Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 91 , Issue 1
Showing 1-12 articles out of 12 articles from the selected issue
Critical Review
  • Jian-Dong Li
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 1-7
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    Although tremendous effort has been put towards identifying the surface molecules of nontypeable Haemophilus influenzae (NTHi) for vaccine development over the past decades, it is only recently that we have begun to appreciate the intricate host epithelial signaling networks activated by NTHi, an important human pathogen causing respiratory infections. From what has been reported, it is evident that NTHi activates multiple signaling pathways in host epithelial cells that, in turn, inadvertently contribute to the pathogenesis. Among those signaling pathways, activation of NF-κB leads to up-regulation of IL-1β, IL-8 and TNF-α, mucin MUC2 and Toll-like receptor 2 (TLR2), whereas activation of p38 MAP kinase mediates not only up-regulation of inflammatory mediators and mucin MUC5AC but also down-regulation of TLR2. Interestingly, NTHi-induced activation of the PI3K-Akt pathway, however, leads to inhibition of p38 mitogen-activated protein (MAP) kinase. Moreover, the TGF-β-Smad signaling pathway cooperates with NF-κB to mediate up-regulation of mucin MUC2. Finally, glucocorticoids synergistically enhance NTHi-induced TLR2 expression via specific up-regulation of the MAP kinase phosphatase-1 that, in turn, leads to inactivation of p38 MAP kinase, the negative regulator for TLR2 expression. These studies may bring new insights into the molecular pathogenesis of NTHi-induced infections and open up novel therapeutic targets for these diseases.
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Full Papers
  • Terumasa Hashimoto, Miyuki Yamashita, Hisayuki Ohata, Kazutaka Momose
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 8-14
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    Lysophosphatidic acid (LPA) has been shown to be a chemoattractant in in vitro studies. The present study was carried out to determine whether LPA enhances infiltration of inflammatory cells in in vivo studies with guinea pigs. LPA (1 – 10 μg/ml), when by guinea pigs for 5 min, substantially increased the numbers of eosinophils and neutrophils in the bronchoalveolar lavege fluid (BALF), which was recovered at over 4 h after the inhalation of LPA. Infiltration in BALF was significantly inhibited by inhalation of Y-27632, an inhibitor of Rho-associated protein kinase (ROCK). LPA also increased superoxide production of eosinophils and neutrophils. In contrast, Y-27632 inhibited superoxide production. These findings suggest that LPA may contribute to infiltration and activation of inflammatory cells in bronchial asthma; furthermore, the Rho/ROCK-mediated pathway may be involved.
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  • Tatsuki Oyoshi, Masahiro Nomoto, Hirofumi Hirano, Jun-ichi Kuratsu
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 15-22
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    Nitric oxide (NO) is thought to be a mediator in many of the processes of malignant brain tumor progression. We examined NO production in the brain of normal conscious, freely moving rats with or without implanted C6 glioma. Both nitrite (NO2) and nitrate (NO3) in the dialysates of the two groups were measured using an in vivo microdialysis technique. The mean concentration of NO2 in the glioma group was two-times higher than that in the control group (P<0.01). Concentrations of both NO2 and NO3 in the glioma and control groups decreased following intraperitoneal injection of NG-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NO synthase (NOS). NO production was also significantly suppressed in the glioma group, but not the control group, by intraperitoneal injection of 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a selective inhibitor of inducible NOS (iNOS). On immunohistochemical examination, diffuse iNOS-positive cells were located within glioma tissue. ED1-positive cells (microglia/macrophages) were intermingled between glioma cells on double immunostaining. These results indicate that the basal level of NO production in the glioma group is higher than that in the control group and that the increased NO production was continuously induced by iNOS-expressing cells in glioma.
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  • Masahiro Kawamura, Osamu Terasaka, Takanori Ebisawa, Ichiro Kondo, Eij ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 23-33
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    Store-operated Ca2+ entry channels (SOCs) play an important role in the regulation of diverse non-excitable cell functions. However, the precise mechanism of SOCs activation is still controversial. Uridine 5'-triphosphate (UTP) was shown to induce Ca2+ entry in a dihydropyridines-insensitive manner and accelerated steroidogenesis in bovine adrenocortical fasciculata cells (BAFCs) via the Gq/11 protein-coupled P2Y2 receptor. Therefore we investigated whether UTP is involved in SOCs activation and the mechanism of UTP-induced SOCs activation. Fura 2-loaded BAFCs were used for the measurement of intracellular concentration of Ca2+ ([Ca2+]i) mobilization. Extracellular UTP evoked Ca2+ release from intracellular stores followed by an increase in Ca2+ entry. The Ca2+ influx elicited by UTP was inhibited not by nifedipine, but by Zn2+, Cd2+, and Ni2+ (potency order: Zn2+ > Cd2+ >> Ni2+), and the effect of UTP was also attenuated by a phospholipase C inhibitor (U73122). These results indicate that UTP activates SOCs in BAFCs. The increase in [Ca2+]i by UTP was attenuated by ML-9, a myosin-light chain kinase inhibitor, and calmodulin inhibitors, W-7 and E6 berbamine, in a concentration-dependent manner. These reagents depolymerized actin filaments with rhodamine staining in BAFCs. Cytochalasin D also inhibited UTP-activated SOCs and depolymerized actin filaments. From these results, we proposed that calcium/calmodulin dependent myosin-light chain kinase is involved in the mobilization of actin filaments and the integrity of actin-network plays an important role in UTP-induced SOCs activation in BAFCs.
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  • Kumiko Nakamura, Shoshiro Okada, Kunihiko Yokotani
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 34-40
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    We examined the effect of endothelin-1, endothelin-3 and sarafotoxin S6c on the release of noradrenaline from gastric sympathetic nerve terminals using an isolated, vascularly perfused rat stomach. The release of noradrenaline evoked by electrical stimulation of the gastric postganglionic sympathetic nerves (at 2.5 Hz for 1 min) was inhibited by endothelin-1 (1010 – 108 M), endothelin-3 (109 – 108 M) and sarafotoxin S6c (a highly selective agonist of endothelin ETB receptors) (109 – 108 M) in a concentration-dependent manner; the inhibitory potencies were as follows: endothelin-1 > endothelin-3 > sarafotoxin S6c. The inhibitory effect of endothelin-1 (3 × 109 M) on noradrenaline release was abolished by BQ-123 (a selective antagonist of endothelin ETA receptors) in a dose-dependent manner (107 and 106 M), but not influenced by BQ-788 (a selective antagonist of endothelin ETB receptors) (107 and 106 M). The endothelin-1-induced inhibition of noradrenaline release was attenuated by pretreatment with pertussis toxin (10 μg/animal, i.v., 4 days before experiments), but not influenced by indomethacin (3 × 106 M). These results indicate that endothelin ETA and ETB receptors located on the sympathetic nerve terminals play a role in the inhibition of noradrenaline release from the rat stomach: endothelin ETA receptor-mediated inhibition is carried out by pertussis toxin-sensitive and indomethacin-insensitive mechanisms.
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  • Tomohisa Ishikawa, Yukiko Kaneko, Fumi Sugino, Koichi Nakayama
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 41-46
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    The present study investigated the effects of cGMP on cytosolic Ca2+ concentration ([Ca2+]c) of isolated rat pancreatic β-cells. In the presence of 7.0 mM glucose, NOC 7, a nitric oxide (NO) donor, caused an increase in [Ca2+]c of the β-cells, which was abolished by the soluble guanylate cyclase inhibitor ODQ. Similar [Ca2+]c elevation was evoked by 8-bromo-cGMP. The [Ca2+]c elevating responses to NOC 7 and 8-bromo-cGMP were abolished by nicardipine or in a Ca2+-free medium, but were not affected by thapsigargin, suggesting that they are produced by the Ca2+ influx through L-type voltage-operated Ca2+ channels. In contrast, NOC 7 and 8-bromo-cGMP decreased the [Ca2+]c when it was raised in advance by the elevation of external K+ concentration to 30 mM or by 4-aminopyridine. The pretreatment with thapsigargin almost abolished the [Ca2+]c reduction induced by the agents, suggesting that the action is likely to be primarily attributable to an acceleration of the Ca2+ sequestration into the endoplasmic reticulum. These results suggest that cGMP has two distinct effects on the [Ca2+]c of rat pancreatic β-cells: a facilitation of the Ca2+ influx through L-type voltage-operated Ca2+ channels and an acceleration of the Ca2+ sequestration in the endoplasmic reticulum.
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  • Mihoko N. Nakashima, Ken-ichi Ajiki, Kenichiro Nakashima, Masakatsu Ta ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 47-52
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    The possible role of nitric oxide (NO) in anxiety following transient cerebral ischemia by a 10-min bilateral carotid occlusion was examined in mice. Two days after the ischemia, mice showed a significant decrease in time spent on the open arms in the elevated plus-maze test; and likewise, they showed shortened social interaction time in the social interaction test, suggesting the induction of anxiety. Such anxiety behavior, however, was diminished 7 days after the treatment in both tests. A nonselective nitric oxide synthase (NOS) inhibitor, N ω-nitro-L-arginine methyl ester (L-NAME), and a selective inducible NOS (iNOS) inhibitor, S-ethylisothiourea (EIT), given twice after reperfusion, produced an anxiolytic effect in the elevated plus-maze test 2 days after the ischemia, while only the former produced antianxiety in the social interaction test. A relatively selective neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI), failed to decrease the level of anxiety in both tests. These results suggest that the production of NO participates in the anxiogenic behavior by the ischemia. Furthermore, NO generated by endothelial NOS (eNOS) or eNOS with iNOS, with no involvement of nNOS, plays an important role in the anxiety induced by the ischemia. Thus, we conclude that 10-min bilateral carotid occlusion provides a useful exploratory animal model for anxiety following transient cerebral ischemia.
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  • Shih-Hurng Loh, Jong-Shiaw Jin, Chien-Sung Tsai, Chao-Ming Chao, Yin T ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 53-60
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    Hydrogen peroxide (H2O2) and its metabolites have been shown to exert complex effects on the cardiac muscle during cardiac ischemia/reperfusion. The aim of the present study, by perfusing H2O2 or/and different scavengers of oxygen free radicals (OFRs) into the human atrium, is to characterize the electropharmacological effects of H2O2 and explore its possible underlying mechanism. Atrial tissues obtained from the heart of 19 patients undergoing corrective cardiac surgery were used. Transmembrane action potentials were recorded using the conventional microelectrode technique, and contraction of atrial fibers was evaluated in normal [K]o (4 mM) in the absence and presence of tested agents. H2O2 (30 μM-3 mM) had a biphasic effect on the contractile force (an increase, followed by a decrease), reduced the 0-phase depolarizing slope (dV/dt), and prolonged the action potential duration (APD) in a concentration-dependent manner. However, even at a concentration as high as 3 mM, H2O2 did not influence diastolic membrane potential (DMP). Pretreatment with N-(mercaptopropionyl)-glycine (N-MPG), a specific scavenger of the · OH free radical, significantly blocked the 3 mM H2O2-induced electromechanical changes, while the pretreatment with L-methionine (L-M), a specific scavenger of HOCl free radical, did not. Our data suggests that the toxic effects of H2O2 are caused mainly through the generation of · OH, which is attributed to the electropharmacological inhibitory effects seen in the human atrium.
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  • Toshiki Ogawa, Kazuhiko Maeda, Shunsuke Tonai, Takashi Kobayashi, Take ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 61-70
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    Menetrier's disease is characterized by giant gastric folds with foveolar hyperplasia and cystic dilatation, hypoproteinemia, and enhanced mucus secretion. The etiology remains unresolved and an effective treatment has yet to be established. Here we show that histamine H2-receptor deficient mice developed gastric pathophysiological changes resembling Menetrier's disease for up to 17 months of observation. Mutant mice were found to have an increased stomach weight, enlarged gastric folds with cystic dilatation, hypergastrinemia, hypoalbuminemia, increased mucus secretion and overexpression of mucosal transforming growth factor (TGF) α. Both a cholecystokinin (CCK)2-receptor antagonist and an epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor significantly reduced the increase in stomach weight. It appears that lack or downregulation of histamine H2-receptors might be involved in the pathogenesis of Menetrier's disease.
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  • Yoshifumi Inoue, Masakazu Isobe, Hideya Hayashi
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 71-78
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    CX-659S ((S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione), a newly discovered anti-inflammatory compound, exerts inhibitory effects against picryl chloride-, oxazolone-, and dinitrochlorobenzene-induced acute contact hypersensitivity responses (CHRs) characterized by Th1-type reactions. Furthermore, this compound suppressed chronic CHRs characterized by Th2-type reactions, which is well known to mimic many, if not all, events occurring within the lesional skin of patients with atopic dermatitis (AD). The present study was conducted to determine the combined effect of topical CX-659S with topical corticosteroid on immediate type (ITR), late type (LTR), and delayed type hypersensitivity (DTHR) allergic reactions that are involved in AD. An ineffective dose of CX-659S (0.03 mg/ear) combined with betamethasone valerate (BV) significantly potentiated inhibitory activity of BV alone (0.1 μg/ear and 0.3 μg/ear) on both the ITR and the LTR in mice with the ovalbumin (OVA)-induced biphasic cutaneous reaction. Furthermore, the combined effect of CX-659S with BV was also observed on dinitrochlorobenzene (DNCB)-induced DTHR in guinea pigs. These results indicate that CX-659S has a combined effect with corticosteroids on every ITR, LTR, and DTHR. Proper treatment with corticosteroids for a safe and effective treatment of AD is needed. Thus, the combination therapy of topical CX-659S with topical corticosteroid would be one of the potential approaches for devising a proper treatment with corticosteroids.
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Short Communications
  • Kageyoshi Ono
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 79-82
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    The role of ETA endothelin receptor (ETAR) in the regulation of the delayed rectifier potassium current (IK) was examined in guinea pig atrial myocytes. Application of ET-1 (10 nM) together with an ETB-receptor-selective antagonist, BQ-788 (300 nM), significantly increased the voltage-dependent activation of IK without affecting its half-activation voltage or the slope factor, while it suppressed the calcium current (ICaL) and displaced the time-independent background current to the outward direction. The data suggests that the augmentation of IK contributes to the ETA-receptor-mediated shortening of action potential duration, and hence to the negative inotropic response, in atria.
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  • Hiromi Nakao, Chisato Umebayashi, Mami Nakata, Yasutaka Nishizaki, Kat ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 1 Pages 83-86
    Published: 2003
    Released: January 24, 2003
    JOURNALS FREE ACCESS
    To test the possibility that micromolar formaldehyde, a metabolite of methanol derived from aspartame, exerts cytotoxicity, its effect on rat thymocytes was examined under the in vitro condition using a flow cytometer. Incubation of thymocytes with formaldehyde at 100 μM or more for 24 h significantly increased the populations of shrunken cells and cells with hypodiploid DNA. The peak blood concentration of methanol in human subjects administered abuse doses of aspartame has been reported to exceed 2 mg/dL (625 μM). It would increase the population of thymocytes undergoing apoptosis if formaldehyde at 100 μM or more appears in the blood after administration of aspartame.
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