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Biomedical subjects

A Nishida

Publications and source records attributed to A Nishida.

At least 55 records · Page 3Linked to original sources
PubMed1998

Agonist-induced desensitization of adenylyl cyclase activity mediated by 5-hydroxytryptamine7 receptors in rat frontocortical astrocytes.

Our previous study has demonstrated that astrocytes derived from the rat frontal cortex contain 5-hydroxytryptamine (5-HT)7 receptors positively coupled to adenylyl cyclase. In this study, we observed a desensitization of 5-HT7 receptors induced by a treatment with agonists (0.1, 1, and 10 muM, 0.5 to 3.5 h). Maximum responses, but not the EC50 values, in the concentration-response curve of 5-HT-induced cyclic AMP formation were decreased after pretreatment with 5-HT. Pretreatment with 5-carboxamidotryptamine (5-CT) elicited a potent desensitization of 5-HT-induced cyclic AMP formation. Neither 2-methyl-5-HT nor alpha-methyl-5-HT caused the desensitization. When the astrocytes were treated with isoproterenol, N-ethylcarboxamidoadenosine, and dibutyryl cyclic AMP (all of which increase intracellular cyclic AMP levels), 5-HT-induced cyclic AMP responses were not affected. Conversely, adenylyl cyclase activity mediated by either isoproterenol or N-ethylcarboxamidoadenosine was attenuated by pretreatment with each of these agonists, but not 5-HT. In addition, our study showed that the administration of 5-HT, 5-CT, and 8-hydroxy-2-(di-n-propylamino)tetralin to the astrocytes stimulated cyclic AMP formation both in the presence and absence of forskolin, whereas in neuron-rich cultures of the frontal cortex, these agonists did not change basal cyclic AMP levels and decreased forskolin-stimulated cyclic AMP formation. Neurons may predominantly contain 5-HT1A receptors that are negatively coupled to adenylyl cyclase. These results suggest that 5-HT7 receptors are highly expressed in astrocytes but not in neuronal cells, and that pretreatment with their agonists results in a homologous desensitization of the receptors.

Adenylyl Cyclases↗
PubMed1998

Positive influence of a liaison program on the rate of psychiatric consultation referrals for cancer patients.

To improve access to psychiatric consultation for cancer patients as well as non-cancer patients with psychiatric disorders, a psychiatric liaison programme to communicate closely with physicians and ward staff regarding anticipated psychiatric morbidity in patients, was introduced in each ward of a general hospital. The rate of psychiatric consultation referrals for cancer patients was significantly higher after the psychiatric liaison programme was established. The programme had a greater impact on the rate of psychiatric consultation in a unit with cancer patients who were informed of their diagnoses. The greater consultation rates in cancer patients after the liaison programme might be, in part, associated with the physicians' attitude toward the more open disclosure of the cancer diagnosis.

Aged↗
PubMed1998

Spectrophotometric determination of neutrophil cytochrome b558 of chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disease characterized clinically by severe recurrent bacterial infections from infancy. This disease is a disorder of the formation of superoxide (O2-) by the neutrophil NADPH oxidase system, mostly due to defects in cytochrome b558 (cyt b558), which is one of the oxidase components. Diagnosis of CGD has been performed by the assay of the O2- forming activity, immunological determination of defects in the oxidase components, and or spectrophotometry of cyt b558. However, spectrophotometric analysis of the b-type heme is difficult with small amounts of blood from infant CGD patients, as the limited amounts of neutrophils are contaminated with a relatively high ratio of hemoglobin (Hb) that interferes with the heme spectrum of cyt b558. This report presents an accurate method for the spectrophotometric analysis of cyt b558 in a small amount of CGD neutrophils that were treated with CO gas in a safe procedure instead of the previously reported CO-bubbling method. METHODS AND RESULTS: The difference of the reduced minus oxidized cyt b558 spectrum was measured under no interference from oxy Hb at the alpha and beta bands and differentiated as d[delta A]/d lambda (lambda = wavelength) to obtain further evidence for the defects of the cyt b558 heme spectrum. The interference from CO-insensitive met Hb was eliminated by subtracting the absorption peak at the Soret (gamma) band of the contaminating met Hb, which was estimated from the CO-treated and untreated spectra of the same, hemolyzed sample. CONCLUSIONS: This spectrophotometric method is feasible for the determination of abnormality and heme content of cyt b558 with a small amount of CGD neutrophils in 10-20 mL of blood even in the presence of contaminating Hb.

Cytochrome b Group↗
PubMed1998

Histological variations of canine deciduoma induced in non pregnant horn at different stages of unilateral pregnancy.

Histological variations of canine deciduoma which was induced in the non pregnant horn at several stages of unilateral pregnancy were examined. In the first half of the unilateral pregnancy, deciduoma was characterized by the cystic glandular hyperplasia corresponding to each of the stages in normal early placentation. In the second half, deciduoma could not be induced and few histological reactions were recognized. The endometrium looked normal for late diestrus with no growth of the uterine glands. These differences might reflect the latent strength of the uterine glands to proliferate and dilate in the stimulated periods.

Animals↗
PubMed1998

Effects of YF476, a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion in beagle dogs with gastric fistula.

The antisecretory effects of the gastrin/cholecystokinin-B (CCK-B) receptor antagonist YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl) 1H-1,4-benzodiazepin-3-yl]-3-(3-methylaminophenyl)-urea, CAS 155488-25-8) on secretagogue- and peptone-induced gastric acid secretion in beagle dogs with chronic gastric fistula were examined. Plasma gastrin concentrations were evaluated following introduction of peptone into the stomach. Intravenous administration of YF476 dose-dependently inhibited pentagastrin (1 microgram/kg/h)-induced gastric acid secretion, with an ED50 value of 0.0023 mumol/kg. In contrast, intravenous administration of YF476 (0.3 mumol/kg) did not affect histamine (15 micrograms/kg/ h)-induced gastric acid secretion. Oral administration of YF476, famotidine and omeprazole dose-dependently inhibited peptone (8%, 200 ml)-induced gastric acid secretion with ED50 values of 0.11, 0.76 and 4.28 mumol/kg, respectively. The antisecretory effect of YF476 was about 7 and 40 times more potent than that of famotidine and omeprazole, respectively. Plasma gastrin concentrations were increased by introduction of peptone. These results suggest that YF476 is an extremely potent and selective antisecretory drug and the endogenous gastrin plays an important role in peptone-induced gastric acid secretion in dogs.

Animals↗
PubMed1997

Effect of a selective 5-HT3 receptor agonist on gastric motility in fasted and fed dogs.

The effect of m-chlorophenylbiguanide, a selective 5-HT3 receptor agonist, on gastric antral motility was investigated in conscious dogs with a force transducer implanted chronically. m-Chlorophenylbiguanide (0.1-1 mg/kg i.v.) dose dependently enhanced antral motility in the fasted state, and the amplitude of m-chlorophenylbiguanide (1 mg/kg i.v.)-induced antral contractions reached the level of natural phase III contractions. In contrast, m-chlorophenylbiguanide reduced the amplitude of antral contractions in the fed state. A selective 5-HT3 receptor antagonist, ramosetron (0.0003-0.03 mg/kg i.v.), inhibited both effects of m-chlorophenylbiguanide. m-Chlorophenylbiguanide (1 mg/kg i.v.)-induced contractions were inhibited by atropine (0.03 or 0.1 mg/kg i.v.). These results indicate that pharmacological activation of 5-HT3 receptors has opposite effects on canine gastric antral motility in the fasted and in the fed state, being stimulatory and inhibitory, respectively. The stimulatory effect seems to be mediated mainly via the release of acetylcholine.

Animals↗
PubMed1997

Phosphatidylethanol inhibits phosphatidylinositol-phospholipase C activity in a competitive manner with phosphatidylinositol-4,5-bisphosphate.

The effect of phosphatidylethanol (PEth) on phosphatidylinositol-phospholipase C (PLC) activity was investigated in rat cerebral cortex. PEth decreased PLC activity in both the membrane and the cytosol of the cortex in a concentration-dependent manner, varying from 6 to 400 microM, and PLC activity was almost entirely inhibited at concentrations of PEth over 200 microM (90% inhibition). The IC50 of PEth in the cytosol was 25.2 microM and was 22.1 microM in the membrane. Preincubation of the cytosol with anti-PLC-beta 1, anti-PLC-gamma 1 or anti-PLC-delta 1 antibodies did not prevent the decrease in PLC activity. These results suggest that PEth caused the decrease in PLC activity without isozyme specificity. The sensitivity of PLC to Ca2+ in the cytosol and membrane was not changed by PEth, suggesting that PEth may act on PLC at a site different from that of Ca2+ activation. In higher concentrations of the PLC substrate, PEth did not inhibit PLC activity, indicating that PEth inhibited PLC activity in a substrate competitive manner. Neomycin, which binds to negatively charged phospholipids such as phosphatidylinositol-4,5-bisphosphate (PIP2) and thus causes inhibition of PLC activity, attenuated the PEth-induced decrease in PLC activity. This result suggests that the inhibitory action of PEth on PLC may be related to the fact that PEth is a negatively charged phospholipid similar to PIP2.

Animals↗
PubMed1997

(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): a potent and orally active gastrin/CCK-B antagonist.

A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in vivo included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N-[1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyri dyl) -1H-1,4-benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N-[1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5- (2-pyridyl)-1H-1,4-benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl ]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21nmol/kg po in dogs. 15c is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).

Administration, Oral↗
PubMed1997

Cu, Zn-superoxide dismutase reaction in neonatal pontosubicular neuron necrosis.

The immunohistochemical localization and changes in copper/zinc superoxide dismutase (Cu, Zn-SOD) were examined in 14 neonates with pontosubicular neuron necrosis (PSN), as compared with those in 15 controls in which the cytoplasm of neurons and glial cells showed SOD immunoreactivity. In the temporal lobes and hippocampus with PSN, Cu, Zn-SOD reactivity was negative in neurons at 0 and 1 days after birth, but was positive after 5 days of age in 8 of 10 cases. In the pons and cerebellum, SOD-positive neurons appeared soon after birth, but eosinophilic or karyorrhectic neurons were SOD negative. On the other hand, glial cells were positive after birth in all cases of PSN, and their reactivity was increased in the cases of reactive astrogliosis. Early loss of the scavenging system directed at free radicals may lead to neuronal damage, and the induction of Cu, Zn-SOD may act as a defense mechanism against damage of neurons in neonates with PSN. Therefore, oxygen-derived free radicals may be one of the pathogenetic factors of PSN with characteristics of apoptosis in neonates.

Case-Control Studies↗
PubMed1997

Chemiluminescence from human polymorphonuclear leukocytes activated with opsonized zymosan.

To prove the mechanism of photon emission during activation of leukocytes, a model system of human polymorphonuclear leukocytes (PMNs)-opsonized zymosan (OZ)-tyrosine (or none) or myeloperoxidase (MPO)-H2O2-tyrosine was employed, and three parameters-chemiluminescence yield and intensity, a metabolite such as bityrosine (BT), and chemiluminescence spectra-were studied. With the PMN system, the luminescence was enhanced by addition of tyrosine, its analogues, or albumin, but was inhibited by hydroxyurea, superoxide dismutase (SOD), or NaN3 (an inhibitor of MPO), indicating participation of tyrosine phenoxyl radicals, O2.- and MPO in the luminescence. With the PMN-OZ-tyrosine system, chemiluminescence yield was parallel to the BT formation. These results were essentially the same as those obtained with the MPO-H2O2-tyrosine system, except that luminescence from the latter system was not inhibited by SOD. When human albumin was exposed to the MPO-H2O2 system, BT was detected after hydrolysis of the protein in the mixture. Judging from the chemiluminescence spectra of activated PMNs and the MPO-catalyzed tyrosine oxidation, at least two excited species in triplet states-one for tyrosine and another for BT-would be generated in these systems. The luminescence may originate from the reaction of tyrosine phenoxyl radicals (cation radicals) with O2.- and/or peroxidase compound III (Fe...IIIO2.-).

Humans↗
PubMed1997

YM022, a potent and selective gastrin/CCK-B receptor antagonist, inhibits peptone meal-induced gastric acid secretion in Heidenhain pouch dogs.

We examined the affinity of YM022, a potent and selective gastrin/CCK-B receptor antagonist, for canine gastrin/CCK-B and CCK-A receptors and the effects of YM022 on secretagogue- and peptone meal-induced acid secretion in the denervated, surgically separated (Heidenhain) canine gastric pouch model in comparison with those of famotidine, an H2-receptor antagonist, and atropine. YM022 inhibited the binding of [(125)I]CCK-8 and [(3)H]devazepide to canine gastrin/CCK-B and CCK-A receptors, with IC50 values of 0.73 and 136 nM, respectively. Intravenous YM022 dose-dependently inhibited pentagastrin- and peptone meal-induced acid secretion with ED50 values of 0.0261 and 0.0654 micromol/kg, respectively, without affecting histamine- or methacholine-induced acid secretion. Famotidine inhibited acid secretion induced by all stimulants, while atropine inhibited the acid secretion induced by every stimulant except histamine. These results indicated that YM022 is a highly potent and selective antagonist for the canine gastrin/CCK-B receptor and suppressed pentagastrin- and peptone meal-induced gastric acid secretion without affecting histamine- or methacholine-induced acid secretion in Heidenhain pouch dogs.

Animals↗
PubMed1997

YF476 is a new potent and selective gastrin/cholecystokinin-B receptor antagonist in vitro and in vivo.

BACKGROUND: We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl)-1H-1, 4benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/cholecystokinin-B (CCK-B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo. METHODS: We examined the binding properties of YF476 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs. RESULTS: YF476 replaced the specific binding of [125I]CCK-8 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, with Ki values of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat brain gastrin/CCK-B receptor was 4100-fold higher than that for rat pancreatic CCK-A receptor. In anaesthetized rats, intravenous YF476 inhibited pentagastrin-induced acid secretion with an ED50 value of 0.0086 micromol/kg, but did not affect histamine- and bethanechol-induced acid secretion at a dose of 10 micromol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhibited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED50 values of 0.018 and 0.020 micromol/kg, respectively, but did not affect histamine-induced acid secretion. CONCLUSION: These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B receptor antagonist, and that the gastrin/CCK-B receptor is not involved in histamine- or bethanechol-induced gastric acid secretion in dogs or rats.

3T3 Cells↗
PubMed1997

Down-regulation of 5-hydroxytryptamine7 receptors by dexamethasone in rat frontocortical astrocytes.

Astrocytes derived from rat frontal cortex contain 5-hydroxytryptamine7 (5-HT)7 receptors positively coupled to adenylyl cyclase. In the present study, we investigated the effects of glucocorticoids on adenylyl cyclase activity and 5-HT7 receptor gene expression in astrocytes. Addition of dexamethasone (0.01-100 nM, 12-72 h) to the culture medium decreased cyclic AMP formation induced by 5-HT in a time- and concentration-dependent manner. Dexamethasone treatment (10 nM, 48 h) reduced maximum responses of cyclic AMP formation induced by 5-HT and 5-carboxamidotryptamine without alterations in the EC50 value. In contrast, treatment with the mineralocorticoid aldosterone (48 h) had no significant effects on 5-HT-induced cyclic AMP formation with concentrations up to 10 nM. It was observed that dexamethasone treatment (1-100 nM, 3-72 h) also decreased the expression of 5-HT7 receptor mRNA, using reverse transcription and polymerase chain reaction analysis. A significant reduction in expression of 5-HT7 mRNA appeared at 3 h of dexamethasone treatment and reached a maximum at 6 h of treatment. On the other hand, dexamethasone treatment (10 nM, 48 h) did not affect basal levels of cyclic AMP and cyclic AMP synthesis stimulated by isoproterenol, N-ethylcarboxamidoadenosine, cholera toxin, and forskolin. These results suggest that dexamethasone decreases the expression of the 5-HT7 receptor gene and, consequently, 5-HT7 receptor-mediated signal transduction in frontocortical astrocytes.

Adenosine↗
PubMed1997

[Reproductive and developmental toxicity studies of taltirelin hydrate (2) teratogenicity study in rats by oral administration].

Teratogenicity study of taltirelin hydrate, a thyrotropin releasing hormone analogue, was carried out in Wistar rats. Female rats were orally given taltirelin hydrate at a dose of 0 (control), 0.15, 1.5, or 15 mg/kg from day 7 to day 17 of gestation. Twenty-seven female rats in each group were sacrificed on day 21 of gestation and their fetuses were examined. The remaining 13 female rats in each group were allowed to deliver spontaneously and their newborns were examined. In the 15 mg/kg group, the dams (P) showed wet dog shaking behavior and hyperlocomotion. No adverse effect of taltirelin hydrate on the body weight gain, food consumption, water intake, and reproductive performance was observed in this group. In the 0.15 and 1.5 mg/kg groups, taltirelin hydrate did not show any adverse effects. In F1 generation groups, taltirelin hydrate had no teratogenic, lethal, or growth retardation effects in any groups. There were also no adverse effects of taltirelin hydrate on postnatal development, emotionality, coordinated activity, sensitivity, learning ability, and reproductive performance of F1 offspring, and development of F2 fetuses. These results show that the no-toxic dose levels of taltirelin hydrate are 1.5 mg/kg for general toxicity in dams, and 15 mg/kg for reproductive function of dams (P) and for development of F1 generation.

Administration, Oral↗
PubMed1997

[Reproductive and developmental toxicity studies of taltirelin hydrate (3) teratogenicity study in rabbits by oral administration].

Teratogenicity study of taltirelin hydrate, a thyrotropin releasing hormone analogue, was carried out in Japanese white rabbits. Female rabbits were orally given taltirelin hydrate at a dose of 0 (control), 0.15, 1.5, or 15 mg/kg from day 6 to day 18 of gestation. Females were sacrificed on day 29 and their fetuses were examined. Neither death nor adverse effects on food consumption in dams were found in any dose groups. In the 15 mg/kg group, rapid breathing and decreased body weight gain in dams were temporally observed. No adverse effect of taltirelin hydrate on reproductive function was detected in any groups. In the fetal examination, taltirelin hydrate had no teratogenic, lethal, or growth retardation effects in any groups. These results show that the no-toxic dose levels of taltirelin hydrate are 1.5 mg/kg for general toxicity in dams, and 15 mg/kg for reproductive function of dams and for development of their offspring.

Administration, Oral↗
PubMed1997

Benefit of multiple trait selection to increase reproductive traits: experimental evidence from golden hamsters.

Fifteen generations of selection were conducted to study responses for litter size at birth (LSB), weight at weaning of standardized litter (LWW), and individual body weight at 8 wk of age (BW8) using golden hamsters as an experimental model for pigs. The experiment involved three lines: selection on an aggregate breeding value of LSB, LWW, and BW8 (line W); selection on an aggregate breeding value of LSB and LWW (line R); and a randomly selected control (line C). Selection in W and R was based on breeding values from a multiple trait animal model. Restricted maximum likelihood with an animal model was used to estimate genetic parameters and genetic trends. Heritability estimates for LSB, LWW, and BW8 were .10, .47, and .52, respectively, and genetic correlations between traits were all positive. The mean estimated breeding value (EBV) for LSB in generation 15 was +2.2 pups in W and R. The mean EBV for LWW in generation 15 was +318 g for W and +174 g for R, and for BW8 means were +64 g and +24 g, respectively. Average inbreeding at generation 16 was 13.4, 19.5, and 8.0% for W, R, and C, respectively. Including BW8 in the selection criterion reduced inbreeding and had a beneficial effect on selection responses in LSB, LWW, and BW8.

Animals↗
PubMed1997

Pharmacokinetic and pharmacodynamic evaluation of central effect of the novel antiallergic agent betotastine besilate.

Betotastine besilate (betotastine CAS 125602-71-3, TAU-284) is a novel antiallergic agent with histamine H1 receptor antagonistic activity. As the classical antihistamines are known to produce drowsiness, the present study was conducted to assess a possible influence of betotastine on the central nervous system (CNS). Measurement of the drug concentration in brain and plasma after i.v. administration revealed that betotastine, as well as cetirizine and epinastine, poorly penetrate into the CNS, while terfenadine do so slightly more and ketotifen remarkably more. In vitro receptor binding assays demonstrated that betotastine is a highly specific histamine H1 receptor ligand, having no significant binding affinity for histamine H3, adrenergic alpha 1, alpha 2, beta, dopamine D2L, serotonin 5-HT2, muscarinic, and benzodiazepine receptors. On global behavior of mice, oral administration of betotastine did not produce any marked changes at the doses of 100-1000 mg/kg, but suppressed huddling behavior at 1000 mg/kg and caused slight mydriasis at 300 mg/kg and more. Betotastine did not significantly affect spontaneous motor activity (SMA) and hexobarbital-induced anesthesia in mice up to 300 mg/kg p.o. In the sleep-wakefulness pattern of cats, it reduced the total duration of sleep at 10 mg/kg p.o., but did not show significant effect at 30 and 100 mg/ kg p.o. Cetirizine showed a similar profile as betotastine in these experiments, whereas ketotifen and epinastine induced sedative signs or toxic symptoms in lower doses, and terfenadine affected SMA and the anesthesia at a high dose. These results suggest the very low liability of betotastine to produce sedative side-effect in a therapeutic dose range.

Animals↗