The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 82 , Issue 3
Showing 1-14 articles out of 14 articles from the selected issue
Reviews
  • Atsufumi Kawabata, Ryotaro Kuroda
    2000 Volume 82 Issue 3 Pages 171-174
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    The protease-activated receptor(PAR)belongs to the large superfamily of G-protein-coupled seven trans-membrane domain receptors.The activation of PARs is achieved by proteolytic unmasking of the cryptic N-terminal receptor-activating sequence that binds to the body of the same receptor molecule.PARs-1, -3 and -4 are activated by thrombin, while PAR-2 is activated by trypsin or mast cell tryptase, but not by thrombin.PARs are weidely distributed to a variety of tissues and participate in a number of physiological or pathophysiological phenomena such as platelet aggregation, inflammation and cardiovascular, digestive or respiratory functions.Thus, PARs are of physiological importance and also of pharmacological interest as the novel target for drug development.
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  • Yuko Fukunaga, Shiroh Kishioka
    2000 Volume 82 Issue 3 Pages 175-180
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    The effects of opioid(e.g., morphine)withdrawal on levels on endogenous opioid peptides and their mRNA in the various brain regions have been studied.However, the role of this opioidergic mechanism in the mediation of opioid withdrawal is not fully understood.Preproenkephalin(PPE)mRNA in the caudal periaqueductal gray(cPAG), an important brain region in opioid withdrawal, is increased by both opioid antagonist(naloxone)-precipitated and spontaneous morphine withdrawal, but not by various other stresses in rats, indicating a role of endogeneous enkephalins in the cPAG in morphine withdrawal.In addition, PPE mRNA levels in the cPAG increase in the course of the dissipation of morphine withdrawal, and they are returned to the control levels after disappearance of morphine withdrawal signs.Local administration of an enkephalin analog or peptidase inhibitors into the cPAG suppresses morphine withdrawal signs.These facts suggest that enkephalinergic neurons in the PAG may have a critical role in the recovery phase of morphine withdrawal.Recently, an involvement of transcription factors in morphine withdrawal has been suggested.Thus, the possible role of transcription factors in the regulation of PPE gene expression in the cPAG during morphine withdrawal is also discussed.
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Full Papers
  • Seok Ho Cha, Tae-Won Hahn, Takashi Sekine, Kweon-Haeng Lee, Hitoshi En ...
    2000 Volume 82 Issue 3 Pages 181-187
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    In the present study, we investigated the effect of adenosine triphosphate(ATP)on cytosolic free calcium mobilization and mitogenic activity in cultured bovine corneal endothelial cells(BCEC).The[Ca2+]i was determined using a Ca2+ sensitive indicator, Fura-2/AM, and cell proliferation was evaluated by counting the cell number.ATP, its metabolites and analogs caused transient increase in[Ca2+]i in a concentration-dependent manner(10-7M−10-3M)and the potency of agonists was ordered as follows:2-methylthio-ATP>uridine triphosphate>ATP>adenosine diphosphate.Adenosine monophosphate and adenosine did not affect[Ca2+]i.ATP(10-4M)also promoted the accumulation of inositol trisphosphate(IP3).The ATP-induced transient[Ca2+]i increase and IP3 accumulation were attenuated by pretreatment with a phospholipase C inhibitor, U-73122(5μM), for 30 min.ATP(10-5M)significantly enhanced the proliferation of BCEC.ATP-induced[Ca2+]i increase and cell proliferation were inhibited by a purinoceptor antagonist, suramin(10-4M).Thus, the present study indicates that BCEC contain P2 purinoceptors that regulate their proliferation.
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  • Hiroyasu Hirose, Toshifumi Kimura, Megumu Okada, Yoshiki Itoh, Fumiaki ...
    2000 Volume 82 Issue 3 Pages 188-198
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    We investigated the effects of NSP-513, (R)-4, 5-dihydro-5-methyl-6-[4-(2-propyl-3-oxo-1-cyclo-hexenyl)amino]phenyl-3(2H)-pyridazinone, on phosphodiesterase(PDE)isozyme activities, in vitro platelet aggregation and in vivo thrombus formation.NSP-513 selectively inhibited human platelet PDE 3 isozyme with an IC50 value of 0.039μM.In an in vitro human platelet aggregation assay, the IC50 values(μM)of NSP-513 for platelet aggregation induced by collagen, U-46619, arachidonic acid, adenosine diphosphate(ADP), epinephrine and thrombin were 0.31, 0.25, 0.082, 0.66, 0.23 and 0.73, respectively.In a mouse pulmonary thromboembolism model, orally administered NSP-513 showed in vivo antithrombotic effects that were 320 to 470 times more potent than those of cilostazol.In a rat carotid arterial thrombosis model, intraduodenally administered NSP-513(0.1mg/kg), cilostazol(30mg/kg)and aspirin(30mg/kg)reduced thrombus formation by 75%, 66% and 48%, respectively.However, intravenously administered dipyridamole(10mg/kg)did not significantly prevent thrombus formation.These results demonstrate that NSP-513 has the potential to prevent not only in vitro platelet aggregation but also in vivo thrombus formation and indicate that the highly selective PDE 3 inhibitory effect of NSP-513 may make this compound useful for assessing the physiological role of PDE 3.
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  • Tomoaki Tokuno, Katsuhiko Muraki, Minoru Watanabe, Yuji Imaizumi
    2000 Volume 82 Issue 3 Pages 199-209
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    Induction of electrical abnormalities(EAs)under simulated ischemic conditions and after reperfusion was measured from single cardiac myocytes isolated from guinea pig ventricle using whole-cell voltage or current clamp with perforated patch variation.Conditions of simulated ischemia were produced by the exchange of medium from the standard one oxygenated with 95%O2−5%CO2 gas(pH7.4)to the modified one, which contained no glucose, 8mM K+ and 30mM sodium-D, L-lactate and was gassed with 90% argon −10%CO2(pH6.6).Under the simulated ischemia for 20min, EAs such as delayed afterdepolarization, early afterdepolarization, automatic activity or transient inward current were observed in about 37% of myocytes driven electrically at 1Hz.Irreversible hypercontracture occurred in myocytes of 10% or less.Upon reperfusion with the standard solution, EAs and hypercontracture were oberved in about 43% and 22% of cells, respectively.Glibenclamide-sensitive current was detected during ischemia, but tended to be enhanced during reperfusion.Amplitude of Ca2+ current and ATP-sensitive K+ current after reperfusion varied widely with time and from cell to cell.When myocytes were pretreated for 10min with 10nM benidipine, a 1, 4-dihydropyridine derivative Ca2+ blocker, the incidence of EAs and hypercontracture was markedly reduced, suggesting the protective effect of benidipine against cardiac cell injury during ischemia and reperfusion.
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  • Ichiro Kondo
    2000 Volume 82 Issue 3 Pages 210-217
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    I investigated the role of protein kinase C(PKC) in regulation of the capacitative Ca2+ entry and steroidogenesis in bovine adrenocortical(BA)cells.Thapsigargin(TG)-treatment depleted intracellular Ca2+ stores followed by induction of Ca2+ influx from the extracellular pool and also increasing of Mn2+ influx as an indicator of divalent cation influx in BA cells.Calphostin C, a PKC inhibitor, inhibited the TG-induced [Ca2+]i elevation dose-dependently(0.1-1μM)and attenuated Mn2+ entry.Phorbol 12-myristate 13-acetate(PMA), an activator of PKC, potentiated the elevation of[Ca2+]i and enhanced Mn2+ entry by TG treatment.These results suggest that PKC may modulate capacitative Ca2+ entry in BA cells.In the presence of extracellular Ca2+, TG enhanced cortisol production in BA cells.Calphostin C attenuated the TG-induced steroidogenesis dose-dependently(0.25-1μM).PMA enhanced the steroidogenesis dose-dependently(1-100nM).These results suggested that PKC may have a modulatory effect on the capacitative Ca2+ entry that links to steroidogenesis in BA cells.
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  • Mikio Ito, Ayako Ban, Masashi Ishihara
    2000 Volume 82 Issue 3 Pages 218-225
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    In this study, we compared the effects of low molecular weight(LMW)chitosan(MW:25, 000-50, 000), high molecular weight(HMW)chitosan(MW:500, 000-1000, 000)and chitin on ethanol-induced gastric mucosal injury and on the healing of acetic acid-induced gastric ulcers in rats.Oral administration of LMW chitosan(250, 500 and 1000mg/kg)dose-dependently prevented ethanol-induced gastric mucosal injury.Repeated oral administration of LMW chitosan(100, 200 and 400mg/kg twice daily)also dose-dependently accelerated the gastric ulcer healing.However, the effects of HMW chitosan and chitin on the gastric mucosal injury formation and the gastric ulcer healing were less potent than those of LMW chitosan.LMW chirosan(250 and 500mg/kg, orally)was ineffective in inhibiting gastric acid secretion in pylorus-ligated rats, although it had a weak acid-neutralizing action.LMW-chitosan(250, 500 and 1000mg/kg orally)dose-dependently prevented the decrease in gastric mucus content induced by ethanol.These results indicate that of the three compounds, LMW chitosan has the most potent gastric cytoprotective and ulcer healing-promoting actions.In addition, gastric mucus-increasing action of LMW-chitosan may be, at least in part, related to the anti-ulcer effect of this compound.
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  • Makoto Nishihara, Kunihiko Yokotani, Shimpei Inoue, Yoshitsugu Osumi
    2000 Volume 82 Issue 3 Pages 226-231
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    Possible roles of thromboxane A2(TXA2)in the release mechanism of hippocampal noradrenaline(NA)were examined in vitro.Slices or crude synaptosomes prepared from the rat hippocampus were superfused with modified Krebs-Ringer solution.Application of 20mM KCl for 5min increase the release of NA from the slices, and this release was consistently reproduced.Application of U-46619(9, 11-dideoxy-9α, 11α-methanoepoxy prostaglandin F), a specific TXA2 mimetic, just before the second KCl(20mM)stimulation decreased the KCl-evoked NA release in a concentration-dependent manner(10-100μM).This U-46619(50μM)-induced inhibition of NA release was abolished by 10μM SQ29548, a specific TXA2 receptor antagonist.In experiments with hippocampal crude synaptosomes, however, KCl(20 and 40mM)-evoked release of NA was not attenuated by U-46619(100μM).Furthermore, the inhibitory effect of U-46619(50μM)in the sliced preparations was not modified by 100μM(−)-bicuculline, a GABAA-receptor antagonist.The present results indicate that U-46619 inhibits the release of NA from the rat hippocampus by activation of TXA2 receptors.Activation of TXA2 receptors probably excites an unidentified but not GABAergic neuron system, thereby inhibiting the NA release from the rat hippocampus.
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  • Takahiro Nakamura, Keizo Okada, Kiyoshi Nagata, Yasushi Yamazoe
    2000 Volume 82 Issue 3 Pages 232-239
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    Properties of cytochrome P450(P450)in rabbit intestines have been investigated to assess the possibility of an experimental model for human intestinal oxidation of drugs.Significant amounts of P450 and cytochrome b5 and activities of NADPH-cytochrome P450 reductase were detected in microsomes from rabbit duodenal, jejunal, ileac and colon mucosa.All the small intestinal fractions mediated phenytoin, dextromethorphan and testosterone oxidations.Several P450 forms belonging to the CYP1A, CYP2C, CYP2D and CYP3A, but not CYP2B and CYP2E, subfamilies were detected in these tissues by Western blotting.A good correlation was observed between immunodetectable levels of CYP3A and activities of testosterone 6β-hydroxylation.Small intestine, but not colon, CYP3A levels were increased by the pretreatment of rabbits with rifampicin(50mg/kg for 4 days, p.o.).The extent of the increase was similar between duodena and livers.These properties of rabbit intestinal P450s were comparable to those of human intestine.These phenomena suggest the possibility that the rabbit is a beneficial in vivo model for the assessment of drug interaction occurring at the first pass of drugs ingested.
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  • Tohru Fukushima, Takaya Nitta, Hiroshi Furuichi, Nobuo Izumo, Tohru Fu ...
    2000 Volume 82 Issue 3 Pages 240-246
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    Using an experimental model of type 1 osteoporosis under the chronic therapy with an anti-inflammatory steroid, the bone anabolic effect of PTH(1-34)was evaluated by histomorphometrical and biomechanical analysis.Wistar female rats(12-week-old)were ovariectomized and allowed to develop an osteopenic model in the presence or absence of methylprednisolone acetate(MPA:0.1mg/kg, s.c., 3-days-a-week basis from the 5th week after ovariectomy(OVX)).The osteopenia that developed for the first 12 weeks after OVX was almost completely normalized by subsequent PTH pulsing(20μg/kg, s.c., 5-days-a-week)for 8 weeks starting at the 13th week;the following characteristics were observed:1)proximal tibial metaphysis:recovered bone volume, rather increased trabecular thickness and osteoid volume, and normalized eroded surface;2)5th lumbar vertebra(L-5):partially recovered trabecullar connectivity;3)femur and 4th lumbar vertebra(L-4):recovered mechanical strength in maximum elastic load and maximum elastic energy.The anabolic effect of PTH(1-34)was not substantially modified by MPA.Salmon calcitonin(SCT:10U/kg per day, s.c., 5-days-a-week, for 8 weeks)was anabolic in limited parameters:decreased number of osteoclasts, recovered maximum elastic load in femur, and partially recovered maximum elastic load in L-4.The results suggest that PTH(1-34)pulsing is able to recover OVX-induced osteopenia in the structure and mechanical strength not only of the cancellous bone but also of the cortical bone, and the anabolic effect can be clinically expected even under steroid medication.
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  • Hung-Ming Wu, Chiung-Chun Huang, Li-Hsin Li, Jing-Jane Tsai, Kuei-Sen ...
    2000 Volume 82 Issue 3 Pages 247-260
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    We evaluated the anticonvulsant effect of Chai-Hu-Long-Ku-Mu-Li-Tan(TW-001), a Chinese herbal medicine, and its mechanisms in several standard rodent models of generalized seizure.TW-001(4 g/kg, p.o.)significantly increased the threshold for tonic electroconvulsions and the thresold for tonic seizures in response to i.v.infusion of pentylenetetrazole(PTZ).In the s.c.PTZ seizure test, both the incidence and severity of seizures were decreased by TW-001.TW-001(1-10mg/ml)did not alter resting membrane potential or input resistance of the hippocampal CA1 neurons, but elicited a reversible suppression of stimulus-triggered epileptiform activity in area CA1 and spontaneously occuring epileptiform burst discharges in area CA3 elicited by picrotoxin.Both field excitatory postsynaptic potentials and population spikes were reversibly depressed by TW-001(0.5-1.5mg/ml)in a concentration-dependent manner.The sensitivity of postsynaptic neurons to a glutamate-receptor agonist, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate, was not altered by TW-001(10mg/ml).However, TW-001(5mg/ml)clearly increased the magnitude of paired-pulse facilitation.TW-001(5-10mg/ml)reversibly limited the repetitive firing and reduced the maximal rate of rise of action potentials elicited by injection of depolarizing current pulses(0.4nA, 200ms)into the pyramidal cells.TW-001(1-10mg/ml)exerted a concentration-dependent reduction of the tetrodotoxin-sensitive sodium currents and high voltage-activated calcium currents.These results suggest that TW-001 is an interesting new anticonvulsant agent that exerts its anticonvulsant activity through inhibition of sodium and calcium channesl, stabilizing neuronal membrane excitability and inhibiting glutamate release.
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Short Communications
  • Katsuyuki Miura, Shinya Yamanaka, Tsuneyuki Ebara, Michiaki Okumura, M ...
    2000 Volume 82 Issue 3 Pages 261-264
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    The present experiments were conducted to clarify the mode of cardiovascular action of carboxy-2-phenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide(carboxy-PTIO), a nitric oxide(NO)scavenger, during rat endotoxic shock by determining cardiac output and systemic arterial tone simultaneously.Lipopolysaccharide(LPS)(10mg/kg, i.v.) decreased systemic blood pressure and cardiac output with transient increases in hematocrit and total vascular resistance.Administration of carboxy-PTIO(1.7mg·kg-1·min-1, i.v.for 60min) at 90min after LPS attenuated further decline in blood pressure and cardiac output without affecting changes in hematocrit or total vascular resistance.It is concluded that carboxy-PTIO attenuates endotoxin-induced hypotension predominantly by maintaining cardiac output in rat experimental endotoxic shock.
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  • Norihisa Miyake, Ryousuke Fujita, Masaaki Ishikawa, Motoaki Takayanagi ...
    2000 Volume 82 Issue 3 Pages 265-268
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    A new type of organic Ca2+ channel blocker, tamolarizine, was examined for its reversing effect on multidrug-resistant tumor cells.Tamolarizine synergistically potentiated the cytotoxicity of doxorubicin for doxorubicin-resistant K562 cells(K562/DXR)at a concentration of 0.1-10μM, but had hardly any synergistic effects in the parental cell line(K562)at the same concentration.Moreover, tamolarizine inhibits the P-glycoprotein pump-efflux activity in a dose-related manner and reduces the expression of the immunoreactive P-glycoprotein in K562/DXR cells as evaluated by cytofluorimetric assay.These results indicate that tamolarizine reverses the multidrug-resistance phenotype through direct interaction with P-gylcoprotein.
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  • Minori Mitsui-Saito, Norimichi Nakahata, Yasushi Ohizumi
    2000 Volume 82 Issue 3 Pages 269-271
    Published: 2000
    Released: January 31, 2001
    JOURNALS FREE ACCESS
    SK&F 96365(1-{β-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl}-1H-imidazole hydrochloride)is widely used as an effective inhibitor of receptor-linked and capacitative Ca2+ entry.Since this inhibitor has additional effects such as inhibition of voltage-dependent Ca2+ channels, sarco- and endoplasmic reticula Ca2+ pumps and cell proliferation, its molecular mechanism of action remains to be solved.In the present study, we have investigated the effect of SK&F 96365 on microtubule protein isolated from bovine brain in vitro.SK&F 96365 depolymerized the polymerized microtubules in a concentration-dependent manner.This result suggests that SK&F 96365 directly depolymerizes microtubules, an effect that may contribute to the various actions of this compound.
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