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Volume 79 (1999)
- Issue 4 Pages 403-
- Issue 3 Pages 263-
- Issue 2 Pages 125-
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Volume 79, Issue 1
Displaying 1-17 of 17 articles from this issue
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Reviews
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Yoshihisa Kitamura, Takashi Taniguchi, Shun Shimohama1999 Volume 79 Issue 1 Pages 1-5
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSIt is now generally accepted that massive neuronal death due to oxidative stress is a common characteristic of brains in neurodegenerative disease. Recently, numerous apoptosis-regulating factors and multiple pathways have been identified, and apoptotic cell death has been implicated in neuronal loss in Alzheimer's disease. Although glial cells are more resistant to oxidative stress than neurons, extensive oxidative stress seems to cause apoptotic cell death in glial cells. In fact, signs of apoptosis are observed in both neurons and glial cells in the brains of patients with Alzheimer's disease. This review summarizes current findings regarding apoptotic processes and discusses the possible involvement of apoptosis-regulating factors in the pathology of Alzheimer's disease.View full abstractDownload PDF (686K) -
Current Studies on a Working Model of CaM Kinase II in Hippocampal Long-Term Potentiation and MemoryKohji Fukunaga, Eishichi Miyamoto1999 Volume 79 Issue 1 Pages 7-15
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSThere have been recent advances in understanding the molecular basis of the long-term potentiatiion (LTP) of synaptic transmission in the hippocampus. This review documents current views on mechanisms underlying LTP induction, from activation of the NMDA receptor to stimulation of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). We will focus in particular on recent findings of how CaM kinase II encodes the frequency of synaptic usage and serves as a molecular memory switch at the synapse. Furthermore, a role for CaM kinase II in spatial learning and memory is demonstrated by recent studies using transgenic mice.View full abstractDownload PDF (1243K)
Regular Papers
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Hong Ma, Hiroko Hashizume, Akiyoshi Hara, Kazuto Yazawa, Yasushi Abiko1999 Volume 79 Issue 1 Pages 17-24
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSWe examined the effects of quinaprilat, an active metabolite of quinapril (an angiotensin converting enzyme (ACE) inhibitor) on the increase in intracellular concentration of Ca2+ ([Ca2+]i) (Ca2+-overload) induced by lysophosphatidylcholine (LPC) in isolated rat cardiomyocytes. LPC (15 μM) produced Ca2+-overload with a change in cell-shape from rod to round. Quinaprilat but not quinapril at 20 or 50 μM attenuated the LPC-induced increase in [Ca2+]i and the change in cell-shape in a concentration-dependent manner. Since quinaprilat has an inhibitory action on ACE and quinapril has practically no inhibitory action on ACE, it is likely that the inhibitory action of quinaprilat on ACE is necessary for the protective effect of the drug against LPC-induced changes. We therefore examined the effects of enalapril (another ACE inhibitor with the weak inhibitory action on ACE) and enalaprilat (an active metabolite of enalapril with an inhibitory action on ACE) on the LPC-induced changes. Both enalapril and enalaprilat attenuated the LPC-induced Ca2+-overload, suggesting that the inhibitory action on ACE may not mainly contribute to the protective effect of ACE inhibitors against LPC-induced Ca2+-overload. This suggestion was supported by the fact that neither ACE (0.2 U/ml) nor angiotensin II (0.1 - 100 μM) increased [Ca2+]i in isolated cardiomyocytes. Furthermore, application of bradykinin (0.01 - 10 μM) did not enhance the protective effect of quinaprilat against LPC-induced changes. LPC also increased release of creatine kinase (CK) from the myocyte markedly, and quinaprilat but not quinapril attenuated the LPC-induced CK release. Unexpectedly, both enalapril and enalaprilat did not attenuate the LPC-induced CK release. Neither quinapril nor quinaprilat changed the critical micelle concentration of LPC, suggesting that these drugs do not directly bind to LPC. We conclude that quinaprilat attenuates the LPC-induced increase in [Ca2+]i, and that the protective effect of quinaprilat on the LPC-induced change may not be related to a decrease in angiotensin II production or an increase in bradykinin production.View full abstractDownload PDF (1131K) -
Flavia Valladão Thiesen, Helena M.T. Barros, Mario Tannhauser ...1999 Volume 79 Issue 1 Pages 25-31
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSEarly assessment of neurological and behavioral effects is extremely valuable for early identification of intoxications because preventive measures can be taken against more severe or chronic toxic consequences. The time course of the effects of an oral dose of the anticholinesterase agent propoxur (8.3 mg/kg) was determined on behaviors displayed in the open-field and during an active avoidance task by rats and on blood and brain cholinesterase activity. Maximum inhibition of blood cholinesterase was observed within 30 min after administration of propoxur. The half-life of enzyme-activity recovery was estimated to be 208.6 min. Peak brain cholinesterase inhibition was also detected between 5 and 30 min of the pesticide administration, but the half-life for enzyme activity recovery was much shorter, in the range of 85 min. Within this same time interval of the enzyme effects, diminished motor and exploratory activities and decreased performance of animals in the active avoidance task were observed. Likewise, behavioral normalization after propoxur followed a time frame similar to that of brain cholinesterase. These data indicate that behavioral changes that occur during intoxication with low oral doses of propoxur may be dissociated from signs characteristic of cholinergic over-stimulation but accompany brain cholinesterase activity inhibition.View full abstractDownload PDF (924K) -
Shinji Teramoto, Tetsuji Tomita, Hirotoshi Matsui, Eijiro Ohga, Takes ...1999 Volume 79 Issue 1 Pages 33-40
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSAlthough reactive oxygen species (ROS)-related cell damage has been implicated in pathogenesis of fibrogenetic pulmonary disorders, features of ROS-mediated cell death in human lung fibroblasts are not completely understood. We therefore examined the effects of hydrogen peroxide (H2O2) on cell growth kinetics in human lung fibroblasts (HFL-1 cells) and tested the roles of antioxidants on the H2O2-induced cell death (i.e., necrosis and apoptosis) in HFL-1 cells. We found that the relatively low concentrations of H2O2 ranging from 10 μM to 100 μM induced predominantly apoptosis, whereas higher concentration of H2O2 ranging 1 mM - 10 mM induced predominantly necrosis in HFL-1 cells. Extracellular supplementation of glutathione (GSH) in culture media significantly abolished the H2O2-induced cell death, whereas GSH-depleted cells by pretreatment with buthionine sulfoxime (BSO) were likely to undergo cell death caused by a lower concentration of H2O2 than normal HFL-1 cells without BSO treatment. These results indicate that H2O2 induces both necrosis and apoptosis of human lung fibroblasts at least in part through the action of ROS and that modulation of the ROS production inside and outside of cells may influence the cell survival during oxidative insults.View full abstractDownload PDF (1223K) -
Keiko Takemura, Kohei Takada, Shunichi Mameya, Muneshige Kaibara, Koht ...1999 Volume 79 Issue 1 Pages 41-49
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSFunctions and the presence of 5-hydroxytryptamine (5-HT) receptors in the fundus, corpus and antrum of the guinea pig stomach were examined by measuring contractile force and acetylcholine (ACh) release. Stimulation of the 5-HT1 receptor caused tetrodotoxin (TTX)-insensitive relaxations in the preparations from 3 regions. Stimulation of the 5-HT2 receptor caused TTX-insensitive contractions in the preparations of fundus and antrum. Stimulation of 5-HT3 receptors caused contractions that were sensitive to TTX and atropine and enhanced the outflow of [3H]ACh from preparations of only antrum. Stimulation of 5-HT4 receptors caused contractions of antral strips and decreased relaxations of corporal strips and enhanced the outflow of [3H]ACh from the preparations of both corpus and antrum. In the guinea pig stomach, the fundus possesses relaxant 5-HT1 receptor < contractile 5-HT2 receptors and caused the contractile response to 5-HT. The corpus possesses relaxant 5-HT1 receptors and relaxant receptors other than 5-HT1, 5-HT2, 5-HT3 and 5-HT4 receptors > contractile 5-HT4 receptor, and therefore 5-HT caused relaxations. The antrum possesses relaxant 5-HT1 receptor < contractile 5-HT2, 5-HT3 and 5-HT4 receptors, and thus 5-HT caused contractions.View full abstractDownload PDF (1155K) -
Kazushige Sakai, Michitaka Akima, Iwao Katsuyama1999 Volume 79 Issue 1 Pages 51-57
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSThe anti-ulcer effects of nicorandil [N-(2-hydroxyethyl)nicotinamide nitrate ester] were examined on water-immersion plus restraint stress-induced and aspirin-induced gastric ulcers in rats, compared with those of cimetidine. Nicorandil (3 and 10 mg/kg) given orally to rats dose-dependently inhibited the development of acid-related damage (water-immersion- and aspirin-induced gastric lesions) in the models. Cimetidine (50 mg/kg, p.o.) also had anti-ulcer effects in the same models. However, in the presence of glibenclamide (20 mg/kg, i.v.), an antagonist of KATP channels, nicorandil did not inhibit the formation of gastric lesions. Nicorandil (10 mg/kg) given intraduodenally (i.d.), like cimetidine (50 mg/kg), significantly reduced the volume of the gastric content, total acidity and total acid output in the pylorus ligation model. Glibenclamide reversed the changes caused by i.d. nicorandil. I.v. infusion of nicorandil (20 μg/kg per min) significantly increased gastric mucosal blood flow, without affecting blood pressure and heart rate, but the increase in the blood flow was not observed after i.v. treatment with glibenclamide (20 mg/kg). These results indicate that nicorandil administered orally to rats produces the anti-ulcer effect by reducing the aggressive factors and by enhancing the defensive process in the mucosa through its KATP-channel-opening property.View full abstractDownload PDF (905K) -
Dawn Xiao-Dong Zhu, James P. Sullivan, Jorge D.1999 Volume 79 Issue 1 Pages 59-64
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSATP-sensitive K+ channels (KATP) are distributed in a variety of tissues including smooth muscle, cardiac and skeletal muscle, pancreatic β-cells and neurons. Since KATP channels are present in the nigrostriatal dopamine (DA) pathway, the effect of potassium-channel modulators on the release of DA in the striatum of conscious, freely-moving rats was investigated. The extracellular concentration of DA was significantly decreased by the KATP-channel opener (-)-cromakalim but not by diazoxide. (-)-Cromakalim was effective at 100 and 1000 μM concentrations, and the maximum decrease was 54% below baseline. d-Amphetamine significantly increased extracellular DA levels at the doses of 0.75 and 1.5 mg/kg, s.c. with a 770% maximum increase. (-)-Cromakalim had no effect on d-amphetamine-induced DA release, while glyburide, a KATP blocker, significantly potentiated the effects of a low dose of d-amphetamine. These data indicate that K+ channels present in the nigrostriatal dopaminergic terminals modulate basal release as well as evoked release of DA.View full abstractDownload PDF (818K) -
Tsuneo Yasuda, Takeshi Iwamoto, Masayuki Ohara, Seiji Sato, Hideaki Ko ...1999 Volume 79 Issue 1 Pages 65-73
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSWe investigated the effects of OT-7100, a novel analgesic compound (5-n-butyl-7-(3, 4, 5-trimethoxybenzoylamino)pyrazolo[1, 5-a]pyrimidine), on prostaglandin E2 biosynthesis in vitro, acute hyperalgesia induced by yeast and substance P in rats and hyperalgesia in rats with a chronic constriction injury to the sciatic nerve (Bennett model), which is a model for peripheral neuropathic pain. OT-7100 did not inhibit prostaglandin E2 biosynthesis at 10-8 - 10-4 M. Single oral doses of 3 and 10 mg/kg OT-7100 were effective on the hyperalgesia induced by yeast. Single oral doses of 0.1, 0.3, 1 and 3 mg/kg OT-7100 were effective on the hyperalgesia induced by substance P in which indomethacin had no effect. Repeated oral administration of OT-7100 (10 and 30 mg/kg) was effective in normalizing the mechanical nociceptive threshold in the injured paw without affecting the nociceptive threshold in the uninjured paw in the Bennett model. Indomethacin had no effect in this model. While amitriptyline (10 and 30 mg/kg) and clonazepam (3 and 10 mg/kg) significantly normalized the nociceptive threshold in the injured paw, they also increased the nociceptive threshold in the uninjured paw. These results suggest that OT-7100 is a new type of analgesic with the effect of normalizing the nociceptive threshold in peripheral neuropathic hyperalgesia.View full abstractDownload PDF (1031K) -
Shoichiro Goto, Teruhiko Shimokawa1999 Volume 79 Issue 1 Pages 75-82
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSYM-16638 ([[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1, 3, 4-thiadiazol-2-yl]thio] acetic acid) showed a strong hypocholesterolemic effect in humans and monkeys. To clarify the mechanism of this hypocholesterolemic effect, the action of YM-16638 on cholesterol biosynthesis in the cultured human hepatoma cell line HepG2 and cynomolgus monkey liver was examined. Cholesterol biosynthesis activity derived from [14C]acetic acid, [3H/14C]mevalonic acid or [14C]isopentenyl pyrophosphate substrates was significantly decreased, but not that from [3H]farnesyl pyrophosphate or [3H]squalene substrates in HepG2 cells treated with YM-16638. Simultaneously, treatment of these cells with YM-16638 changed neither the rate of apolipoprotein B synthesis from [35S]methionine nor its secretion. In addition, the activities of hepatic cholesterol biosynthesis enzymes HMG-CoA reductase, mevalonate kinase (MK), isopentenyl pyrophosphate isomerase (IPPI), farnesyl pyrophosphate synthase (FPPS), squalene synthase and squalene epoxidase were measured in monkeys fed a diet supplemented with YM-16638. Among these enzymes, MK, IPPI and FPPS activities in the YM-16638-treated group significantly decreased by 38%, 56% and 30%, respectively, when compared to those from control animals receiving no drug treatment. These results indicate that YM-16638 has the characteristics of a cholesterol biosynthesis inhibitor.View full abstractDownload PDF (1107K) -
Masakatsu Takahashi, Hiroshi Kaneto1999 Volume 79 Issue 1 Pages 83-87
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSThe antinociceptive effect induced by exposure to socio-psychological (PSY) stress using a communication box was assessed by the formalin test in mice, compared with those by exposure to footshock (FS) stress and forced swimming (SW) stress. After the termination of stress exposure, whereas exposure to FS- and SW-stress resulted in the attenuation of the formalin-induced biphasic pain response over 15 min, no appreciable antinociceptive effect was found in the case of PSY stress. When exposure to PSY stress was started during the period of early or late phase of pain after the formalin injection, the antinociceptive effect was maintained for 5 - 15 min; however, further exposure to PSY stress was not effective for producing antinociception. In the tail-pinch test, likewise, exposure to PSY stress longer than 5 min rather decreased the intensity of antinociception. We conclude that PSY stress in this tonic pain paradigm produces antinociception, but further continuous exposure to the emotional stress caused mice to become recuperative even in such a fear-inducing situation.View full abstractDownload PDF (534K) -
Luciano Saso, Giovanni Valentini, Maria Luisa Casini, Eleonora Mattei, ...1999 Volume 79 Issue 1 Pages 89-99
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSNatural hydrophobic substances like bile salts (cholate, deoxycholate, chenodeoxycholate, lithocholate and their conjugates with glycine and taurine), fatty acids (caprylic, capric, lauric, myristic, palmitic, stearic, oleic, linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acid) were much more active (EC50≅10-4 - 10-5 M) than selected amino acids (EC50 >10-2 M) and inorganic salts (EC50≅10-1 M) in inhibiting heat-induced denaturation of human serum albumin in vitro. Fish oil, rich in n-3-polyunsaturated acids such as eicosapentaenoic acid and docosahexaenoic acid, administered p.o. (1 ml/kg) in the rat, protected ex vivo (after 2 hr) serum against heat-induced denaturation more than bendazac, a known antidenaturant drug. Thus, we speculated that the antidenaturant activity of fish oil may be partly (in addition to the known effect on endogenous eicosanoid composition) responsible for its beneficial effects in rheumatoid arthritis and other rheumatic conditions. In this connection, it is of note that the in vitro antidenaturant activity of fish oil fatty acids was higher than that of known antidenaturant drugs such as bendazac and bindarit and nonsteroidal anti-inflammatory drugs like phenylbutazone and indomethacin which could exert beneficial effects in chronic inflammatory conditions by stabilizing endogenous proteins.View full abstractDownload PDF (1459K) -
Satoru Takahashi, Jun-ichi Shigeta, Makoto Ishikawa, Norihiro Kobayash ...1999 Volume 79 Issue 1 Pages 101-107
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSWe investigated the role of thromboxane (TX) A2 in gastric ulcer healing in rats. Acetic acid ulcers were produced in male Donryu rats. TXA2 synthesis in the stomachs with ulcers was significantly elevated in ulcerated tissue, but not in intact tissue, compared with that in the gastric mucosa of normal rats. Indomethacin inhibited both TXA2 and prostaglandin E2 (PGE2) synthesis in ulcerated tissue, while NS-398 (selective cyclooxygenase-2 inhibitor) reduced only PGE2 synthesis. OKY-046 (TXA2 synthase inhibitor) dose-relatedly inhibited only TXA2 synthesis. The maximal effect of OKY-046 (80% inhibition) was found at more than 30 mg/kg. When OKY-046 was administered for 14 days, the drug at more than 30 mg/kg significantly accelerated ulcer healing without affecting acid secretion. The maximal reduction of ulcerated area by OKY-046 was about 30%, compared with the area in the control. Histological studies revealed that regeneration of the mucosa was significantly promoted by OKY-046, but neither maturation of the ulcer base nor angiogenesis in the base were affected. OKY-046 and TXB2 had no effect on proliferation of cultured rat gastric epithelial cells, but U-46619 (TXA2 mimetic) dose-relatedly prevented the proliferation without reducing cell viability. These results indicate that the increased TXA2, probably derived from cyclooxygenase-1 in ulcerated tissue, exerts a weak inhibitory effect on ulcer healing in rats. The effect of TXA2 might be due partly to prevention of gastric epithelial cell proliferation at the ulcer margin.View full abstractDownload PDF (938K)
Short Communications
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Akira Furuichi, Noriaki Makimoto, Masayuki Ogishima, Kanichirou Nakao ...1999 Volume 79 Issue 1 Pages 109-112
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSIntestinal contractility and release of endogenous acetylcholine (ACh) were measured simultaneously in vivo in the small intestine of the anesthetized dog. Electrical stimulation of nerves in the intestinal seromuscular layers caused contractions and increased concentrations of ACh in the dialysate, which were abolished by infusion of tetrodotoxin into the intestinal marginal artery at 75 nmol/ml. Intraarterial administration of atropine at 150 nmol/ml abolished the stimulated contractions, without significant effects on increases in concentrations of dialysate ACh. Thus, the nerve-stimulated contractions were found in vivo to be associated with a local increase in ACh release from the intestinal cholinergic neurons.View full abstractDownload PDF (499K) -
Kazumasa Uemura, Shuko Yoshioka, Denise M. Surina-Baumgartner, Tatsuo ...1999 Volume 79 Issue 1 Pages 113-115
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSWe investigated the effects of intracerebroventricular administration of NIK-247 (9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclo-penta(b)-quinoline monohydrate hydrochloride; a cholinesterase inhibitor) or MKC-231 (2-(2-oxypyrrolidin-l-yl)-N-(2, 3-dimethyl-5, 6, 7, 8-tetrahydrofuro[2, 3-b]quinolin-4-yl) acetoamide; a choline uptake enhancer) on plasma glucose level in comparison with that of neostigmine administration in rats. The extents of NIK-247- and MKC-231-induced hyperglycemia were considerably less than that by neostigmine, suggesting that the potencies of the drugs to produce the peripheral hyperglycemia may be pharmacologically negligible.View full abstractDownload PDF (417K) -
Sebastian Wolfrum, Andreas Dendorfer, Peter Dominiak1999 Volume 79 Issue 1 Pages 117-120
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSKallidin (KD) is an important vasoactive kinin whose physiological effects are strongly dependent on its degradation through local kininases. In the present study, we examined the spectrum of these enzymes and their contribution to KD degradation in isolated perfused rat hearts. By inhibiting angiotensin-converting enzyme (ACE), aminopeptidase M (APM) and neutral endopeptidase (NEP) with ramiprilat (0.25 μM), amastatin (40 μM) and phosphoramidon (1 μM), respectively, relative kininase activities were obtained. APM (44%) and ACE (35%) are the main KD degrading enzymes in rat heart; NEP (7%) plays a minor role. A participation of carboxypeptidase N (CPN) could not be found.View full abstractDownload PDF (505K) -
Kyoji Morita, Itsuo Tokunaga, Shin-ichi Kubo1999 Volume 79 Issue 1 Pages 121-124
Published: 1999
Released on J-STAGE: March 31, 2001
JOURNAL FREE ACCESSAlthough paraquat has been shown to cause oxidative damage to neuronal cells, little is known about its effect on glial cells. Thus the effect of paraquat on glial cells was examined using rat C6 glioma cells as a model system. Paraquat reduced cell viability in a concentration- and time-dependent manner, and this toxic effect was not significantly attenuated by various kinds of antioxidants. Furthermore, paraquat failed to increase 8-hydroxy-deoxyguanosine formation in the cells. These results indicate that paraquat can be toxic to glial cells and suggest that this cytotoxic effect may not be associated with the oxidative damage to the cells.View full abstractDownload PDF (484K)
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