Biomedical subjects

N Shinkai

Publications and source records attributed to N Shinkai.

At least 19 recordsLinked to original sources

PubMed2003

Inhibitory effects of formoterol on lipopolysaccharide-induced premature delivery through modulation of proinflammatory cytokine production in mice.

Previous studies have demonstrated that formoterol, a beta2-adrenoceptor agonist, has potent tocolytic effects in rats. The aim of the present study was to determine whether formoterol treatment affects proinflammatory cytokine production in a lipopolysaccharide (LPS)-treated premature delivery mouse model. Formoterol was continuously administered by osmotic pump and the number of fetuses in the uteri were counted. Samples of amniotic fluid and plasma were collected 8 and 16 h after systemic administration of LPS. LPS induced premature delivery and an increase in prostaglandin F(2alpha) (PGF(2alpha)), interleukin 1alpha (IL-1alpha), IL-6 and IL-10 in the amniotic fluid, and an increase in IL-6 in plasma. Formoterol blocked all changes except the increase in IL-10. These data indicate that formoterol exerts inhibitory effects on proinflammatory cytokine production, and these effects may play an important role in the prevention of premature delivery.

Adrenergic beta-Agonists↗

PubMed2002

Tocolytic activity of formoterol against premature delivery in mice.

The tocolytic activity of formoterol (eformoterol), a long-acting potent beta(2)-adrenoceptor agonist, was assessed in pregnant mice, with determination of uterine effects on the 15th and 16th days of gestation. For examination in the lipopolysaccharide-induced premature delivery model, osmotic pumps filled with formoterol or saline solution were implanted subcutaneously under the back skin. The mice were sacrificed 18-20 h thereafter, and the numbers of fetuses in the uteri and the newborn were counted. The uteri, amniotic membranes and placenta were also rapidly removed for determination of IL-6 concentrations. Furthermore, the effect of formoterol on IL-6 secretion from mouse amnion cells was determined. Formoterol and ritodrine inhibited contraction responses of isolated mouse uteri and their intravenous administration resulted in lowered uterine motility. Lipopolysaccharide (30 microg mL(-1)/mouse) induced premature delivery, attributable to increased IL-6 secretion, and formoterol suppressed this. Doses of 5-500 microg/mouse thus reduced the number of prematurely delivered newborn, and 50 microg/mouse also depressed IL-6 secretion. On histopathologic analysis, the marked oedema and slight haemorrhage in the mouse cervix induced by lipopolysaccharide were reduced by administration of the beta(2)-adrenoceptor agonist. Neither formoterol (10(-7)-10(-5) M) nor ritodrine (10(-7)-10(-5) M) influenced spontaneous secretion of IL-6 in amnion cells. However, at 10(-7) and 10(-5) M, and 10(-6) and 10(-5) M, respectively, they inhibited lipopolysaccharide-induced IL-6 secretion and this inhibitory effect was competitively reversed by addition of ICI-118,551 (beta(2)-adrenoceptor antagonist), but not atenolol (beta(1)-adrenoceptor antagonist). These findings strongly suggest that formoterol can suppress premature delivery mediated by its actions on IL-6 secretion.

Adrenergic Agonists↗

PubMed2001

Genetic origin of malignant trophoblastic neoplasms analyzed by sequence tag site polymorphic markers.

OBJECTIVE: To study the causative conception of malignant gestational trophoblastic neoplasms (GTNs), we analyzed malignant GTNs by microsatellite PCR markers. METHOD: DNAs extracted from 12 malignant GTNs were subjected to PCR for five different chromosomal locations. RESULT: Of the 7 cases after a complete mole (CM), 5 were derived from androgenesis, but the remaining 2 were from normal fertilization. Of the 5 cases after nonmolar pregnancies, 2 placental site trophoblastic tumors had alleles from both parents. Of the other 3 choriocarcinomas, 1 was from normal fertilization after spontaneous abortion but 2 originated from androgenesis, suggesting that 1 was from a CM prior to the antecedent abortion, transforming after a long interval. CONCLUSION: By combining the previous cases with these, our analysis of 39 cases demonstrated that trophoblastic neoplasms can arise from at least three different modes of origin (androgenesis, normal fertilization, and parthenogenesis), and antecedent pregnancy is not always identical to the causative conception. Placental site trophoblastic tumors might have different machinery for carcinogenesis because of the predominance of paternal and maternal contributions. In addition, a long dormancy of trophoblasts before malignant transformation, especially for those originating from normal fertilization, was also suggested.

Adult↗

PubMed2000

Asymmetry in the nonmesonic weak decay of polarized (5)(Lambda)He hypernuclei

We have measured the asymmetric emission of protons from the nonmesonic decay of polarized (5)(Lambda)He produced by the (pi(+), K+) reaction. (5)(Lambda)He is an s-shell hypernucleus and its polarization is due to the Lambda. One expects to obtain direct information on the elementary weak Lambda-->p-->np process. The asymmetry parameter has been determined to be 0.24+/-0.22. The implication of the result is discussed.

Journal Article↗

PubMed2000

Tocolytic effects of a long-acting beta2-adrenoceptor agonist, formoterol, in rats.

We have assessed the tocolytic activity of formoterol, a novel long-acting and potent beta2-adrenoceptor agonist, through its production of cyclic adenosine monophosphate, in comparison with ritodrine, a beta2-adrenoceptor agonist used clinically to counter premature delivery. Formoterol and ritodrine inhibited the amplitude and frequency of rat uterine contraction, with IC50 values of 3.8 x 10(-10) and 4.7 x 10(-7) M, respectively. Intravenous administration of formoterol or ritodrine caused inhibition of uterine motility and increased heart rate in a dose-dependent manner. Inhibition of uterine motility by oral administration of formoterol (0.3 and 1 mg kg(-1)) continued for at least 60 min, whereas that with ritodrine (100 mg kg(-1)) persisted for 15 min with rapid recovery thereafter in pregnant rats. The beta-adrenoceptor binding of [125I]iodopindolol to the myometrium of pregnant rats was competitive with formoterol and ritodrine, with Ki values of 0.04 and 6.10 nM, respectively. Formoterol (10(-6)-10(-4) M) and ritodrine (10(-6)-10(-4) M) increased the level of cyclic adenosine monophosphate in lymphocytes in a dose-dependent manner. The results suggested that formoterol caused relaxation of uterine motility through production of cyclic adenosine monophosphate. Thus, formoterol may be useful as a treatment to counter premature delivery.

Administration, Oral↗

PubMed1998

Involvement of dopamine receptors in beneficial effects of tachykinins on scopolamine-induced impairment of alternation performance in mice.

The involvement of dopamine receptors in the beneficial effects of intracerebroventricular injection of substance P, neurokinin A and senktide on the scopolamine-induced impairment of spontaneous alternation performance was investigated in mice. Scopolamine (1 mg/kg) significantly impaired spontaneous alternation performance, while substance P (0.1 microg), neurokinin A (0.3 microg), senktide (0.003 microg) and S(-)-sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, improved the scopolamine (1 mg/kg)-induced disturbance of spontaneous alternation performance. However, the dopamine D1 receptor antagonist SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine maleate) did not influence the scopolamine-induced disturbance of spontaneous alternation performance. The dopamine D2 receptor agonist RU24213 (N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)-ethylamine hydrochloride) (1 mg/kg) but not the dopamine D1 receptor agonist SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrochloride) (3 and 10 mg/kg) reversed the beneficial effects of substance P (0.1 microg) and neurokinin A (0.3 microg) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance. In contrast, neither SKF38393 (3 and 10 mg/kg) nor RU24213 (0.3 and 1 mg/kg) significantly affected the beneficial effects of senktide (0.003 microg) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance. Although RU24213 (1 mg/kg) and SCH23390 (0.03 mg/kg) markedly decreased total arm entries, SKF38393 (10 mg/kg), RU24213 (1 mg/kg), SCH23390 (0.03 mg/kg) or S(-)-sulpiride (10 mg/kg) had no significant effects on spontaneous alternation performance. These results suggest that stimulation of dopamine D2 but not D1 receptors reverses the ameliorative effects of substance P and neurokinin A, whereas neither dopamine D1 nor D2 receptors play an important role in the beneficial effects of senktide on the scopolamine-induced impairment of spontaneous alternation performance associated with spatial working memory.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1998

Ameliorative effects of tachykinins on scopolamine-induced impairment of spontaneous alternation performance in mice.

The present study was designed to clarify whether opioid neuronal systems are involved in the beneficial effects of tachykinins such as the neurokinin NK1 receptor agonist, substance P (SP), the neurokinin NK2 receptor agonist, neurokinin A (NKA), and the neurokinin NK3 receptor agonist, senktide, on the scopolamine-induced impairment of spontaneous alternation performance in mice. Intracerebroventricular injections of SP (0.1 microgram), NKA (0.3 microgram) and senktide (3 ng) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing total arm entries, indicating the antiamnesic effects of tachykinins. Furthermore, the inhibitory effects of SP, but not those of NKA or senktide, were almost completely reversed by pretreatment with naloxone (1 mg/kg). However, the effects of SP on the scopolamine-induced impairment of spontaneous alternation performance were not influenced by pretreatment with the mu-opioid receptor antagonist, beta-funaltrexamine (5 micrograms), the delta-opioid receptor antagonist, naltrindole (4 ng), and the kappa-opioid receptor antagonist, nor-binaltorphimine (4 micrograms). These findings suggest that the effects of SP, unlike those of NKA or senktide, on the scopolamine-induced impairment of spontaneous alternation performance associated with spatial working memory are not mediated simply via a single type of opioid receptors, such as mu, delta or kappa.

Animals↗

PubMed1997

Effects of the kappa-opioid dynorphin A(1-13) on learning and memory in mice.

The effects of intracerebroventricular administration of dynorphin A(1-13) on scopolamine- and pirenzepine-induced amnesia were investigated in mice by observing the step-down-type passive avoidance response and spontaneous alternation performance. The pre- or post-training, or preretention administration of dynorphin A(1-13) (0.3-10 micrograms) alone failed to affect the passive avoidance response, while scopolamine (1 mg/kg) significantly inhibited it. Dynorphin A(1-13) (1 microgram) given 15 min before training and retention tests, but not immediately after training, significantly improved the scopolamine (1 mg/kg)-induced impairment of passive avoidance response, indicating the anti-amnesic effects of dynorphin A(1-13). A lower dose (1 mg/kg) of the kappa-opioid receptor antagonist (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorpha n reversed the anti-amnesic effects of dynorphin A(1-13) (1 microgram). In contrast, although dynorphin A(1-13) (1, 3 and 10 micrograms) did not influence spontaneous alternation performance, scopolamine (1 mg/kg) and the muscarinic M1 receptor antagonist pirenzepine (3 micrograms) markedly decreased spontaneous alternation performance. Dynorphin A(1-13) (3, 5.6 and/or 10 micrograms) significantly improved the scopolamine (1 mg/kg)- and pirenzepine (3 micrograms)-induced impairment of spontaneous alternation performance. The improving effects of dynorphin A(1-13) (3 micrograms) were almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms), a kappa-selective opioid receptor antagonist. These results suggest that the stimulation of kappa-opioid receptors improves memory dysfunctions resulting from the blockade of muscarinic M1 receptors.

Analgesics, Opioid↗

PubMed1997

Effects of Tyr-D-Arg-Phe-beta-Ala-NH2, a novel dermorphin analog, on elevated plus-maze learning and spontaneous alternation performance in mice.

1. The effects of intracerebroventricular administration of Tyr-D-Arg-Phe-beta-Ala-NH2 (TAPA), a novel dermorphin analog, on plus-maze learning and spontaneous alternation performance were investigated in mice. 2. The pre- or posttraining or preretention administration of TAPA (0.3-3.0 ng) alone failed to affect transfer latency of plus-maze learning, whereas TAPA (3 ng) produced a significant decrease in percent alternation without affecting total arm entries. 3. beta-Funaltrexamine (5 micrograms) almost completely reversed the TAPA (3 ng)-induced decrease in percentage of alternation. 4. These results suggest that stimulation of mu-opioid receptors disrupts spontaneous alternation performance associated with spatial working memory.

Analgesics, Opioid↗

PubMed1996

Neurokinin A and senktide attenuate scopolamine-induced impairment of spontaneous alternation performance in mice.

The effects of intracerebroventricular injections of the neurokinin-2 (NK-2) receptor agonist neurokinin A and the neurokinin-3 (NK-3) receptor agonist senktide on scopolamine (sc)-induced amnesia were investigated based on spontaneous alternation performance in mice. Spontaneous alternation performance is based on spatial working memory which produces a natural tendency to explore a less recently visited arm in a Y-maze. Neurokinin A (0.1-3 micrograms) or senktide (0.0003-0.03 microgram) alone did not influence either spontaneous alternation performance or total arm entries. However, neurokinin A (0.3 and 1 microgram) and senktide (0.003 and 0.03 microgram) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without affecting the scopolamine (1 mg/kg)-induced increase in total arm entries. Although the effects of neurokinin A (0.3 microgram) on the scopolamine-induced impairment of spontaneous alternation performance were almost completely antagonized by pretreatment with the NK-2 receptor antagonist cyclo (Gln-Trp-Phe-Gly-Leu-Met) (1 microgram), the inhibitory effects of senktide (0.003 microgram) were not influenced by pretreatment with the NK-3 receptor antagonist [Trp7, beta-Ala8]neurokinin A-(4-10). These findings suggest that neurokinin A inhibits the scopolamine-induced impairment of spontaneous alternation performance associated with working memory through the mediation of tachykinin NK-2 receptors, while senktide has some pharmacological action other than its effects on NK-3 receptors.

Amnesia↗

PubMed1995

Attenuation of memory with Tyr-D-Arg-Phe-beta-Ala-NH2, a novel dermorphin analog with high affinity for mu-opioid receptors.

The involvement of mu-opioid receptors in memory retrieval was examined in mice by using Tyr-D-Arg-Phe-beta-Ala-NH2 (TAPA), a novel dermorphin analog with high affinity for mu-opioid receptors, and passive avoidance learning. TAPA was intracerebroventricularly administered to mice before retention tests of passive avoidance learning. A 0.3-ng dose of TAPA markedly shortened step-down latency of passive avoidance learning, and the shortening of step-down latency was reversed by treatment with beta-funaltrexamine (5 micrograms), a mu-opioid receptor antagonist, indicating that TAPA (0.3 ng) attenuates memory retrieval. Although the attenuating dose (0.3 ng) of TAPA failed to affect horizontal or vertical locomotor activity, a 3-ng dose of TAPA showed a tendency to decrease vertical locomotor activity. A 30-ng dose of TAPA produced a significant increase in horizontal locomotor activity accompanied by a marked reduction of vertical locomotor activity. TAPA (3 ng) produced a significant increase in step-down latency of passive avoidance learning with lower intensity of electroshock or without electroshock during training. These results suggest that the activation of mu-opioid receptors impairs memory retrieval.

Amino Acid Sequence↗

PubMed1995

kappa-Opioid receptor agonists improve pirenzepine-induced disturbance of spontaneous alternation performance in the mouse.

We investigated the effects of kappa-opioid receptor agonists such as dynorphin A-(1-13) and U-50,488H on the muscarinic M1-selective receptor antagonist pirenzepine (3 micrograms, i.c.v.)-induced impairment of spontaneous alternation performance in the mouse. Although dynorphin A-(1-13)(1-5.6 micrograms, i.c.v.) or U-50,488H ((+/-)trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide, methanesulfonate hydrate) (0.1-1 mg/kg, i.p.) alone did not influence either spontaneous alternation performance or total arm entries, pirenzepine (3 micrograms, i.c.v.) impaired spontaneous alternation performance without producing any significant change in total arm entries. In contrast, dynorphin A-(1-13) (3 and 5.6 micrograms, i.c.v.) and U-50,488H (0.3 and 1 mg/kg, i.p.) ameliorated the pirenzepine (3 micrograms, i.c.v.)-induced impairment of spontaneous alternation performance. The ameliorating effects of dynorphin A-(1-13)(3 micrograms, i.c.v.) and U-50,488H (0.3 mg/kg, i.p.) were almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms, i.c.v.), a kappa-opioid receptor antagonist. These results suggest that the stimulation of kappa-opioid receptors improves memory dysfunctions resulting from the blockade of muscarinic M1 receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1995

Substance P markedly ameliorates scopolamine-induced impairment of spontaneous alternation performance in the mouse.

We investigated the effects of intracerebroventricular injection of substance P (SP) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance in the mouse. SP (0.001-3 micrograms) alone did not influence either spontaneous alternation performance or total arm entries. Scopolamine (1 mg/kg) impaired spontaneous alternation performance accompanied by an increment in total arm entries. In contrast, SP (0.01-1 micrograms) significantly improved the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing the scopolamine (1 mg/kg)-induced increase in total arm entries. The effects of SP (0.1 micrograms) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance were almost completely reversed by pretreatment with WIN 62577 (1 mg/kg), a tachykinin NK-1 receptor antagonist. These results suggest that SP improves the scopolamine-induced impairment of spontaneous alternation performance through the mediation of tachykinin NK-1 receptors.

Androstenes↗

PubMed1995

Dynorphin A-(1-13) potently improves scopolamine-induced impairment of passive avoidance response in mice.

The effects of intracerebroventricular administration of dynorphin A-(1-13) on scopolamine-induced amnesia were investigated in mice by using a step-down type passive avoidance task. The pre- or post-training, or pre-retention administration of dynorphin A-(1-13)(0.3-10 micrograms) alone failed to affect step-down latency of the passive avoidance response, while scopolamine (1 mg/kg) significantly shortened step-down latency. Dynorphin A-(1-13)(1 microgram) given 15 min before training and retention tests but not immediately after training significantly improved the scopolamine (1 mg/kg)-induced shortening of step-down latency of the passive avoidance response, indicating antiamnesic effects of dynorphin A-(1-13) (1 microgram). A lower dose (1 mg/kg) of the kappa-opioid receptor antagonist, (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)- 2'-hydroxy-6,7-benzomorphan, reversed the anti-amnesic effects of dynorphin A-(1-13) (1 microgram). These results suggest that the antiamnesic effects of dynorphin A-(1-13) depend on the timing of drug treatments.

Amnesia↗

PubMed1995

Cholinergic receptor agonists inhibit pirenzepine-induced dysfunction of spontaneous alternation performance in the mouse.

1. The present study was designed to examine the effects of intracerebroventricular injection of several cholinergic drugs on the impairment of spontaneous alternation performance induced by the M1-selective muscarinic receptor antagonist pirenzepine. 2. Pirenzepine (3 and 10 micrograms) significantly reduced spontaneous alteration performance related to working memory without producing any marked increase in total arm entries, which are considered to reflect locomotor activity. 3. Physostigmine (3.47 micrograms), a cholinesterase inhibitor, and McN-A-343 (20 micrograms), and M1-selective muscarinic receptor agonist, significantly improved the pirenzepine (3 micrograms)-induced impairment of spontaneous alternation performance, although oxotremorine (0.68 microgram), a nonselective muscarinic receptor agonist, showed a tendency to reverse the pirenzepine (3 micrograms)-induced impairment. 4. These findings suggest that the blockade of muscarinic M1 but not M2 receptors results in the impairment of spontaneous alternation performance associated with working memory.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1991

[Changes in serum levels of gynecological tumor markers throughout the period from early gestation to puerperium].

The aim of this study is to elucidate the change in serum levels of gynecological tumor markers throughout the period from the early gestational stage to puerperium. We measured eight tumor markers of--CA 125, TPA, SCC, AFP, haptoglobin, ferritin, CA19-9 and CEA--in 17 healthy women with a normal course of pregnancy, delivery and puerperium, and obtained the following results: 1) Profiles of change in serum levels of CA125, SCC, haptoglobin and ferritin were similar during pregnancy, with those levels being the highest at 4-15 weeks of gestation and declining gradually from 16 to 27 weeks. Serum levels of these four markers decreased significantly (p less than 0.01) at 16-27 and 28-40 weeks of gestation, respectively. 2) A significant (p less than 0.01) increase in CA125 and SCC was observed 2 hours after delivery compared with the levels in the first stage of delivery. However, these two markers decreased to the normal range after the fifth day postpartum. 3) Serum TPA decreased significantly (p less than 0.05) in 16-27 weeks of gestation, comparing with those of 4-15 weeks. Serum CA19-9 and CEA remained almost unchanged within the normal range throughout the period from pregnancy to puerperium. 4) Tumor markers of CA125, TPA, SCC, haptoglobin, ferritin and CEA of which serum levels decreased during the course of pregnancy and puerperium might be a clue to judge whether gynecological tumors in pregnant women are malignant or benign.

Antigens, Neoplasm↗

PubMed1987

Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancies.

Surgical treatment for tubal pregnancies greatly impairs the subsequent fertility of patients because of salpingectomy and its complicated adhesions. Nonsurgical methotrexate therapy was developed to avoid such complications. Although early detection was of prime importance, resolution of ectopic pregnancy was obtained in 22 patients (95.7%) with methotrexate administration alone. Patency of the oviducts was evaluated with hysterosalpingography and/or laparoscopy in 19 patients after termination of methotrexate treatment. In 10 of 19 patients (52.6%), complete patency of the involved oviduct confirmed the validity of this regimen. Severe side effects were not observed in any of the 23 patients.

Adult↗

PubMed1987

[MTX resistant mechanisms in human choriocarcinoma cells].

Choriocarcinoma cells grown in the presence of MTX have developed resistance in two ways. The HCCM derived sublines (relatively high MTX resistant) produced enhanced levels of DHFR and had relatively unimpaired transport of MTX, though altered transport was the primary determinant of response in the CC1 derived sublines (low MTX resistant). Since the selection procedure used was identical, it was assumed that altered MTX transport was insufficient to account entirely for various degrees of resistance. Increased DHFR activity was necessary for the development of high MTX resistance. The overproduction of DHFR was the consequence of amplification of the DHFR gene sequence. The incidence of DMs in metaphases paralleled the degree of resistance. Since DMs were also present in the cells not showing DHFR gene amplification, mechanisms other than DHFR gene multiplication were responsible for the de novo synthesis of DMs.

Cells, Cultured↗