The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 78 , Issue 1
Showing 1-18 articles out of 18 articles from the selected issue
Regular Papers
  • Nobutoshi Matsushita, Masanori Hizue, Kosuke Aritake, Kumi Hayashi, Ay ...
    1998 Volume 78 Issue 1 Pages 1-10
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The effects of oral administration of 4-benzhydryloxy-1-{3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a newly synthesized antiallergic drug, in various experimental allergic and asthmatic models were investigated. HQL-79 markedly inhibited immediate hypersensitivity reactions such as passive cutaneous anaphylaxis in rats, antigen-induced bronchoconstriction and nasal vascular permeability in actively sensitized guinea pigs, like epinastine and ketotifen did. Airway eosinophilia in repeatedly antigen-exposed guinea pigs was suppressed by chronic administration of HQL-79 for 2 weeks. In another experiment, the antigen-induced late asthmatic response (LAR) in metyrapone-treated guinea pigs was also ameliorated by chronic treatment with HQL-79. Moreover, HQL-79 partially inhibited the toluene diisocyanate-induced delayed-type hypersensitivity (DTH) reaction in mice when administered chronically during the immunization period. The corticosteroid dexamethasone inhibited the airway inflammatory responses in guinea pigs and the DTH in mice. These results indicate that HQL-79 has potent inhibitory effects on the immediate hypersensitivity reactions, and when administered chronically, it also inhibits airway eosinophilia, LAR and DTH, similarly to corticosteroids.
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  • Nobutoshi Matsushita, Kosuke Aritake, Ayumi Takada, Masanori Hizue, Ku ...
    1998 Volume 78 Issue 1 Pages 11-22
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The effects of 4-benzhydryloxy-1-{3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a newly developed antiallergic drug, on various chemical mediators and on chemical mediator release were investigated. Orally administered HQL-79 strongly inhibited the histamine-induced skin reaction in rats, and histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in guinea pigs. HQL-79 inhibited antigen-induced release of leukotriene (LT) B4, LTC4, histamine and prostaglandin (PG) D2 from the chopped lung tissues of actively sensitized guinea pigs. On the other hand, release of PGE2, one of the bronchoprotective prostanoids, was significantly enhanced by HQL-79. In an in vivo experiment, chronic administration of HQL-79 clearly reduced PGD2 contents and enhanced PGE2 contents in the lungs of repeatedly antigen-exposed guinea pigs. In biochemical studies, HQL-79 inhibited mouse spleen PGD synthase in a concentration-dependent manner. None of the antiallergics such as epinastine, terfenadine, oxatomide and cetirizine inhibited the PGD synthase. HQL-79 did not affect PGE synthase in sheep vesicular gland microsomes. These results suggest that antiallergic and antiasthmatic effects of HQL-79 could be ascribed to antihistaminic- and anti-5-HT effects, chemical mediator release inhibition, PGE2-release enhancement and PGD synthase inhibition. It is considered, in particular, that the differential modulation of PGD2 and PGE2 production is a conspicuous pharmacological feature of HQL-79.
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  • Yoshihisa Kitamura, Jun-ichi Kakimura, Takashi Taniguchi
    1998 Volume 78 Issue 1 Pages 23-29
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The planarian, a flatworm, has a high potential for regeneration, and dopamine plays a key role in its behavior. Planarians treated with MPTP underwent autolysis and individual death in a concentration-dependent manner. When the planarian body was cut into anterior, middle and posterior pieces, each piece subsequently regenerated and reorganized to form a new individual within approximately 10 days. The anterior piece was significantly more sensitive than the middle and posterior pieces to MPTP cytotoxicity. Concomitant treatment with talipexole, an anti-parkinsonian drug, inhibited MPTP-induced autolysis and individual death in a concentration-dependent manner. Pramipexole showed a similar protective effect. In addition, post-treatment with talipexole at 1 hr after MPTP completely inhibited MPTP-induced individual death. Although MPTP treatment caused 30% of the planarians to undergo autolysis and individual death within 12 hr, post-treatment with talipexole even at 12 hr completely rescued the remaining 70% of the planarians from death. These results suggest that the MPTP-treated planarian may be useful as a novel parkinsonian model in which talipexole has a protective effect even in the case of post-treatment.
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  • Kayoko Okuyama, Satoko Kiuchi, Masahito Okamoto, Hitoshi Iwasaki, Hiro ...
    1998 Volume 78 Issue 1 Pages 31-37
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    To evaluate the progression of brain edema without modification by the effect of anesthetics, we examined the local and permanent ischemia model in unanesthetized rats. The forebrain embolism was induced by intra-arterial infusion of microspheres of 50-μm diameter in freely moving rats. From 2 to 48 hr following the injection, the water-, Na- and Ca-contents progressively increased while the K content decreased in the microsphere-injected hemisphere. After the 3rd day, the water- and Na-contents gradually decreased and returned to the normal level on the 14th day. In contrast, the Ca level remained elevated even on the 56th day. The animals showed signs of neurological deficits 24 hr after the injection. In histopathological examination, large infarct areas were present in the microsphere-injected hemisphere after 24 to 48 hr. One to two weeks later, the lateral ventricle was expanded. Eight weeks after the injection, the ventricle remained expanded and newly developed infarct areas were observed in a scattered pattern around the fibrotic area. The results show the close correlation between the development of edema and the increase/decrease of Na/K contents from the onset to the recovery from edema, and their changes are similar to those in human stroke. This model enables us to evaluate not only the acute ischemic insult but also the chronic changes of the forebrain following the stroke.
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  • Mariko Kinoshita, Shuji Kaneko, Tohru Yasuno, Nobumichi Yada, Akinori ...
    1998 Volume 78 Issue 1 Pages 39-44
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    Effects of the cerebroprotective agent bifemelane on voltage-dependent Ca2+ channel currents were evaluated in Xenopus oocytes expressing specific Ca2+-channel subtypes. Extracellular perfusion of bifemelane showed a dose-dependent blocking action on both N-type and Q-type Ca2+ channels, but not on cardiac L-type Ca2+ channels expressed in the oocytes, and the inhibitory action on Q-type current was stronger than that on N-type current. The time course of inhibition by bifemelane was comparatively slow; a 20-min perfusion with 1 μM bifemelane was required to reduce the amplitude of the Q-type current to 80% of the control level. When bifemelane was applied intracellularly, the potency and time-course of inhibition was equivalent to that caused by the perfusion of bifemelane. The bifemelane-induced inhibition was voltage-dependent but not use-dependent in Q-type channels since it was apparent at more depolarized potentials but not influenced by the interval of depolarization. These results suggest that bifemelane inhibits the opening of the specific Ca2+ channels located at nerve terminals to suppress excessive neurotransmitter release from neurons in some pathophysiological conditions such as ischemia.
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  • Akihisa Hanatani, Minoru Yoshiyama, Kazuhide Takeuchi, Shokei Kim, Koj ...
    1998 Volume 78 Issue 1 Pages 45-54
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The purpose of this study was to analyze the effect of the angiotensin II type 1-receptor antagonist candesartan cilexitil on left ventricular systolic and diastolic function and mRNA expression of contractile proteins, collagen, and Ca2+ handling protein in myocardial-infarcted rats. After myocardial infarction, the animals were randomly assigned to candesartan cilexitil-treated or untreated groups (MI). We performed Doppler-echocardiographic examination and measured the hemodynamics at four and twelve weeks after myocardial infarction. Following these measurements, their cardiac mRNA was analyzed. At four weeks in MI, left ventricular end-diastolic dimension increased (Control, 6.2±0.6 mm; MI, 8.7±0.6 mm; P<0.01), fractional shortening decreased (Control, 41±5%; MI, 16±3%; P<0.01) and E wave deceleration rate increased (Control, 14.3±2.0 m/sec2; MI, 23.3±2.3 m/sec2; P<0.01). Candesartan cilexitil significantly prevented these changes. The mRNA expressions of β-myosin heavy chain, α-skeletal actin, atrial natriuretic peptide, and collagens I and III in the non-infarcted left ventricle and right ventricle were increased at four weeks and were significantly suppressed by treatment with candesartan cilexitil. At four weeks, Na+-Ca2+ exchanger mRNA expression was increased, and candesartan cilexitil suppressed this increase. At twelve weeks, sarcoplasmic reticulum Ca2+-ATPase mRNA expression in the infarcted region including the adjacent non-infarcted left ventricle and right ventricle were decreased and candesartan cilexitil restored it to the control level. Candesartan cilexitil prevented the systolic and diastolic dysfunction and abnormal cardiac mRNA expression in myocardial-infarcted rats.
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  • Mohammed S. Yassin, Jonas Ekblom, Charlotta Löfberg, Lars Oreland
    1998 Volume 78 Issue 1 Pages 55-61
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The catastrophic epidemic of subacute myelo-optic neuropathy (SMON) affected Japan around 1970 with thousands of victims. The cause was attributed to high doses of locally acting oxyquinolines. It has been speculated that oxyquinoline derivatives of the clioquinol type can disturb the retention of vitamin B12 through chelation of Co2+. In the present paper, possible effects of clioquinol on the uptake and tissue distribution of [57Co]-cyanocobalamin have been studied in mice. In vivo experiments showed markedly decreased accumulation of radiolabelled vitamin B12 in the kidney and skin in animals that were pre-treated with clioquinol. The chloroform:water partition coefficients for [57Co]-cyanocobalamin in the presence or absence of clioquinol were also determined. No statistically significant alterations in the partition coefficient for [57Co]-cyanocobalamin in the presence of clioquinol was evident, indicating that clioquinol does not bind cobalt. In addition, transmethylation reactions in the CNS in mice treated with clioquinol were studied. Specific activities of methionine adenosyltransferase, and S-adenosylhomocysteine levels were not affected. In contrast, clioquinol treatment caused a significant increase in the levels of S-adenosylmethionine in the brain. The data of the present study show that clioquinol treatment can affect the accumulation of vitamin B12 in the kidney and the skin but not in the brain. These results do not support the hypothesis that clioquinol causes its damage to the nervous system by a direct chemical interaction with vitamin B12.
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Short Communications
  • Takashi Asada, Toshikazu Ogawa, Michio Iwai, Masakazu Kobayashi
    1998 Volume 78 Issue 1 Pages 63-67
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We investigated the effect of recombinant insulin-like growth factor-I (rhIGF-I) on the expression of glucose transporters, GLUT 2 in the liver and GLUT 4 in the heart, in streptozotocin (STZ)-diabetic rats by the reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. GLUT 2 and its mRNA in the liver was elevated, whereas GLUT 4 and its mRNA in the heart were decreased in STZ-diabetic rats. A two-week treatment with rhIGF-I mostly restored the expression of GLUT 2 and GLUT 4 to normal rat level. We demonstrated that the effect of IGF-I on the expressions of GLUTs was almost the same as that of insulin.
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  • Chihiro Yamazaki, Jiro Hoshino, Tomoko Sekiguchi, Yusuke Hori, Satoshi ...
    1998 Volume 78 Issue 1 Pages 69-73
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    To elucidate the potential role of superoxide (O2-) and nitric oxide (NO) in the pathogenesis of interstitial pneumonia, the quantity of O2- and NO produced by the alveolar macrophages (AM) were determined in the bleomycin (BLM)-induced interstitial pneumonia mouse model. The production of O2- and NO increased on days 7, 14 and 21 after BLM injection. Strong expression of peroxynitrite (ONOO-) was seen in AM by using immunostaining for nitrotyrosine. The hydroxyproline contents increased on day 21 after BLM injection. O2- and NO are thought to play an important role in the pathology of fibrosis.
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  • Kunihiko Yokotani, Yasunobu Okuma, Yoshitsugu Osumi
    1998 Volume 78 Issue 1 Pages 75-77
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We characterized the voltage-activated Ca2+ channels involved in noradrenaline (NA) release from gastric sympathetic neurons using isolated, vascularly perfused rat stomach. The evoked NA release by electrical stimulation of periarterial nerves was abolished by calcium removal from the perfusion medium and by cadmium. ω-Conotoxin GVIA (N-type Ca2+-channel blocker) effectively and ω-conotoxin MVIIC (N/P/Q-type blocker) slightly inhibited the evoked NA, while ω-agatoxin IVA (P-type blocker) had no effect. These results suggest that ω-conotoxin GVIA and ω-conotoxin MVIIC-sensitive N-type Ca2+ channels are involved in NA release from the rat gastric sympathetic nerve terminals.
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  • Yoko Aniya, Takahiro Yokomakura, Masato Yonamine, Tatsumi Nagamine, Hi ...
    1998 Volume 78 Issue 1 Pages 79-82
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    Antioxidant and hepatoprotective actions of the mold Monascus anka (also called Beni-Koji in Japan) against acetaminophen (AAP)-induced liver toxicity were investigated. Serum aspartate aminotransferase and glutathione S-transferase (GST) activities increased by AAP (180 mg/kg, i.p.) treatment were depressed when the Beni-Koji preparation (4 ml/kg, i.p.) was given 15 and 1 hr before AAP administration. The decrease in liver cytosolic GST activity by AAP, reflecting the release of the enzyme into serum, was also blocked by the mold. Cytochrome P450 activity was inhibited by the Beni-Koji preparation. These results suggest that M. anka prevents AAP-induced liver toxicity by both antioxidant action and the inhibition of AAP metabolism.
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  • Hideyuki Nishiwaki, Noriko Saitoh, Hideaki Nishio, Tadayoshi Takeuchi, ...
    1998 Volume 78 Issue 1 Pages 83-86
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    Endomorphin-1 and -2, putative endogenous ligands for the mu-opioid receptor, inhibited acetylcholine (ACh) release evoked by electrical field stimulation (EFS) at 1 Hz, which partially activates muscarinic autoreceptors, but not at 10 Hz, which fully activates muscarinic autoreceptors, in longitudinal muscle with the myenteric plexus (LMMP) preparations of guinea pig ileum. After blockade of autoinhibition by atropine, the peptides also inhibited EFS-evoked ACh release at 10 Hz. The inhibitory effects on ACh release were abolished by the mu-opioid antagonist cyprodime. These results suggest that endomorphin-1 and -2 inhibit ACh release from LMMP preparations of guinea pig ileum and that the mechanism of the inhibition must have a component in common with muscarinic autoinhibition.
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  • Yasuyuki Suzuki, Kazuhiro Goto, Atsushi Ishige, Yasuhiro Komatsu, Junz ...
    1998 Volume 78 Issue 1 Pages 87-91
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We evaluated the effects of Gosha-jinki-gan on platelet aggregation in streptozotocin-induced diabetic rats. Enhanced ADP (2 μM)-induced aggregation of platelets obtained from diabetic rats was inhibited by a single treatment with Gosha-jinki-gan (0.3, 1.5 g/kg, p.o.). The anti-platelet aggregatory effect of Gosha-jinki-gan (1.5 g/kg, p.o.) was attenuated by simultaneous administration of atropine (1 mg/kg, i.p.) and was abolished by combination of atropine with Hoe 140 (250 μg/kg×2, i.p.), a bradykinin B2 receptor antagonist or L-NAME (10 mg/kg, i.p.), an inhibitor of nitric oxide-synthase. These results suggested that Gosha-jinki-gan could improve platelet aggregation in diabetes through increased production of nitric oxide via bradykinin B2-receptors and muscarinic acetylcholine receptors.
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  • Kunihiko Yokotani, Yoshitsugu Osumi
    1998 Volume 78 Issue 1 Pages 93-95
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We examined the effect of endogenous opioid peptides on vagally evoked release of acetylcholine (ACh) from the isolated, vascularly perfused rat stomach. The vagus nerves were electrically stimulated twice at 2.5 Hz for 2 min, and test substances were administered during the second stimulation. β-Endorphin (10-7 and 3×10-7 M), an endogenous nonselective agonist of μ-receptors, inhibited the release of ACh. However, [Leu5]-enkephalin, an endogenous nonselective agonist of δ-receptors, and U-50488, a κ-receptor agonist, had no effect at a higher dose of 10-6 M. β-Endorphin-induced inhibition was abolished by naloxone. Endomorphins 1 and 2 (3×10-7 and 10-6 M), endogenous selective agonists of μ-receptors, also inhibited the release of ACh. These results suggest that the μ-receptor is involved in the endogenous opioid peptide-induced inhibition of the release of ACh from the rat stomach.
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  • Toshihiro Okamoto, Yoshihisa Nakano, Naoki Tsuzuike, Kaoru Hara
    1998 Volume 78 Issue 1 Pages 97-99
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The administration of concanavalin A (Con A) (0.2 mg/mouse) into mice induced significant elevation of plasma alanine aminotransferase (ALT) at 8.5 hr after Con A treatment. CD8 mRNA, which is a marker of cytotoxic T-cell, was strongly induced at 16 and 24 hr after Con A treatment. Although pretreatment with cyclosporine A (CsA) (50 and 100 mg/kg, i.p.) inhibited Con A-induced elevation of plasma ALT, it did not inhibit Con A-induced CD8 mRNA expression. Morphological study revealed lymphoid cell infiltration in the liver, but the lymphoid cells were not present at the site of hepatocyte necrosis. These results suggest that Con A-induced CD8+ T-cell infiltration has a minimal effect in the development of hepatitis.
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  • Toshihiro Okamoto, Osamu Maeda, Naoki Tsuzuike, Kaoru Hara
    1998 Volume 78 Issue 1 Pages 101-103
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    The effect of Kupffer cell depression on concanavalin A (Con A)-induced cytokine mRNA expression in the liver was studied. Gadolinium chloride (GdCl3) is a commonly used Kupffer cell inhibitor. GdCl3 (40 mg/kg, i.p.) was injected into each mouse, and 24 hr later, Con A (0.2 mg/mouse) was administered. Plasma was obtained at 24 hr after Con A treatment for alanine aminotransferase (ALT) measurement. GdCl3 treatment inhibited Con A-induced elevation of ALT. However, it did not inhibit Con A-induced interleukin-2 or tumor necrosis factor-α mRNA expression. The present results suggest that Kupffer cells are not responsible for Con A-induced cytokine expression in the liver.
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  • Ikumi Arai, Takao Shimazoe, Akiko Yoshimatsu, Hirotaka Inoue, Shigenob ...
    1998 Volume 78 Issue 1 Pages 105-108
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    We examined the influence of ischemia on methamphetamine (MAP)-induced behavioral sensitization and enhancement of dopamine (DA) release. After the recovery period of the ischemia operation, rats were treated with MAP (1 mg/kg, i.p.) once daily for 6 consecutive days. Re-administration of MAP (0.5 mg/kg, i.p.) potentiated the increase of locomotor activity after a 3-day withdrawal and the enhancement of DA release from striatal slices after a 6-day withdrawal. The MAP-induced sensitization was impaired by 5 min ischemia. On the other hand, the increase of locomotor activity induced by single MAP (1 mg/kg, i.p.) administration was impaired by 20 min of ischemia. Moreover, in saline-treated rats the increase of DA release from striatal slices induced by MAP (10 μM) application was also impaired by 20 min of ischemia. These results indicate that the neuronal plastic change may be very vulnerable to ischemia in MAP-induced sensitization.
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Rapid Communication
  • Akinori Ueno, Hiroaki Naraba, Sachiko Oh-ishi
    1998 Volume 78 Issue 1 Pages 109-111
    Published: 1998
    Released: April 26, 2001
    JOURNALS FREE ACCESS
    A novel non-peptide bradykinin B2-receptor agonist, FR190997 (8-[2, 6-dichloro-3-[N-[(E)4-(N-methylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy) quinoline), induced dose-dependent and longer-lasting swelling than bradykinin in the mouse paw. The swelling, peaking around 30 min, was suppressed dose-dependently by intraperitoneal administration of FR173657, a novel non-peptide B2-receptor antagonist. A known B2-antagonist, Hoe 140, also significantly suppressed this edema. The result indicates that the novel B2-agonist FR190997, being more stable than bradykinin, could induce plasma exudation locally in mice via the B2-receptor as a substitute for bradykinin.
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