The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 81, Issue 1
Displaying 1-18 of 18 articles from this issue
Reviews
  • Makoto Tsuda, Norifumi Shimizu, Tsutomu Suzuki
    1999 Volume 81 Issue 1 Pages 1-6
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Recent research has demonstrated that the receptor for glutamate, a major excitatory neurotransmitter, may play an important role in the expression of benzodiazepine withdrawal signs. This proposal is based on various observations. For example, antagonists for N-methyl-D-aspartate (NMDA), non-NMDA and metabotropic glutamate (mGlu) receptors can suppress the behavioral signs of benzodiazepine withdrawal in mice and rats. Furthermore, the NMDA receptor in the cerebrocortical area of diazepam-withdrawn rats is upregulated. Finally, the stimulation of phosphoinositide hydrolysis mediated by mGluR is enhanced in cerebrocortical slices from lorazepam-withdrawn mice. These findings show that the upregulation of signal transduction mediated by glutamate receptors during diazepam withdrawal plays a role in the neuroadaptive response responsible for the expression of diazepam withdrawal signs. Furthermore, ligands for glutamate receptors may be suitable targets for treating benzodiazepine withdrawal signs.
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Full Papers
  • Ediz Demirpençe, Hakan Caner, Murat Bavbek, Kamer K¹l¹n ...
    1999 Volume 81 Issue 1 Pages 7-11
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Mexiletine is a class Ib antiarrhythmic drug used in the treatment of ventricular arrhythmias. The Na+ channel blocker mexiletine inhibits calcium influx in cells via decreasing reverse operation of the Na+-Ca2+ exchanger. Thus this drug is shown to protect the CNS white matter against anoxic/ischemic injury. The aim of our study was to investigate if this drug could act as an antioxidant drug as well. The antioxidant action of this drug was studied under different oxidant conditions in vitro, and thiobarbituric acid - reactive substances were measured to follow lipid peroxidation. Mexiletine inhibited iron-ascorbate-H2O2 - induced lipid peroxidation in brain membranes, liver microsomes and phospholipid liposomes, being most effective in brain membranes. The inhibition was dose- and time-dependent. Mexiletine also inhibited copper-ascorbate-H2O2 - induced lipid peroxidation but to a lesser extent. It is concluded that mexiletine has a dual effect toward oxidative injury in brain, both by inhibiting Na+-Ca2+ exchanger-dependent Ca2+ influx and by acting as an inhibitor of lipid peroxidation. However, as this drug is effective at millimolar concentrations, it should be considered less active than natural antioxidants that are effective at micromolar concentrations.
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  • Chiyuki Akiyama, Taku Nagao, Hitoshi Kurose
    1999 Volume 81 Issue 1 Pages 12-20
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    When the wild type β1-adrenergic receptor (WT-β1AR) was expressed in Sf9 cells, the β1AR-stimulated adenylyl cyclase activities were desensitized by prior treatment with isoproterenol. The extent of β1AR desensitization was not modified, and the onset was not promoted by the overexpression of G protein-coupled receptor kinase 2 (GRK2), GRK5 or GRK6. However, overexpression of the dominant negative mutant of GRK2 appeared to inhibit desensitization of the β1AR. The change of the potential protein kinase A phosphorylation site located at the intracellular third loop did not affect β1AR desensitization. Desensitization of the truncated mutant, in which nearly all of the serine and threonine residues from the carboxyl terminus were eliminated, was the same as that of the WT-β1AR. A deletion mutant that lacked serine and threonine residues of the intracellualr third loop was also desensitized by isoproterenol stimulation. Furthermore, the deletion of serine and threonine residues from both the intracellular third loop and carboxyl terminus did not affect desensitization of the β1AR. These results suggested that phosphorylation by endogenous GRKs in Sf9 cells contributed to desensitization of the β1AR and that the regions other than third intracellular loop and carboxyl terminus may be responsible for β1AR desensitization.
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  • Hiroshi Azuma, Jun Sato, Hiroshi Masuda, Moritaka Goto, Satoru Tamaoki ...
    1999 Volume 81 Issue 1 Pages 21-28
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The present experiments were designed to investigate the effect of ATZ1993 {3-carboxy-4, 5-dihydro-1-[1-(3-ethoxyphenyl)propyl]-7-(5-pyrimidinyl)methoxy-[1H]-benz[g]indazole} on the intimal hyperplasia after balloon endothelial denudation of the rabbit carotid artery. ATZ1993 inhibited the specific [125I]endothelin (ET)-1 binding not only to ET-receptor subtype A (ETA) with a pKi value of 8.69±0.02, but also to ET-receptor subtype B (ETB) with a pKi value of 7.20±0.03. Counterscreening in the binding assay (30 different receptors) confirmed that ATZ1993 had a high selectivity for ET receptors. Increases in intima:media ratio and DNA content in the vessel wall were significantly (P<0.005) inhibited by ATZ1993 in a daily dose of 30 mg·200 ml-1·kg-1 for 1 week before and 6 weeks after balloon denudation. Inhibition of the intimal hyperplasia with ATZ1993 was determined as approximately 77% for increases in intima:media ratio and DNA content. Plasma concentrations of ATZ1993 ranged between 121.6±26.6 and 131.7±20.9 nM throughout experimental periods. Mean arterial blood pressure, heart rate and body weight gain remained unaffected by administering ATZ1993. These results demonstrate that ATZ1993 is a novel nonpeptide and nonselective ETA/ETB-receptor antagonist, and the agent when administered orally inhibits effectively intimal hyperplasia after balloon denudation of the rabbit carotid artery.
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  • Muchun Wang, Kunihiko Yokotani, Kumiko Nakamura, Yoshinori Murakami, S ...
    1999 Volume 81 Issue 1 Pages 29-33
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Central effects of melatonin on the sympatho-adrenomedullary outflow were investigated in urethane-anesthetized rats. In the intact animals, intracerebroventricularly (i.c.v.) administered interleukin-1β (IL-1β) (100 ng/animal) slightly, but significantly, elevated the plasma level of noradrenaline (NA), but not the level of adrenaline (Ad). Melatonin (100 βg/animal, i.c.v.) did not modulate the effects of IL-1β on plasma levels of catecholamines. In the pinealectomized animals, however, the same dose of IL-1β markedly elevated plasma levels of both Ad and NA, and the elevation of Ad was more potent than that of NA. In these pinealectomized animals, the serum level of melatonin was significantly lower than that in the sham-operated control animals. Furthermore, the IL-1β-induced elevations of plasma catecholamines in these pinealectomized animals were attenuated by i.c.v. administered melatonin. These results suggest that melatonin plays an inhibitory role in the central regulation of sympatho-adrenomedullary outflow in rats.
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  • Carla Ghelardini, Nicoletta Galeotti, Lia Fantetti, Fulvio Gualtieri, ...
    1999 Volume 81 Issue 1 Pages 34-37
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    R-(+)-Hyoscyamine (1 - 10 μg/kg, s.c.) dose-dependently increased the local anesthetic effect of procaine (50 μg/ml) and lidocaine (50 μg/ml) in the conjunctival reflex test in the rabbit. This potentiating effect is completely prevented by the M1 antagonist dicyclomine (10 mg/kg, s.c.). The intensity of R-(+)-hyoscyamine antinociception was comparable to that induced by morphine (2 mg/kg, s.c.) and minaprine (15 mg/kg, s.c.), used as analgesic reference drugs. In the same experimental conditions, the S-(-)-enantiomer of atropine (0.1 - 10 μg/kg, s.c.), was completely ineffective. The present results confirm the ability of R-(+)-hyoscyamine to produce a paradoxical antinociceptive effect mediated by a cholinergic mechanism not only in rodents but also in the rabbit.
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  • Andrew K.S. Ho, Richard McLaughlin, Albert Chan, Rose Duffield
    1999 Volume 81 Issue 1 Pages 38-47
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    6-Hydroxydopamine (6-OHDA) was injected into the air sac of developing chicken embryos on day E3 in order to study its effects on cardiac development both morphologically and biochemically. A dose-dependent teratogenic effect and fetotoxicity were observed in the 6-OHDA-treated embryos. Cardiac malformations, including ventricular septal lesions, detachment of the apical portions of the ventricles, cardiac hypertrophy, areas of coagulative necrosis with pyknotic nuclei and broken nuclear membranes, and swollen mitochondria were evident from gross histologic and ultrastructural examinations. A LD50 of 0.3 mg/egg on day E11 was obtained. Biochemically, 6-OHDA induced a significant dose-dependent reduction in the total cardiac choline acetyltransferase (ChAT) activities on days E8 and E11, followed by a recovery on days E15 and E20. The effects on muscarinic acetylcholine receptors (mAChRs) were less marked than on ChAT, indicating the effects on the cholinergic nervous system development are primarily presynaptic. There was a significant decrease in the level of norepinephrine (NE) and a delay in the appearance of detectable cardiac NE. It is suggested that 6-OHDA-induced cardiac malformation can be a useful model to study the mechanisms of cardiovascular development.
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  • Kazunori Yamashita, Takeshi Nabe, Hisao Tomioka, Shigekatsu Kohno
    1999 Volume 81 Issue 1 Pages 48-55
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The contributions of histamine, cysteinyl leukotrienes (CysLTs) and thromboxane A2 (TXA2) to the asthmatic responses and the magnitudes of blood and lung eosinophilia at acute and chronic stages of our asthmatic model were comparatively determined. Guinea pigs were alternately sensitized/challenged by inhalation with ovalbumin+Al(OH)3 and ovalbumin, once every 2 weeks. Effects of mepyramine, pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist) on the early (EAR) and/or the late asthmatic response (LAR) were assessed at the second and fourth antigen challenges. The second challenge caused EAR but not LAR. Although the EAR was decreased at the fourth challenge, a substantial LAR was seen. Both mepyramine and seratrodast inhibited the EAR at the second challenge by approximately 50%. However, at the fourth challenge, these drugs did not inhibit the EAR. The LAR at the fourth challenge was attenuated by pranlukast and seratrodast by 45% and 40%, respectively. Both the blood and lung eosinophilia were modestly and markedly induced 5 h after the second and fourth challenges, respectively. These results strongly suggest that repetition of antigen challenge induces quantitative alterations of chemical mediators participating in the asthmatic responses and a change of the body state under which eosinophils exhibit enhanced migratory activities.
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  • Kenji Kashiwagi, Yoko Iizuka, Shigeo Tsukahara
    1999 Volume 81 Issue 1 Pages 56-62
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The intraocular metabolism of isopropyl unoprostone, a novel prostaglandin-related anti-glaucoma compound, was investigated using pigmented rabbits to clarify which metabolites are involved in actions in the eye. Tritium-labeled isopropyl unoprostone eyedrops were administered. The cornea, aqueous humor, iris, ciliary body and retina were then collected at 5, 15 or 30 min or at 2, 6 or 12 h after instillation. Isopropyl unoprostone and its metabolites were fractionated using high-performance liquid chromatography, and the radioactivity of each fraction was measured. Unmetabolized isopropyl unoprostone was never detected in any sample at any time point. In the cornea, only the de-esterificated metabolite, M1, and the further metabolized compound, M2, were detected; and the concentrations of these metabolites decreased with time. In the aqueous humor, M1, M2 and another metabolite, M3, were detected, with peak concentrations of M1 at 30 min and M2 at 2 h. The iris and ciliary body showed a similar metabolism with peak concentrations of M1 and M2 at 30 min. In the aqueous humor, iris and ciliary body, M2 was the dominant metabolite from 30 min. In the retina, only total radioactivity was detected. These results indicate that the main metabolites involved in actions in the eye are M1 and M2.
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  • Yoshihiro Hashimoto, Rikiya Ohashi, Koichi Minami, Hiroshi Narita
    1999 Volume 81 Issue 1 Pages 63-72
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Losartan is a prodrug type Angiotensin II (Ang II) AT1-receptor antagonist whose efficacy depends on the oxidase activity of individuals. In addition, losartan affects the normal blood pressure and can potentialy cause orthostatic hypotension. In this report, we examined effects of TA-606 {(3-pentyloxy)carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2’(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-4, 5, 6, 7-tetrahydro imidazo[4, 5-c]pyridine-4-carboxylate hydrochloride}, a prodrug type AT1-receptor antagonist, on the Ang II-induced pressor response and hypertension in a dog model, which is known to have lower oxidase activity than other species, and orthostatic hypotension in the rat tilting model. The results indicated that TA-606 was immediately converted to its active form, 606A, after oral administration, and it demonstrated potent inhibition of the Ang II-induced pressor response in conscious normotensive dogs (0.3 - 3 mg/kg, p.o.). It also had a potent hypotensive effect in conscious 2K, 1C-renal hypertensive dogs (0.3 - 10 mg/kg, p.o.). These effects of TA-606 were 32 and 30 times more potent than those of losartan, respectively. In addition, EXP3174 (1, 10 mg/kg, i.v.), an active metabolite of losartan, but not 606A (1 - 30 mg/kg, i.v.) showed an orthostatic hypotensive effect in the rat tilting model. These results suggest that TA-606 is an effective Ang II receptor antagonist without the drawbacks of losartan.
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  • Shinji Teramoto, Takeshi Matsuse, Hirotoshi Matsui, Eijiro Ohga, Takeo ...
    1999 Volume 81 Issue 1 Pages 73-78
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Replication-defective adenoviruses (Ad) are used as vectors for delivering therapeutic genes to human airway cells. We examined whether E1-deleted Ad vectors (Ad5-CMV-LacZ) had effects on cell kinetics in SPOC1 cells, which is a rat airway epithelial mucous goblet cell line. There was a vector multiplicity of infection (moi)-dependent increase of the transduction efficiency of the LacZ reporter gene in SPOC cells. Cell proliferation was inhibited in the vector-infected cells compared with that in vehicleexposed cells. However, increased cell death was observed in the vector-infected cells with a higher moi. The morphology of vector-exposed cells revealed apoptotic features including nuclear condensation and a fragmented nucleus. These results indicate that higher moi of vectors allows the cells to achieve higher gene transfer, but also induce apoptosis of infected cells. Minimizing the induction of apoptosis of vectorinfected cells may be an important strategy for the prolongation of transduction efficiency of Ad vectors in airway epithelial mucous goblet cells.
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  • Yoshioki Satoh, Atsushi Sugiyama, Kohji Tamura, Keitaro Hashimoto
    1999 Volume 81 Issue 1 Pages 79-85
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The cardiovascular profile of dofetilide was examined using halothane-anesthetized, closed-chest in vivo canine model (n=6). Dofetilide was administered at the dose of 1, 10 or 100 μg/kg, i.v. over 10 min with a pause of 20 min. After the lowest infusion rate, no significant change was detected in any of the cardiovascular parameters. Infusion of 10 μg/kg dofetilide, which was close to the submaximal clinically effective antiarrhythmic dose, decreased the heart rate and prolonged the ventricular repolarization phase and refractory period. After the highest dose of dofetilide, the cardiac output and left ventricular contraction decreased during sinus rhythm, the latter of which was not changed during the constant heart rate of 150 beats/min, while the dose-related effects were observed on the heart rate, repolarization phase and refractory period. The afterload and preload to the left ventricle and AV nodal as well as intraventricular conductions were hardly affected even at 100 μg/kg, i.v. These results obtained in the in vivo canine model support the previous reports describing that dofetilide possesses a highly selective blocking property for IKr. Moreover, the absence of effects on the afterload and preload to the left ventricle and the cardiac conduction makes dofetilide favorable as an antiarrhythmic drug because it is often used for patients with moderate to severe left ventricular dysfunction.
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  • Hisamasa Kodaira, Kazuhiko Ishihara, Kyoko Hotta, Masatoyo Kagoshima, ...
    1999 Volume 81 Issue 1 Pages 86-93
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The sialylated mucus components of the normal gastric mucosa and mucous gel layer of rats were studied by using various histochemical staining methods including Maackia amurensis II (MAL-II) and Sambucus nigra (SNA) lectins, alcian blue (AB) pH 2.5 - periodic acid Schiff (PAS) and high iron diamine (HID) - AB pH 2.5. The acidic and neutral mucins characterized by the AB-PAS staining were abundantly present in the mucous gel layer as well as in the gastric mucosa. The sialomucin characterized by HID-AB was barely found in either the mucous gel layer or the mucosa. The sialomucin positive to MAL-II and SNA, which react with the N-acetyl neuraminic acid residue linked to galactose via an α-linkage, was moderately detected only in the mucous gel layer, but not in the entire mucosal layer. Furthermore, in animals given surgery to form an esophageal fistula through which saliva was excluded or in animals subjected to salivectomy, the mucous gel layer stained with MAL-II and SNA lectins was markedly decreased. These results indicate that a part of the sialomucin containing-mucous gel layer covering normal rat gastric mucosa originates from the saliva and that MAL-II and SNA lectins are useful for detecting this specific sialomucin.
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  • Takehiro Ochi, Takashi Fujii, Yukio Motoyama, Toshio Goto
    1999 Volume 81 Issue 1 Pages 94-98
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The mechanism of action of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole), a novel anti-inflammatory compound, in a rat yeast-induced hyperalgesic model was investigated and compared with those of indomethacin and morphine. We tested the inhibitory effects of FR140423 on the formation of arachidonic acid metabolites, prostaglandin (PG) E2, thromboxane (TX) B2 and leukotriene (LT) B4, in yeast-injected inflamed paws and the effect of the opioid receptor antagonist naloxone on FR140423-induced anti-hyperalgesic effect and inhibition of the formation of arachidonic acid metabolites. Oral administration of FR140423 showed a dose-dependent anti-hyperalgesic effect. This effect was fourfold more potent than that of indomethacin but less potent than that of morphine. Unlike morphine, FR140423 suppressed the levels of PGE2 and TXB2 but not LTB4 in inflamed paws. FR140423 did not inhibit yeast-induced paw edema. The anti-hyperalgesic effect of FR140423 in yeast-injected rat paws was partially blocked by naloxone. However, the inhibitory effects of FR140423 on the formation of PGE2 and TXB2 in yeast-injected rat paws were not antagonized by naloxone. These results suggest that FR140423 shows a potent anti-hyperalgesic effect mediated by inhibition of PGs in inflamed tissue and by activation of opioid receptors.
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  • Iveta Bernátová, Ol’ga Pechánová, Franti# ...
    1999 Volume 81 Issue 1 Pages 99-106
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The aim of the present study was to determine whether decreased nitric oxide (NO) synthase production or rather NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertension was responsible for metabolic and structural remodelling of the rat aorta during four-week L-NAME treatment. Three groups of male Wistar rats were investigated: control, treated with 20 mg/kg per day L-NAME (L-NAME20), and treated with 40 mg/kg per day L-NAME (L-NAME40). Systolic blood pressure significantly increased in L-NAME20 to 146% and in L-NAME40 to 149% of the control value. NO synthase activity in the aorta significantly decreased in L-NAME20 and L-NAME40 to 86% and 65% of the control values, respectively. Proteosynthesis was significantly elevated in both L-NAME groups, while nuclear DNA concentration was significantly elevated only in the L-NAME40 group. Cyclic GMP concentration significantly decreased in L-NAME20 to 73% and in L-NAME40 to 46% of the control. Cyclic AMP concentration significantly increased in L-NAME20 and L-NAME40 to 128% and 145% of the control value, respectively. The diameter and wall thickness-to-diameter ratio were significantly elevated only in the L-NAME40 group. We conclude that remodelling of the aorta in L-NAME-treated rats was rather associated with NO deficiency than L-NAME-induced hypertension.
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  • Yukihiro Chino, Toshiya Minagawa, Yoshiro Kohno, Kiyomi Fukushima, Kaz ...
    1999 Volume 81 Issue 1 Pages 107-114
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Prostaglandin E1 incorporated in lipid microspheres (lipo PGE1) was administered to the umbilical vein of neonatal rats. Morphological measurement and quantitative autoradioluminography assessed the relationship between the vasodilating effect and tissue accumulation of lipo PGE1 in the ductus arteriosus. In the morphological measurement under microscopy, the inner diameter ratio of the ductus arteriosus to the main pulmonary artery after infusion of 3H-labeled lipo PGE1 (3H-lipo PGE1) continued to remain significantly higher than that of free 3H-PGE1. Autoradioluminography of the frozen frontal section of neonates after intravenous infusion of 3H-lipo PGE1 for 2 h revealed that the ductus levels of radioactivity were higher than those of free 3H-PGE1 in saline solution, although the blood levels were almost equal. Localization of lipo PGE1 labeled with a lipophilic fluorescent probe, 1, 1′-dioctadecyl-3, 3, 3′, 3′-tetramethyl-indocarbocyanine perchlorate (diI), in the endothelial cells of the ductus arteriosus was confirmed by confocal laser scanning microscopy. These findings suggest that the incorporation of lipid microspheres by the endothelial cells is one of the mechanisms that enables lipo PGE1 to accumulate to higher levels in the ductus tissue and to act more efficiently than free PGE1 in neonatal rats.
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  • Toru Egashira, Fusako Takayama, Yasumitsu Yamanaka
    1999 Volume 81 Issue 1 Pages 115-121
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The effects of the antidepressant drugs zimeldine, imipramine, maprotiline or nomifensine on mitochondrial monoamine oxidase (MAO) activity in mouse, rat, dog and monkey brains were compared in vitro. Mouse, rat, dog and monkey brain MAO-B activities were inhibited by zimeldine more potently than MAO-A activity. Imipramine inhibited MAO-B more potently than MAO-A activity in mouse and rat brains. When dog and monkey brains were investigated, MAO-A activity was inhibited more potently than MAO-B activity at high concentrations of imipramine, while at low concentrations, MAO-B activity was more potently inhibited. Maprotiline and nomifensine inhibited mouse and rat brain MAO-B activity more potently than MAO-A activity, while the inverse was true for dog and monkey brains. All four drugs are competitive inhibitors of MAO-A, but noncompetitive inhibitors of MAO-B in all animal brains. The respective Ki values of these reagents for monkey brain MAO-A and MAO-B were low compared to those of mouse, rat and dog. These results indicate that monkey brain MAOs are more sensitive to antidepressant drugs than those in rodent brain.
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