curve. These procedures were undertaken using Sigma Stat (Version 1.0; Jandel, San Rafael, CA, USA). Throughout the paper `n' refers to the number of women from whom specimens were obtained; P < 0.05 was considered to be statistically significant.
Results
All tissues used in this study contracted in response to the high potassium-containing solution indicating their viability. SP, NKA, NKB and [Lys5, MeLeu9, Nle10]NKA(4–10) were able to induce contractions of the isolated myometrium. [Sar9,Met(O2)11]SP and [N-MePhe7]NKB were without effect (Figure 1). In an initial subset of experiments SP was inactive in the absence of peptidase inhibitors (n = 5) Its effects were, however, enhanced in the presence of thiorphan (10 µmol/l; n = 6). NKA produced concentration related contractions of the myometrial preparations (0.1, 1 and 3 µmol/l; n = 3). Responses to NKA (0.01, 0.1, 1 and 3 µmol/l) were also enhanced in the presence of thiorphan (10 µmol/l; n = 5).
|
and 
respectively.Results of a two-way repeated measures analysis of variance (ANOVA) indicated a significant difference in agonist potencies (P < 0.05). In the presence of the peptidase inhibitors NKA was the most potent mammalian tachykinin with a negative log EC50 value of 7.6 ± 0.13 (n = 6). It was 57.3 and 66.3-fold more potent than SP [95% confidence limits (CI) = 25.7, 179.2; degrees of freedom (df) = 35] and NKB (95% CI = 25.7, 297; df = 35) respectively (Figure 2
).
|
), neurokinin A (NKA; 
) and neurokinin B (NKB; 
) in the presence of the peptidase inhibitors captopril (10 µmol/l), thiorphan (3 µmol/l) and bestatin (10 µmol/l) and to the stable NK2 receptor-selective analogue [Lys5, MeLeu9,Nle10]NKA(4–10) (
) on human isolated gravid myometrial preparations. Each point is the mean ± SEM, n = 6.Of the neurokinin receptor-selective agonists, only the NK2 receptor-selective agonist [Lys5, MeLeu9, Nle10]NKA(4–10) induced contractions of the isolated myometrium (Figure 2
). The negative log EC50 value was 7.5 ± 0.08 (n = 6). In contrast, the NK1 and NK3 receptor-selective agonists [Sar9,Met(O2)11]SP and [N-MePhe7]NKB elicited no response in either the absence or presence of enzyme inhibitors (Figure 3).
|
The NK2 receptor-selective antagonist SR48968 (Emonds-Alt et al., 1992
) at 1, 3 and 10 nmol/l produced concentration-related rightward shifts in the log concentration curve to [Lys5, MeLeu9, Nle10]NKA(4–10) (Figure 4; P < 0.05, two-way repeated measures ANOVA; Dunnett's test). The maximum response to [Lys5, MeLeu9, Nle10]NKA(4–10) was depressed. Two-way repeated measures ANOVA indicated that all log concentration-response curves obtained in the presence of the antagonist were significantly different from the control curve.
|
), 3 nmol/l (
) and 10 nmol/l (
) SR48968 on human isolated gravid myometrial preparations. Each point is the mean ± SEM, n = 6–9.Discussion
This study has shown for the first time that the mammalian tachykinins, SP, NKA and NKB elicit contractions of human myometrium obtained from pregnant women near term. This finding is in contrast to a previous report that tachykinins were without effect on myometrial tissue obtained from pregnant women (Barr et al., 1991). A possible explanation for this difference of results could be attributed to the use of peptidase inhibitors in the present study.
It has been extensively documented that tachykinins are susceptible to hydrolysis by numerous peptidases. Endopeptidase 24.11 (EC 24.11) is the most effective of the peptidases hydrolysing not only the mammalian tachykinins (Matsas et al., 1983, 1985) but also several of the receptor-selective analogues (Medeiros and Turner, 1995). SP is also a substrate for angiotensin converting enzyme (ACE) (Yokosawa et al., 1983; Cascieri et al., 1984; Skidgel et al., 1984), while both NKA and NKB are substrates for bestatin-sensitive aminopeptidases (Hooper and Turner, 1985; Nau et al., 1986). All three peptidases can be found in the mammalian uterus (Cushman and Cheung, 1971; Casey et al., 1991; Imai et al., 1992) and during pregnancy additional sources of EC 24.11 and bestatin-sensitive aminopeptidases include the amniotic fluid and placenta (Spillantini et al., 1990; Mizutani et al., 1993). In the present study experiments involving the mammalian tachykinins were conducted in the presence of a `peptidase inhibitor cocktail', comprising thiorphan, captopril and bestatin. This was based on the findings of Pennefather et al., (1993b) who reported that the actions of SP, NKA and NKB in the rat uterus were enhanced in the combined presence of EC 24.11, ACE and bestatin-sensitive aminopeptidase inhibitors. Thus, the absence of peptidase inhibitors in the study by Barr et al., (1991) could in part explain their negative findings.
As stated above it was found that in the presence of peptidase inhibitors, SP, NKA and NKB all produced concentration-related contractions of the human isolated myometrial preparations. The relative order of potency was NKA > SP = NKB indicating that as in the rat uterus (Fisher and Pennefather, 1997), responses were mediated through activation of NK2 receptors. Further support for this conclusion came from the use of neurokinin receptor-selective agonists, with only the NK2 receptor-selective agonist [Lys5, MeLeu9,Nle10]NKA(4–10) producing contractile responses, whereas [Sar9,Met(O2)11]SP and [N-MePhe7]NKB had no effect.
Antagonist studies confirmed that tachykinin activity was mediated through an NK2 receptor. The non-peptide NK2 receptor-selective antagonist SR48968 (Emonds-Alt et al., 1992) (1–10 nmol/l) produced non-competitive antagonism of the effects of [Lys5, MeLeu9, Nle10]NKA(4–10) in the gravid human uterus. The significant rightward shifts observed were, however, consistent with the reported high potency of this antagonist at NK2 receptors (Emonds-Alt et al., 1992). Concentration-dependent depression of maximum response to a tachykinin agonist by this antagonist has previously been reported to occur in preparations of human bronchus (Qian et al., 1994) and rat oesophageal tunica muscularis mucosae (Croci et al., 1995). It is interesting to note that although Croci et al. (1995) had observed this non-competitive antagonism in the rat oesophagus it was not seen in the rat duodenum, prompting speculation that this may be due to differing subtypes of tachykinin NK2 receptors in various tissues.
Peptidase inhibitors were not included in the bathing medium when [Lys5, MeLeu9,Nle10]NKA(4–10) was tested since it has been shown to be metabolically stable (Fisher et al., 1993; Fisher and Pennefather, 1997). In contrast [ß-Ala8]NKA(4–10), the NK2 receptor-selective agonist used by Barr et al. (1991), is a substrate for EC 24.11 (Medeiros and Turner, 1995). This may explain why Barr et al. (1991) did not observe enhancement of uterine contractions in the presence of this peptide. The NK1-receptor-selective agonist, [Sar9,Met(O2)11]SP, has also been reported as being metabolically stable (Brokaw and White, 1994). In the current study, peptidase inhibitors did not potentiate the response of myometrial preparations to this agonist nor to that of the NK3 receptor-selective agonist [N-MePhe7]NKB. These observations indicate that the lack of activity of the latter agonists is not due to their inactivation but rather to their lack of affinity for NK2 receptors.
An excitatory effect of tachykinins on the near term gravid uterus could indicate a role for these peptides in the initiation of parturition, where the release of tachykinins could contribute to the cascade of events leading to labour. In mammalian species, including the human, it is well known that the uterine noradrenergic innervation degenerates as pregnancy progresses (Sjoberg, 1968; Alm et al., 1979; Thorbert et al., 1979; Owman, 1981; Wikland et al., 1984). However, it has been observed that no comparable degeneration of the afferent innervation occurs in the rat uterus during pregnancy (Traurig et al., 1984). Indeed, Amira et al., (1995) reported hypertrophy of the afferent innervation in the rat uterus during pregnancy. The presence of tachykinins during pregnancy has also been reported in the placenta (Sastry et al., 1981; Graf et al., 1996) and amniotic fluid (Sanfilippo et al., 1992). On the basis that maternal immunoreactive SP concentrations in plasma are low during pregnancy and found to be higher immediately post-partum, some workers (Skrabanek et al., 1980) suggest the possibility that there is a rise in immunoreactive SP concentrations around the time of parturition. This could result from the increased production of tachykinins, or from their altered degradation, if for example the activity of one or more uterine peptidases were to decline just prior to parturition. The present study has shown that SP and other tachykinins, including NKA, can produce marked uterotonic effects on near-term gravid human uterus. Taken together these findings may indicate a physiological role for these peptides in modulating uterine contractility near term.
Acknowledgments
The authors are grateful to Dr S.Lavielle from Lab De Chimie Organique Biologique and Dr X.Emonds-Alt from Sanofi Recherche for their generous gifts of [Lys5, MeLeu9,Nle10]NKA(4–10) and SR48968 respectively.
Notes
3 To whom correspondence should be addressed at: Department of Pharmacology, Monash University, Clayton, Vic 3800, Australia. E-mail: margot.story{at}med.monash.edu.au 
References
Alm, P., Alumets, J., Brodin, E. et al. (1978) Peptidergic (substance P) nerves in the genito-urinary tract. Neuroscience, 3, 419–425.[ISI][Medline]
Alm, P., Bjorklund, A., Owman, C. et al. (1979) Tyrosine hydroxylase and DOPA decarboxylase activities in the guinea-pig uterus: further evidence for functional adrenergic denervation in association with pregnancy. Neuroscience, 4, 145–154.[ISI][Medline]
Alm, P. and Lundberg, L.M. (1988) Co-existence and origin of peptidergic and adrenergic nerves in the guinea pig uterus. Retrograde tracing and immunocytochemistry, effects of chemical sympathectomy, capsaicin treatment and pregnancy. Cell. Tiss. Res., 254, 517–530.[ISI][Medline]
Amira, S., Morrison, J.F. and Rayfield, K.M. (1995) The effects of pregnancy and parturition on the substance P content of the rat uterus: uterine growth is accompanied by hypertrophy of its afferent innervation. Exp. Physiol., 80, 645–650.[Abstract]
Barr, A.J., Watson, S.P., Bernal, A.L. et al. (1991) The presence of NK3 tachykinin receptors on rat uterus. Eur. J. Pharmacol., 203, 287–290.[ISI][Medline]
Brokaw, J.J. and White, G.W. (1994) Differential effects of phosphoramidon and captopril on NK1 receptor-mediated plasma extravasation in the rat trachea. Agents Actions, 42, 34–39.[ISI][Medline]
Burcher, E., Mussap, C.J., Geraghty, D.P. et al. (1991) Concepts in characterization of tachykinin receptors. Ann. N.Y. Acad. Sci., 632, 123–136.[ISI][Medline]
Cascieri, M.A., Bull, H.G., Mumford, R.A. et al. (1984) Carboxyl-terminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422. Mol. Pharmacol., 25, 287–293.[Abstract]
Casey, M.L., Smith, J.W., Nagai, K. et al. (1991) Progesterone-regulated cyclic modulation of membrane metalloendopeptidase (enkephalinase) in human endometrium. J. Biol. Chem., 266, 23041–23047.
Chassaing, G., Lavielle, S., Loeuillet, D. et al. (1991) Selective agonists of NK-2 binding sites highly active on rat portal vein (NK-3 bioassay). Neuropeptides, 19, 91–95.[ISI][Medline]
Croci, T., Emonds-Alt, X., Le Fur, G. et al. (1995) In vitro characterization of the non-peptide tachykinin NK1 and NK2-receptor antagonists, SR140333 and SR48968 in different rat and guinea-pig intestinal segments. Life Sci., 56, 267–275.[ISI][Medline]
Cushman, D.W. and Cheung, H.S. (1971) Concentrations of angiotensin-converting enzyme in tissues of the rat. Biochim. Biophys. Acta, 250, 261–265.[Medline]
Drapeau, G., D'Orleans-Juste, P., Dion, S. et al. (1987) Selective agonists for substance P and neurokinin receptors. Neuropeptides, 10, 43–54.[ISI][Medline]
Emonds-Alt, X., Vilain, P., Goulaouic, P. et al. (1992) A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. Life Sci., 50, L101–106.
Fisher, L. and Pennefather, J.N. (1997) Potencies of agonists acting at tachykinin receptors in the oestrogen-primed rat uterus: effects of peptidase inhibitors. Eur. J. Pharmacol., 335, 221–226.[ISI][Medline]
Fisher, L., Pennefather, J.N. and Hall, S. (1993) Tachykinin receptors in the rat isolated uterus. Regul. Pept., 46, 396–398.[ISI][Medline]
Graf, A.H., Hutter, W., Hacker, G.W. et al. (1996) Localization and distribution of vasoactive neuropeptides in the human placenta. Placenta, 17, 413–421.[ISI][Medline]
Heinrich, D., Reinecke, M. and Forssmann, W.G. (1986) Peptidergic innervation of the human and guinea pig uterus. Arch. Gynecol., 237, 213–219.[ISI][Medline]
Henry, J.L. (1987) Discussion of nomenclature for tachykinins and tachykinin receptors. In Henry, J.L., Couture, R., Cuello, A.C. et al. (eds), Substance P and Neurokinins. Springer-Verlag, New York, USA.
Hooper, N.M. and Turner, A.J. (1985) Neurokinin B is hydrolysed by synaptic membranes and by endopeptidase-24.11 (enkephalinase) but not by angiotensin converting enzyme. FEBS Lett., 190, 133–136.[ISI][Medline]
Huang, W.M., Gu, J., Blank, M.A. et al. (1984) Peptide-immunoreactive nerves in the mammalian female genital tract. Histochem. J., 16, 1297–1310.[ISI][Medline]
Imai, K., Maeda, M., Fujiwara, H. et al. (1992) Human endometrial stromal cells and decidual cells express cluster of differentiation (CD) 13 antigen/aminopeptidase N and CD10 antigen/neutral endopeptidase. Biol. Reprod., 46, 328–334.[Abstract]
Lembeck, F. and Holzer, P. (1979) Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn Schmiedebergs Arch. Pharmacol., 310, 175–183.[ISI][Medline]
Lentner, C. (ed.) (1982) Introduction to statistics, statistical tables, mathematical formulae. In Geigy Scientific Tables. Vol. 2. 8th edn. Ciba-Geigy Ltd, Basle, Switzerland, pp. 214.
Maggi, C.A. and Meli, A. (1988) The sensory-efferent function of capsaicin-sensitive sensory neurons. Gen. Pharmacol., 19, 1–43.[ISI][Medline]
Maggi, C.A., Patacchini, R., Rovero, P. et al. (1993) Tachykinin receptors and tachykinin receptor antagonists. J. Auton. Pharmacol., 13, 23–93.[ISI][Medline]
Magraner, J., Pinto, F.M., Anselmi, E. et al. (1998) Characterization of tachykinin receptors in the uterus of the oestrogen-primed rat. Br. J. Pharmacol., 123, 259–268.[ISI][Medline]
Matsas, R., Fulcher, I.S., Kenny, A.J. et al. (1983) Substance P and [Leu]enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli. Proc. Natl Acad. Sci. USA, 80, 3111–3115.
Matsas, R., Rattray, M., Kenny, A.J. et al. (1985) The metabolism of neuropeptides. Endopeptidase-24.11 in human synaptic membrane preparations hydrolyses substance P. Biochem. J., 228, 487–492.[ISI][Medline]
Medeiros, M.D. and Turner, A.J. (1995) Metabolic stability of some tachykinin analogues to cell-surface peptidases: roles for endopeptidase-24.11 and aminopeptidase N. Peptides, 16, 441–447.[ISI][Medline]
Mizutani, S., Goto, K., Nomura, S. et al. (1993) Possible action of human placental aminopeptidase N in feto-placental unit. Res. Commun. Chem. Pathol. Pharmacol., 82, 65–80.[ISI][Medline]
Molina, E. and Zappia, L. (1976) In vitro activity of some natural and synthetic substances on non-pregnant human myometrium. Farmaco–Edizione Pratica, 31, 329–336.
Mussap, C.J., Geraghty, D.P. and Burcher, E. (1993) Tachykinin receptors: a radioligand binding perspective. J. Neurochem., 60, 1987–2009.[ISI][Medline]
Nau, R., Schafer, G., Deacon, C.F. et al. (1986) Proteolytic inactivation of substance P and neurokinin A in the longitudinal muscle layer of guinea pig small intestine. J. Neurochem., 47, 856–864.[ISI][Medline]
Otsuka, M. and Yoshioka, K. (1993) Neurotransmitter functions of mammalian tachykinins. Physiol. Rev., 73, 229–308.
Ottesen, B., Sondergaard, F. and Fahrenkrug, J. (1983) Neuropeptides in the regulation of female genital smooth muscle contractility. Acta Obstet. Gynecol. Scand., 62, 591–592.[ISI][Medline]
Owman, C. (1981) Pregnancy induces degenerative and regenerative changes in the autonomic innervation of the female reproductive tract. Ciba Foundation Symposium, 83, 252–279.[Medline]
Papka, R.E., Cotton, J.P. and Traurig, H.H. (1985) Comparative distribution of neuropeptide tyrosine-, vasoactive intestinal polypeptide-, substance P-immunoreactive, acetylcholinesterase-positive and noradrenergic nerves in the reproductive tract of the female rat. Cell. Tiss. Res., 242, 475–490.[ISI][Medline]
Pennefather, J.N., Paull, J.D., Story, M.E. et al. (1993a) Supersensitivity to the stimulant action of noradrenaline on human myometrium near term. Reprod. Fertil. Dev., 5, 39–48.[Medline]
Pennefather, J.N., Zeng, X.P., Gould, D. et al. (1993b) Mammalian tachykinins stimulate rat uterus by activating NK-2 receptors. Peptides, 14, 169–174.[ISI][Medline]
Qian, Y., Advenier, C., Naline, E. et al. (1994) Effects of SR 48968 on the neuropeptide gamma-induced contraction of the human isolated bronchus. Fundam. Clin. Pharmacol., 8, 71–75.[ISI][Medline]
Regoli, D., Drapeau, G., Dion, S. et al. (1987) Pharmacological receptors for substance P and neurokinins. Life Sci., 40, 109–117.[Medline]
Reinecke, M., Gauwerky, J.F. and Schneider, K. (1989) [Peptidergic (NPY, NT, VIP, SP, CGRP) innervation of the functional systems of the uterus and fallopian tube in the human]. Arch. Gynecol. Obstet., 245, 399–401.[Medline]
Samuelson, U.E., Dalsgaard, C.J., Lundberg, J.M. et al. (1985) Calcitonin gene-related peptide inhibits spontaneous contractions in human uterus and fallopian tube. Neurosci. Lett., 62, 225–230.[ISI][Medline]
Sanfilippo, J.S., Botti, J.J., Wild, R.A. et al. (1992) Amniotic fluid levels of substance P. J. Reprod. Med., 37, 733–736.
Sastry, B.V., Tayeb, O.S., Barnwell, S.L. et al. (1981) Peptides from human placenta: methionine enkephalin and substance P. Placenta, 3 (Suppl.), 327–337.[Medline]
Sjoberg, N.O. (1968) Considerations on the cause of disappearance of the adrenergic transmitter in uterine nerves during pregnancy. Acta Physiol. Scand., 72, 510–517.[ISI][Medline]
Skidgel, R.A., Engelbrecht, S., Johnson, A.R. et al. (1984) Hydrolysis of substance p and neurotensin by converting enzyme and neutral endopeptidase. Peptides, 5, 769–776.[ISI][Medline]
Skrabanek, P., Balfe, A., McDonald, D. et al. (1980) Substance P in human cord blood and its degradation by placenta in vitro. Eur. J. Obstet. Gynecol. Reprod. Biol., 11, 157–161.[ISI][Medline]
Spillantini, M.G., Sicuteri, F., Salmon, S. et al. (1990) Characterization of endopeptidase 3.4.24.11 (`enkephalinase') activity in human plasma and cerebrospinal fluid. Biochem. Pharmacol., 39, 1353–1356.[ISI][Medline]
Story, M.E., Hall, S., Ziccone, S.P. et al. (1988) Effects of adrenaline, isoprenaline and forskolin on pregnant human myometrial preparations. Clin. Exp. Pharmacol. Physiol., 15, 703–713.[ISI][Medline]
Thorbert, G., Alm, P., Bjorklund, A.B. et al. (1979) Adrenergic innervation of the human uterus. Disappearance of the transmitter and transmitter-forming enzymes during pregnancy. Am. J. Obstet. Gynecol., 135, 223–226.[ISI][Medline]
Traurig, H., Saria, A. and Lembeck, F. (1984) Substance P in primary afferent neurons of the female rat reproductive system. Naunyn Schmiedebergs Arch. Pharmacol., 326, 343–346.[ISI][Medline]
Traurig, H.H., Papka, R.E. and Shew, R.L. (1991) Substance P and related peptides associated with the afferent and autonomic innervation of the uterus. Ann. N.Y. Acad. Sci., 632, 304–313.[ISI][Medline]
Wikland, M., Lindblom, B., Dahlstrom, A. et al. (1984) Structural and functional evidence for the denervation of human myometrium during pregnancy. Obstet. Gynecol., 64, 503–509.
Yokosawa, H., Endo, S., Ogura, Y. et al. (1983) A new feature of angiotensin-converting enzyme in the brain: hydrolysis of substance P. Biochem. Biophys Res. Comm., 116, 735–742.[ISI][Medline]
Submitted on November 8, 1999; accepted on March 9, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. N. Pennefather, E. Patak, S. Ziccone, A. Lilley, F. M. Pinto, N. M. Page, M. E. Story, S. Grover, and M. L. Candenas Regulation of the Stimulant Actions of Neurokinin A and Human Hemokinin-1 on the Human Uterus: A Comparison with Histamine Biol Reprod, September 1, 2006; 75(3): 334 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Patak, F. M. Pinto, M. E. Story, C. O. Pintado, A. Fleming, N. M. Page, J. N. Pennefather, and M. L. Candenas Functional and Molecular Characterization of Tachykinins and Tachykinin Receptors in the Mouse Uterus Biol Reprod, May 1, 2005; 72(5): 1125 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. O. Pintado, F. M. Pinto, J. N. Pennefather, A. Hidalgo, A. Baamonde, T. Sanchez, and M. L. Candenas A Role for Tachykinins in Female Mouse and Rat Reproductive Function Biol Reprod, September 1, 2003; 69(3): 940 - 946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Candenas, J. Magraner, C. P. Armesto, E. Anselmi, P. M. Nieto, J. D. Martin, C. Advenier, and F. M. Pinto Changes in the Expression of Tachykinin Receptors in the Rat Uterus During the Course of Pregnancy Biol Reprod, August 1, 2001; 65(2): 538 - 543. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||