The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 79 , Issue 2
Showing 1-17 articles out of 17 articles from the selected issue
Reviews
  • Toshio Nakaki, Tomoko Fujii
    1999 Volume 79 Issue 2 Pages 125-129
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Several lines of evidence have been accumulated for occurrence of nitration in vivo. In this brief review, we summarized nitration studies on functional changes of proteins, hormones and neurotransmitters, before as well as after the discovery of peroxynitrite. Most of nitrated molecules exhibit less active properties than the parental compounds. It is still unknown whether nitration is merely a footprint of oxidative stress, an important pathway of nitric oxide metabolisms or a part of integral processes for maintaining cellular homeostasis.
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Regular Papers
  • Keifu Song, Hironori Kanehara, Shinji Takai, Naotaka Shiota, Takeo Wad ...
    1999 Volume 79 Issue 2 Pages 131-139
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Inhibition of angiotensin (Ang) II type 1 (AT1) receptors in various target tissues of adult Sprague-Dawley rats was studied after single oral administration of TCV-116. The effects of TCV-116 on Ang II-receptor binding were assessed by quantitative in vitro autoradiography using 125I-[Sar1, Ile8]Ang II as a ligand. Four hours after the administration of TCV-116 (1 mg/kg), Ang II-receptor binding was mark- edly inhibited in the kidney (20% of control), adrenal cortex (27%), thoracic aorta (57%), heart (55%) and testis (76%) where AT1 receptors predominate. In the brain, orally administered TCV-116 produced a significant inhibition of binding both to the circumventricular organs (38%), which are devoid of the bloodbrain barrier (BBB), and to the discrete regions within the BBB such as the paraventricular hypothalamic nucleus (48%), nucleus of the solitary tract (60%). Twenty-four hours after the administration, Ang IIreceptor binding had partly recovered to approximately 50 - 85% of control levels. In contrast, throughout the experimental period, Ang II-receptor binding was little affected in sites where Ang II type 2 (AT2) receptors predominate such as the adrenal medulla and the nucleus of the inferior olive. These data indicate that orally administered TCV-116 specifically binds to AT1 receptors both in peripheral tissues and the central nervous system.
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  • Blythe B. Holmes, Jodie J. Rady, David J. Smith, James M. Fujimoto
    1999 Volume 79 Issue 2 Pages 141-149
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Intracerebral injection of neurotensin into specific brain loci in rats produces hyperalgesia due to the release of cholecystokinin (CCK) in the spinal cord. The present purpose was to show in another species that neurotensin can antagonize the antinociceptive action of morphine through the spinal CCK mechanism in mice. Neurotensin given intracerebroventricularly (i.c.v.) at doses higher than 100 ng produced antinociception in the tail flick test. However, at lower doses between 1 pg to 25 ng, neurotensin antagonized the antinociceptive action of morphine given intrathecally (i.t.), thus demonstrating the antianalgesic activity of neurotensin. The rightward shift in the morphine dose-response curve produced by i.c.v. neurotensin was eliminated by an i.t. pretreatment with CCK8 antibody (5 μl of antiserum solution diluted 1:1000). I.t. administration of lorglumide, a CCKA-receptor antagonist (10 - 1000 ng), and PD135, 158, a CCKB-receptor antagonist (250 - 500 ng), also eliminated the antianalgesic action of neurotensin. Thus, the mechanism of the antianalgesic action of neurotensin given i.c.v. involved spinal CCK. This mode of action is similar to that for the antianalgesic action of supraspinal pentobarbital which also involves spinal CCK.
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  • Yukimasa Azuma, Takashi Kawasaki, Katsutoshi Ohno, Jiro Seto, Toshihir ...
    1999 Volume 79 Issue 2 Pages 151-158
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    We studied the effect of NTE-122 (trans-1, 4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl) ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on intracellular cholesterol esterification and the secretion of apolipoprotein B100 (apoB)-containing lipoprotein and bile acids in the human hepatoma cell line HepG2. NTE-122 markably inhibited [3H]oleate incorporation into cholesteryl esters in HepG2 cells incubated with 5 μg/ml 25-hydroxycholesterol as a stimulus for ACAT (IC50=6.0 nM). On the other hand, NTE-122 did not affect [3H]oleate incorporation into triglycerides and phospholipids and [14C]acetate incorporation into cholesterol. The stimulation of ACAT by 25-hydroxycholesterol caused significant increases in the secretion of radiolabeled cholesteryl esters, radiolabeled triglycerides and apoB mass. NTE-122 pronouncedly inhibited the secretion of radiolabeled cholesteryl esters in proportion to the inhibition of cellular cholesterol esterification, and it significantly reduced the secretion of radiolabeled triglycerides and apoB mass in HepG2 cells incubated with 25-hydroxycholesterol. Furthermore, NTE-122 increased the secretion of bile acids synthesized from [14C]cholesterol. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing both the cholesterol content and the amount of secreted very low-density lipoprotein and enhancing the excretion of bile acid from the liver.
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  • Yukimasa Azuma, Takashi Kawasaki, Kiyohito Ikemoto, Katsutoshi Ohno, T ...
    1999 Volume 79 Issue 2 Pages 159-167
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    We investigated the effects of a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, NTE-122 (trans-1, 4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), on ACAT activities in macrophages originating from several species and high-density lipoprotein (HDL)-induced cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. NTE-122 inhibited cell-free ACAT activities in human PMA-treated THP-1 cells and mouse J774.1 cells with IC50 values of 0.88 and 360 nM, respectively. NTE-122 competively inhibited the ACAT activity in PMA-treated THP-1 cells. NTE-122 also inhibited cellular ACAT activities in PMA-treated THP-1 cells, rat peritoneal macrophages and J774.1 cells with IC50 values of 3.5, 84 and 6800 nM, respectively. Furthermore, NTE-122 prevented cholesterol accumulation in PMA-treated THP-1 cells incubated with acetylated low density lipoprotein, simultaneously with HDL, while it caused accumulation of a significant amount of free cholesterol in the absence and even in the presence of HDL. NTE-122 also enhanced HDL-induced cholesterol efflux from established foam cells converted from PMA-treated THP-1 cells. These results suggest that NTE-122, capable of inhibiting macrophage ACAT activity in humans more strongly than those in the other species, exhibits anti-atherogenic effects by preventing the foam cell formation and enhancing the foam cell regression in humans.
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  • Yasuyuki Suzuki, Kazuhiro Goto, Atsushi Ishige, Yasuhiro Komatsu, Junz ...
    1999 Volume 79 Issue 2 Pages 169-175
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    We evaluated the antinociceptive effect of Gosha-jinki-gan, a Kampo medicine including processed Aconiti tuber, and its mechanism in streptozotocin-induced diabetic mice. Gosha-jinki-gan (0.1 - 1.0 g/kg, p.o.) showed a more potent antinociceptive effect in diabetic mice than in non-diabetic mice. The antinociceptive effect of Gosha-jinki-gan (0.3 g/kg, p.o.) in diabetic mice was inhibited by administration of either anti-dynorphin antiserum (5 μg, i.t.) or nor-binaltorphimine (10 mg/kg, s.c.), a κ-opioid antagonist. The antinociceptive activity of Gosha-jinki-gan (0.3, 1.0 g/kg, p.o.) was decreased by excluding processed Aconiti tuber. Furthermore, the antinociceptive effect of processed Aconiti tuber (0.03, 0.1 g/kg, p.o.) was also shown to be enhanced in diabetic mice. These results suggest that the increased antinociceptive effect of Gosha-jinki-gan in diabetic mice is partly derived from the action of processed Aconiti tuber and that it is based on stimulation of spinal κ-opioid receptors via dynorphin release. Gosha-jinki-gan was considered useful for treating painful diabetic neuropathy.
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  • Yutaka Tanimoto, Yoshiaki Onishi, Yutaka Sato, Harutoshi Kizaki
    1999 Volume 79 Issue 2 Pages 177-183
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Peripheral-type benzodiazepines have been shown to exert immunological effects. In this study, we examined the effects of the peripheral-type benzodiazepines on murine thymocytes. Murine thymocytes that were incubated with the peripheral-type benzodiazepines underwent apoptosis associated with the collapse of mitochondrial transmembrane potential (Δφm). The drugs stimulated dexamethasone- and etoposide-induced apoptosis with the enhanced collapse of Δφm. The central-type benzodiazepines had no effect on either the Δφm or apoptosis. The reduction of Δφm depended on protein synthesis and protein phosphorylation. These results suggest that the immunomodulating effect of benzodiazepines is in part due to the modulation of thymocyte apoptosis associated with the collapse of Δφm.
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  • Motomaru Masutani, Mitsumasa Ohyanagi, Jun Shibuya, Yasuhiro Ishigami, ...
    1999 Volume 79 Issue 2 Pages 185-193
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The inhibitory GTP-binding protein (Gi protein) plays an important role in regulation of vascular tone. Many studies have implicated the role of Gi protein in conduit vessels. However, the physiological role of Gi protein in the control of peripheral microvascular tone in hypertension has not been established yet. Therefore, we investigated the concentration of Gi protein in the peripheral resistance arteries and aorta in the spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY) and renovascular hypertensive rats (RHR), using immunohistochemical methods semiquantitatively. Changes in the function of Gi protein in relation to α2-adrenoceptor were also investigated by microcannulation techniques. We have shown that the amount of α2 subunits of Gi protein in the cremaster small artery was significantly lower in SHR aged 4 weeks and older than in age-matched WKY and that there were no significant differences between RHR and WKY. We also demonstrated that the function of Gi protein in relation to α2-adrenoceptor was already lower in SHR before the onset of hypertension. The quantitative and functional decline in Gi protein in the smooth muscle cells of peripheral small arteries were observed in SHR even before the onset of hypertension, whereas rats with secondary hypertension did not exhibit this finding.
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  • Shigeki Marubuchi, Yukio Mori, Masahiko Noto, Noriko Urata, Midori Miz ...
    1999 Volume 79 Issue 2 Pages 195-202
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The relationship of endogenous nitric oxide (NO) to the gastric mucosal protective effect of the novel anti-ulcer agent T-593, (±)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3-[2-[[[5-(methylamino)methyl-2-furyl]methyl]thio]ethyl]-2-(methylsulfonyl) guanidine, was investigated in rats. T-593 (3 - 30 mg/kg, p.o.) dose dependently prevented the formation of gastric mucosal lesions induced by oral administration of aspirin (200 mg/kg) in 0.15 N HCl (HCl-aspirin). Pretreatment with NG-nitro-L-arginine methylester (L-NAME), a selective inhibitor of NO synthase (NOS), attenuated the mucosal protective effect of T-593. This effect of L-NAME was antagonized by pretreatment with L-arginine, a substrate of NOS, but not with D-arginine. Activity of total NOS composed of inducible and constitutive NOS in the gastric mucosa was decreased by HCl-aspirin, and T-593 inhibited this decrease. On the other hand, HCl-aspirin and T-593 did not affect inducible NOS activity in the gastric mucosa. Furthermore, we confirmed that T-593 inhibits the decrease in gastric mucosal blood flow (GMBF) induced by HCl-aspirin, and this effect is completely inhibited by pretreatment with L-NAME. These results suggest that the mucosal protective effect of T-593 is partly mediated by endogenous NO via improvement of GMBF and that a possible mechanism for the effect of T-593 is the maintenance of constitutive NOS activity in gastric mucosa.
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  • Motohiro Takeda, Katsura Tsukamoto, Yuka Mizutani, Tsunemasa Suzuki, K ...
    1999 Volume 79 Issue 2 Pages 203-212
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The pharmacological profile of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl) ethyl]-5-chloro-2, 3-dihydro-2-methylbenzo[b]furan-7-carboxamide hemifumarate) was identified in relation to serotonin 5-HT3 and 5-HT4 receptors by the receptor binding assay and functional studies. The receptor binding assay showed that SK-951 bound to the 5-HT3 receptor with a high affinity, to the 5-HT4 receptor with relatively higher affinity and to the muscarinic M2 receptor with a low affinity, but not to dopamine D1 and D2 and serotonin 5-HT1 and 5-HT2 and muscarinic M1 and M3 receptors. SK-951 caused relaxations of tunica muscularis mucosae preparations from rat esophagus which were precontracted with carbachol, and the effects were antagonized by GR113808, a selective 5-HT4 antagonist. In the longitudinal muscle with myenteric plexus (LMMP) preparations from guinea pig ileum, SK-951 enhanced the electrically-stimulated contraction of preparations in which the 5-HT1, 5-HT2 and 5-HT3 receptors were blocked, and it enhanced the electrically-stimulated release of [3H]acetylcholine (ACh). These effects of SK-951 were antagonized by GR113808. SK-951 inhibited the 5-HT3 receptor-mediated contractions. These results indicate that SK-951 possesses properties of an agonist for the 5-HT4 receptor and an antagonist for the 5HT3 receptor. Thus, SK-951 is a new and potent 5-HT4-receptor agonist and causes contractions of guinea pig ileum mediated by enhancement of ACh release via the 5-HT4 receptor.
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  • Yukitaka Ideyama, Masafumi Kudoh, Kyoko Tanimoto, Yoko Susaki, Taiki N ...
    1999 Volume 79 Issue 2 Pages 213-220
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1H-imidazol4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17αHydroxyprogesterone, a product of 17α-hydroxylase, was increased by YM116 (1 - 30 nM) and by ketoconazole (10 - 300 nM) and then was decreased at higher concentrations of both agents (IC50: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17α-hydroxylase. Compatible with these findings, progesterone, a substrate of 17α-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC50: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC50: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity.
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  • Hiromu Kawasaki, Masatoshi Okazaki, Akira Nakatsuma, Yuichi Mimaki, Hi ...
    1999 Volume 79 Issue 2 Pages 221-229
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Effects of long-term treatment with angiotensin converting enzyme (ACE) inhibitor on decreased function of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRP nerves) in mesenteric resistance artery were investigated in spontaneously hypertensive rats (SHR). Eight-week-old SHR were treated for 7 weeks with 0.1% captopril, 0.01% temocapril, 0.05% pindolol or 0.005% hydralazine in drinking water. Long-term treatment with each drug significantly lowered mean blood pressure of SHR. In isolated and perfused mesenteric vascular beds with active tone, periarterial nerve stimulation (PNS) (0.5 to 8 Hz) produced frequency-dependent vasodilations, which were abolished by CGRP(8 - 37) (CGRP-receptor antagonist) and significantly smaller in SHR than in normotensive Wistar Kyoto rats. Treatment of SHR with captopril and temocapril but not with pindolol and hydralazine resulted in significantly greater PNS-induced vasodilation than in non-treated SHR, but ACE-inhibitor treatment did not affect vasodilation induced by exogenous CGRP. In captopril-treated SHR preparations, PNS evoked significantly larger CGRP-like immunoreactive release than in non-treated SHR. In non-treated 15-week-old SHR preparations, direct perfusion of captopril or temocapril (0.1 μM and 1 μM) did not modify frequency-dependent vasodilation in response to PNS. These results suggest that long-term ACE inhibitor treatment prevents or restores CGRP nerve function reduction in SHR.
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  • Hiroko Fukunaga, Masakatsu Takahashi, Hiroshi Kaneto, Masaaki Yoshikaw ...
    1999 Volume 79 Issue 2 Pages 231-235
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The role of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) in biological responses to stress exposure was examined in mice. Intraperitoneal or intracerebroventricular administration of Tyr-MIF-1 attenuated not only footshock (FS)- and forced swimming (SW)-stress-induced analgesia (SIA) but also socio-psychological (PSY)-SIA that, when using the communication box, is produced without any direct physical nociceptions. Tyr-MIF-1 also disrupted the suppressive effect of concurrent exposure to FS- and PSY-stress on the development of morphine antinociceptive tolerance. In elevated-plus-maze tests, mice treated with Tyr-MIF-1 tended to spend more time in the open arms compared with the control group, suggesting the anxiolytic properties of the peptide. Thus, the finding that Tyr-MIF-1 modulates these stress responses suggests that the peptide regulates an endogenous biological alert system responding to stress exposure, perhaps, counteracting the excessive response of the system. Furthermore, Tyr-MIF-1, in the case of PSY-stress, through the attenuation of emotional factors such as fear and anxiety, may suppress PSY-SIA and inhibition by PSY-stress of the development of morphine tolerance.
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  • Hiromi Tsushima, Mayumi Mori
    1999 Volume 79 Issue 2 Pages 237-241
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Intracerebroventricular injections of capsaicin at 100 - 500 nmol elicited dose-dependent decreases in urine outflow volume in anesthetized, hydrated rats. The capsaicin (500 nmol)-induced anti- diuresis was inhibited by pretreatment with CP96345 (30 nmol, a neurokinin-1-receptor antagonist), but not by that with phenoxybenzamine (20 nmol, an alpha-adrenoceptor antagonist), timolol (100 nmol, a beta-adrenoceptor antagonist) or atropine (300 nmol, a muscarinic antagonist) into the hypothalamic supraoptic nucleus (SON). Intravenous injections of d(CH2)5-D-Tyr(Et)VAVP (50 μg/kg, a vasopressin-receptor antagonist) completely blocked the antidiuresis. In intra-SON microdialysis experiments, acetylcholine concentration in the perfusate of the capsaicin-injected rats was not different from that of the vehicle-injected rats. These findings suggested that capsaicin stimulated substance P release in the SON and caused the antidiuresis as a result of the increased release of vasopressin into the circulation from the neurohypophysis mediated through neurokinin-1 receptors in the SON.
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  • Taeko Hata, Hiroyuki Nishikawa, Eiji Itoh, Akiko Watanabe
    1999 Volume 79 Issue 2 Pages 243-249
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The effects of various types of stress and drugs were studied to assess mouse performance in forced swimming tests, following characterization of SART (specific alternation of rhythm in environmental temperature) stress. Immobility time in the test decreased in mice subjected to SART, acute cold and restraint stress. No change was noted due to chronic cold stress or repeated fasting. The shortened time did not recover even 24 hr after the end of SART and chronic restraint stress. The time in SART-stressed mice finally recovered at 5 - 7 days. Shortening of immobility time in SART-stressed mice was inhibited by diazepam and repeated imipramine but not by lithium carbonate. In chronic restraint-stressed mice, this time was inhibited by repeated lithium carbonate but not diazepam or imipramine. SART stress would thus appear related to anxiety and depression and may be useful for detecting new types of antidepressants.
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Short Communications
  • Yasuhiro Teranishi, Tsutomu Kumazaki, Ryoji Ozono, Hiromichi Tsuru
    1999 Volume 79 Issue 2 Pages 251-255
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The interaction between [Arg8]-vasopressin and a vasopressin receptor antagonist, [d(CH2)51, O-Me-Tyr2, Arg8]-vasopressin, was examined in Hiroshima rats and normotensive control rats under pentobarbital anesthesia. [Arg8]-vasopressin dose-dependently increased the arterial pressure in both the Hiroshima and control rats, the pressor effect being greater in the Hiroshima rats. After the administration of a vasopressin antagonist (0.01 mg/kg), which by itself decreased arterial pressure only in the Hiroshima rats, the dose-response curve for [Arg8]-vasopressin was much more greatly shifted to the right in the control rats. These results indicate that with or without a vasopressin antagonist, the exogenous [Arg8]-vasopressin induced more powerful pressor actions in the Hiroshima rats compared to the control rats.
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  • Kazuhiro Tamura, Kenichi Kumasaka, Hiroshi Kogo
    1999 Volume 79 Issue 2 Pages 257-262
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The effects of ovarian steroids on the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in rat uterus were examined. Intense expression of GM-CSF mRNA was dispersedly located in the endometrial-myometrial junction and stroma of the uterus. GM-CSF was immunohistochemically localized in stromal cells and luminal epithelium. Ovariectomy significantly reduced the appearance of GM-CSF-mRNA-positive cells and the levels of expression for GM-CSF mRNA in the whole uterus, whereas treatment with 17β-estradiol (E2) or a combination of E2 and progesterone (P4) for 5 days on ovariectomized animals recruited GM-CSF-mRNA-positive cells and stimulated its expression. The combined treatment with E2 and P4 also stimulates the expression for GM-CSF mRNA and the production of immunoreactive GM-CSF in the stromal tissues. These data suggest that the expression of GM-CSF in uterine stromal cells is partially regulated by ovarian steroids.
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