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a Department of Physiology and Pharmacology, James Cook University, Townsville, Queensland 4811, Australia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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SP, NKA, and neurokinin B (NKB) are members of the mammalian neurokinin family. Pharmacological and ligand binding studies suggest that the biological actions of these neurokinins are mediated through three related G protein-coupled receptors, termed NK1, NK2, and NK3 [7, 8]. The endogenous neurokinins can activate all three receptor types; however, they each interact preferentially with a specific neurokinin receptor (NK-R); SP interacts preferentially with NK1-R, while NKA and NKB interact preferentially with NK2-R and NK3-R, respectively [8, 9]. The NK-R story may be even more complex, as an increasing body of evidence suggests that there are multiple receptor subtypes and distinct species variation in the rank order of receptor affinity for agonists and antagonists [10].
Functional NK1-, NK2-, and NK3-R appear to be distributed throughout the rat uterus, and activation with NK-R agonists stimulates uterine contraction mediated by each distinct receptor type [11, 12]. Investigations of NK-R-mediated uterine contraction in intact rats injected with estrogen have suggested that neurokinin-mediated contractions are primarily mediated through the NK2-R [12–14].
This study has focused upon investigating the contractile response of the rat uterus, at various stages of the estrous cycle, to selective NK-R agonists in order to determine the relative role of the NK-Rs in different hormonal states. To further examine the role of estrogen in regulating NK-R-mediated uterine contractile activity, studies were conducted in ovariectomized animals with or without estrogen treatment.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Female Sprague-Dawley rats (150–200 g) were housed in standard temperature-controlled conditions in a 14L:10D photoperiod with food (commercial rat cubes; Norco, Lismore, Australia) and water available ad libitum. For studies requiring animals in different stages of the estrous cycle, vaginal smears were taken at the start of the light period, and animals were used after at least 2 consecutive 4-day estrous cycles had been observed. Ovariectomy was performed 7–10 days before each experiment, and 0.1 mg/kg estradiol-17ß benzoate (Intervet; Castle Hill, Australia) was administered s.c. 48 h prior to collection of estrogen-dominated tissue. Animal studies were conducted in accordance with the Guide for Care and Use of Laboratory Animals (copyright 1996, National Academy of Science) as approved by the James Cook University Animal Ethics Review Committee.
Tissue Preparation
Animals were killed by cervical dislocation after brief exposure to CO2, and uterine preparations were mounted in a 20-ml tissue bath containing De Jalon's solution (consisting of [mM] NaCl, 154; KCl, 5.6; NaHCO3, 5.9; glucose, 2.5; CaCl2, 0.27), gassed with 95% CO2 and 5% O2 (BOC Gases, Townsville, Australia), and maintained at 32°C. This protocol has previously been shown to produce a stable myometrial preparation in which contractile effects of agonists are clearly seen [15]. The preparations were left to equilibrate for 60 min, during which time they were washed at 15-min intervals. Resting tension was maintained at 0.4–0.5 g throughout the experiment. In tissue obtained from estrogen-dominated states, no spontaneous contractions were observed after the equilibration period. In tissue from non-estrogen-dominated states, spontaneous contractions were infrequent, irregular in nature, and clearly distinguishable and did not exceed 5–10% of the response to acetylcholine. Isometric contractions were recorded using a Grass FT03 strain gauge transducer (Grass Instruments, Quincy, MA) and a MacLab data acquisition system (AD Instruments, Castle Hill, Australia).
Experimental Protocol
The maximal effective dose of each agonist was determined in a series of preliminary experiments (not shown); these doses were used throughout this study to enable evaluation of the influence of hormonal state on myometrial responses to NK-R stimulation. The neurokinin agonists were chosen based on their NK-R type specificity and were [Sar9,Met(O2)11]substance P (SarMet SP), [ß-Ala8]neurokinin A (4–10) (ß-Ala NKA), and senktide (Research Biochemicals International, Castle Hill, Australia) selective for the NK1-, NK2-, and NK3-R, respectively [16, 17]. These agonists are highly selective; and while the most likely cross-reactivity is between NK2- and NK3-R, the selective agonists are at least 100-fold more effective at their specific receptor. At the other end of the spectrum, the selective NK2-R and NK3-R agonists are almost completely ineffective at the NK1-R, and similarly the NK1-R-selective agonist is ineffective at NK2- and NK3-R. In each experiment, acetylcholine (Sigma, Castle Hill, Australia) to the concentration of 10-4 M was applied to the tissue to check stability after the equilibration period. NK-R agonists were added in random order—preliminary studies showed no evidence of heterologous desensitization. A final acetylcholine exposure was used to check the viability of the tissue preparation. Tissue was exposed to each agonist for 90 sec, after which it was washed three times over a 90-sec period and left for 5 min before the next agonist addition. In some experiments the NK3-R-specific non-peptide antagonist SR142801 [18] (donated by Dr. Maurice Soifer; Sanofi, Sanofi Recherche, Gentilly Cedex, France) was added to the organ bath after the equilibration period, 30 min prior to the addition of senktide (the NK3-R-specific agonist), and remained in the bath throughout agonist additions.
Reagents
Unless otherwise specified, all laboratory chemicals were of analytical research grade, obtained from Ajax Chemicals (Auburn, Australia).
Data Analysis
The response to each agonist addition was evaluated as the maximum net increase in contractile force measured in milligrams. Results obtained with the NK-R agonists are presented as the percentage response in comparison with the maximum net increase in contractile force induced by acetylcholine (10-4 M). The response of the myometrium to acetylcholine has previously been shown to be independent of hormonal status [19].
Statistical Analysis
Where appropriate, statistical analyses were performed by one-way ANOVA followed by comparison of groups by Newman-Keuls multiple comparison test. Variations between group means were designated as statistically significantly different for a value of P 
0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Action of the NK1-R-selective agonist SarMet SP on uterine contractility Addition of SarMet SP (10-7 M) resulted in contraction of uterine preparations obtained from all stages of the rat estrous cycle (Fig. 1). The highest level of response was recorded in tissue from animals in diestrus and metestrus and was comparable to the maximal response to acetylcholine (97.9 ± 6.5% and 85.1 ± 3.4% of maximal response to acetylcholine, respectively). In contrast, the response to SarMet SP (10-7 M) in tissue from estrous and proestrous rats was considerably reduced, with maximum responses of 6.9 ± 1.2% and 13.0 ± 2.0% of the maximum acetylcholine response, respectively. Responses recorded in tissue obtained from proestrous and estrous animals were significantly reduced compared to the response in tissue obtained from either diestrus or metestrus (P < 0.001 for all comparisons).
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Action of the NK2-R-selective agonist ß-Ala NKA on uterine contractility Significant contractile activity in response to ß-Ala NKA (10-7 M) was observed in uterine preparations obtained from all stages of the rat estrous cycle (Fig. 2). Although significant responses were apparent in tissue from the estrogen-dominated stages of proestrus and estrus (51.3 ± 1.6% and 53.0 ± 3.1% response to acetylcholine, respectively), there was a trend for maximum contractile force to be reduced compared to that in tissue obtained from the non-estrogen-dominated stages of metestrus and diestrus. The highest level of response was recorded in tissue collected from animals in diestrus (79.8 ± 5.4% response to acetylcholine); this was significantly greater than the response in tissue from rats in proestrus and estrus (P < 0.01).
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Action of the NK3-R-selective agonist senktide on uterine contractility Addition of senktide (10-7 M) to the organ bath resulted in a contraction in uterine preparations obtained from all stages of the rat estrous cycle (Fig. 3). Consistent with the responses to the selective NK1-R and NK2-R agonists, the highest level of responsiveness to the selective NK3-R agonist was recorded in tissue obtained from animals in metestrus and diestrus (100.6 ± 2.0% and 97.7 ± 3.7% response to acetylcholine, respectively). The maximum response to senktide in tissue from proestrous rats (80.6 ± 1.8% response to acetylcholine) was significantly reduced compared to the maximum response in both metestrous and diestrous tissue (P < 0.05). Furthermore, the maximum response to senktide in tissue from estrous rats (66.3 ± 6.1% peak response to acetylcholine) was also significantly reduced compared to that in metestrous and diestrous tissue (P < 0.01).
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Effect of Specific NK-R Agonists on Uterine Tissue Obtained from Ovariectomized Animals With or Without Estrogen Treatment
In tissue from the estrogen-dominated state of estrus, the response to all three specific NK-R agonists was significantly reduced compared to that in the non-estrogen-dominated state of diestrus (Figs. 1–3). Thus we sought to further investigate the role of estrogen in the regulation of uterine contractile responsiveness to specific NK-R agonists using the estrogen-treated ovariectomized rat model.
For all selective NK-R agonists tested, the greatest response was found in tissue from ovariectomized animals (Fig. 4). The contractile response to all specific NK-R agonists was significantly reduced in estrogen-treated ovariectomized animals compared to ovariectomized controls (Fig. 4). A comparison of the contractile response to the specific NK-R agonists in tissue from the various hormonal environments (estrogen dominated vs. non-estrogen dominated) is shown in Table 1. Stimulation with the selective NK-R agonists did not result in a significant difference in maximum contractile response between tissue from ovariectomized animals and animals in diestrus. The maximum contractile response to senktide or ß-Ala NKA in estrogen-treated ovariectomized tissue was not significantly different from the maximum response to either agonist in tissue obtained at estrus. However, the response to the NK1-R-specific agonist SarMet SP in tissue from estrogen-treated ovariectomized rats (51.7 ± 6.6% response to acetylcholine) was significantly increased compared to the peak response in tissue from animals in estrus (6.9 ± 1.2% response to acetylcholine; P < 0.001).
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Nature of the Uterine Contractile Response to Selective NK-R Agonists in Different Hormonal Environments
Addition of SarMet SP to the organ bath resulted in an apparently monophasic contraction that typically lasted approximately 40 sec. The nature of the response did not appear to differ in tissue obtained from estrogen- and non-estrogen-dominated states. Addition of ß-Ala NKA to the organ bath resulted in phasic contractions that continued until washout of agonist; however, like the response to SarMet SP, the nature of the response to ß-Ala NKA did not differ in tissue obtained from estrogen- versus non-estrogen-dominated states. In contrast, a dramatic difference in the nature of the response to senktide was observed dependent upon the hormonal environment from which the tissue was collected. In tissue obtained from ovariectomized or diestrous animals, a sustained contraction that remained until washout (Fig. 5A) was observed in response to senktide. However, in tissue obtained from estrogen-treated ovariectomized animals or estrous animals, a monophasic contraction typically lasting approximately 42 sec was observed (Fig. 5B).
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Inhibition of Senktide-Induced Uterine Contractility by the Specific NK3-R Antagonist SR142801
This is the first report of the rat uterine contractile response to the NK3-R-selective agonist senktide in tissue obtained from ovariectomized animals and from animals at different stages of the rat estrous cycle. However, other investigators have reported that rat uterine responsiveness to NK3-R-preferring agonists in tissue obtained from animals after estrogen treatment (ovariectomized plus estrogen or intact plus estrogen) was negligible [12–14]. Thus we have further examined the specificity of the response to the NK3-R-selective agonist senktide in competition experiments with the NK3-R-specific antagonist SR 142801 [16–18].
The contractile response to senktide in uterine tissue obtained from both ovariectomized control and estrogen-treated animals was effectively reduced by preincubation of uterine strips with 10 nM, 100 nM, and 1 µM SR142801. Peak contractile response in tissue obtained from ovariectomized animals was significantly (P < 0.01) reduced by approximately 27% and 53% following preincubation with 10 nM SR142801 and 100 nM SR142801, respectively (Fig. 5C). Similar reductions in peak contractile response to senktide in tissue obtained from estrogen-treated animals pretreated with the specific NK3-R antagonist SR142801 were observed. In both preparations, a dose of 1 µM SR142801 almost completely inhibited the contractile response to the maximal dose of senktide.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To date, three distinct NK-Rs have been characterized. Pharmacological and biochemical studies suggest that the NK1-R has the highest affinity for SP while the NK2-R and NK3-R have the highest affinity for NKA and NKB, respectively [8–10]. Conclusive evidence for the expression of all three NK-Rs in the rat uterus is accumulating. Ligand binding studies initially suggested that all three NK-R types are expressed by myometrial cells [11]. These studies, followed by pharmacological investigations using selective NK-R agonists, suggested that both NK1- and NK2-R are expressed in the uterus and are functional [11–13]. More recent studies utilizing reverse transcription-polymerase chain reaction have detected specific mRNAs for all three NK-Rs in uterine tissue [14, 20]. Investigations of the neuropeptide content of sensory nerve fibers in the female reproductive tract have clearly identified both SP and NKA [5, 6]. However, to our knowledge, NKB has not yet been found in female reproductive tissue.
Although it is well established that uterine contractility is highly dependent upon the hormonal environment, investigation of hormonal regulation of uterine contractility in response to NK-R activation is limited. Previous studies have focused on the role of the NK-Rs in activating myometrial contractility in models of the estrogen-dominated rat uterus produced by injection of a variety of estradiol analogues into intact or ovariectomized rats [3, 12–14]. These studies did not examine the contractile response to NK-R activation in the non-estrogen-dominated uterus or in tissue from discrete stages of the rat estrous cycle.
We have utilized peptidase-resistant receptor-specific agonists to determine the contractile response to activation of NK1-, NK2-, and NK3-R in the major stages of the rat estrous cycle. Addition of SarMet SP, ß-Ala NKA, or senktide (selective agonists for NK1-, NK2-, and NK3-R, respectively) to isolated uterine preparations from all stages of the estrous cycle resulted in a significant contractile response. However, the magnitude of the contractions was found to be dependent upon the hormonal state of the animal, being significantly reduced in tissue from the estrogen-dominated states of proestrus and estrus. In these estrogen-dominated tissues, the response to either ß-Ala NKA or senktide was moderately reduced (approximately 40%) while the response to SarMet SP was substantially reduced (approximately 90%), compared to responses in non-estrogen-dominated tissue (metestrus and diestrus). Interestingly, an earlier study using uterine tissue from undetermined stages of the estrous cycle showed that response to NK1-R stimulation was highly variable with uterine preparations from 7 of 12 animals not responding [11]. Our results suggest that the nonresponding preparations were obtained from animals in either proestrus or estrus. This suggests that estrogen plays a role in regulating uterine responsiveness to NK-R activation.
To further examine the role of estrogen in the regulation of uterine contractility in response to NK-R activation, we utilized ovariectomized rats with or without administration of exogenous estrogen. Consistent with findings from our studies in intact animals, a significant contractile response to all three agonists was observed in tissues from estrogen-dominated and non-estrogen-dominated animals, and the response was significantly decreased in tissues obtained from estrogen-dominated animals. The extent of reduction in response to ß-Ala NKA and senktide was similar to that seen in intact animals (approximately 40%); however, the response to SarMet SP was reduced by only 50% in estrogen-treated rats as opposed to the 10-fold reduction in intact animals in proestrus and estrus. The exact cause of the reduction of uterine responsiveness to NK1-R activation in estrogen-dominated states is not clear. Recent studies have suggested that SarMet SP is susceptible to the action of proteases that are up-regulated in the estrogen-dominated rat uterus [13], which may partially explain the reduction in response to SarMet SP in estrogen-dominated versus non-estrogen-dominated states. However, the magnitude of the difference in SarMet SP-stimulated contractions between estrogen-dominated stages of the estrous cycle and estrogen-dominated ovariectomized rats seen in this study suggests that factors other than estrogen and protease expression may be influencing responsiveness to NK1-R activation.
Pinto et al. [21] recently reported that NK-R mRNA expression in the uterus is modulated by estrogen and progesterone. They showed that NK1- and NK2-R mRNA in uteri of ovariectomized rats treated with estrogen increased compared to values in ovariectomized controls while NK3-R mRNA levels decreased. Furthermore, NK1-R mRNA was found to decrease in uteri from ovariectomized rats treated with progesterone. Correlation of our contractility data with the earlier study is difficult, as those authors examined changes in receptor mRNA expression in the whole uterus. A previous report has suggested that NK-Rs in the uterus are not restricted to myometrial cells and that expression in different uterine cell types is dependent upon the steroid hormone environment [22]. Correlation of contractile data with receptor mRNA expression data therefore requires specific knowledge of mRNA levels in the myometrium. The study of Pinto et al. [21] also showed that strength of uterine contraction in response to SarMet SP was greater in uteri from ovariectomized rats treated with estrogen compared to progesterone; however, the response in ovariectomized controls was not reported. Interestingly, our studies clearly suggest that in the presence of estrogen, uterine contractility mediated by activation of the NK1-R is reduced. We propose that regulation of NK1-R-mediated uterine contractility is tightly controlled by the precise hormonal environment and that differences in receptor expression and activation in studies to date are a result of variations in the precise concentration of estrogen and progesterone that the uterine tissue has been exposed to. Perhaps our study of uterine tissue obtained from different stages of the rat estrous cycle gives the most physiologically relevant indication of the hormonal dependence of the contractile response to NK1-R activation.
Further evidence of hormonal regulation of uterine contractile response to NK-R activation is evident in the nature of the contractions seen in the present study. In tissue obtained from non-estrogen-dominated states, addition of senktide (an NK3-R-selective agonist) induced a significant and sustained contraction. However, in tissue obtained from estrogen-dominated states, senktide stimulated a short-lived monophasic contraction. This suggests that the hormonal environment regulates not only the strength of contraction induced by activation of the NK3-R, but also the nature of the contractile event. Such complexity is not surprising, and previous studies have clearly demonstrated that the dominant steroid hormone environment in the rat uterus modulates interactions between longitudinal and circular smooth muscle layers and the nature of the resultant contractile event [23]. This suggests that estrogen and/or progesterone may regulate response to senktide in circular and longitudinal myometrial layers, possibly altering the nature of the response.
Interestingly, recent studies utilizing uterine tissue from intact animals treated with estrogen have suggested that NK3-R activation plays no role in regulating uterine contractility [12, 13]. In contrast, the current study showed a significant contractile response to addition of the selective NK3-R agonist senktide in uterine preparations obtained from a number of different hormonal states. The response was inhibited by preincubation of tissue with SR142801 at doses consistent with antagonism of NK3-R activation [13, 24]. This strongly suggests that the senktide-induced contractions were mediated by the NK3-R. Furthermore, our study suggests that the magnitude and nature of the response to NK3-R activation are dependent upon the hormonal environment; thus it is possible that variations in the response to senktide in estrogen-dominated states in our study compared to others may be due to differences in the precise hormonal environment from which tissue was obtained. Interestingly, Pinto et al. [21] observed significant contractile response to NK3-R activation in uteri from ovariectomized progesterone-treated animals. Their study also suggested that NK3-R mRNA levels in the uterus are regulated by estrogen. Our study and that of Pinto et al. clearly suggest that NK3-R activation is potentially important in the regulation of rat uterine contractility in non-estrogen-dominated states. Thus earlier reports on NK-R-mediated contractility in estrogen-dominated tissues—suggesting that only NK2-R activation was important in the regulation of uterine contractility—may have been oversimplified. In fact, one could speculate that NK1- and NK3-R activation may be more important than NK2-R activation in regulating hormonally dependent fine control of uterine contractility, as the response to NK2-R activation does not appear to be as sensitive to the hormonal environment. However, a definitive understanding of the role of neurokinins and their receptors in regulation of uterine contractility and the hormonal modulation of their role requires investigation in models more closely resembling hormonal states present in the estrous cycle.
In conclusion, we have investigated the role of NK-Rs in regulation of the mechanical activity of the rat uterus at the major stages of the estrous cycle. Contractions were observed in tissue obtained from all stages of the estrous cycle in response to addition of the selective NK-R agonists SarMet SP (NK1-R), ß-Ala NKA (NK2-R), and senktide (NK3-R). However, the magnitude of the response was found to be dependent upon the stage of the estrous cycle from which uterine tissue was obtained. Responses to all agonists, and most notably SarMet SP, were reduced in tissue obtained from the estrogen-dominated states of estrus and proestrus. Additionally, the nature of the response to senktide was found to be dependent upon the hormonal environment. Studies conducted with tissue preparations from ovariectomized rats treated with and without estradiol supported the observation that uterine responsiveness to neurokinins is dependent on the hormonal environment. Currently we are examining the potential physiological role of the NK-Rs in the rat uterus utilizing the technique of video laparoscopy to examine in vivo myometrial responses to neurokinins during the major phases of the estrous cycle.
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FOOTNOTES |
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1 This work was supported by the National Health and Medical Research Council of Australia project grant number 971164. 
2 Correspondence. FAX: 61 7 47791526; linda.crane{at}jcu.edu.au
Accepted: January 10, 2000.
Received: September 14, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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