The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 79, Issue 4
Displaying 1-15 of 15 articles from this issue
Reviews
  • Andreas Dendorfer, Sebastian Wolfrum, Peter Dominiak
    1999 Volume 79 Issue 4 Pages 403-426
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Kinins are peptide hormones that can exert a significant influence on the regulation of blood pressure and vascular tone due to their vasodilatatory, natriuretic and growth modulating activity. Their cardiovascular involvement in physiological and pathophysiological situations has been studied intensively since inhibitors for angiotensin I-converting enzyme and selective receptor antagonists have become available for pharmacologically potentiating or inhibiting kinin-mediated reactions. Molecular biological analysis and the establishment of genetically modified animal models have also allowed newer information to be acquired on this subject. In this review, the components and cardiovascularly relevant mechanisms of the kinin-kallikrein system shall be described. Organ-specific effects concerning the kidneys, the vascular system, the heart and nervous tissue shall also be illustrated. On this tissue, the physiological functions and pathophysiological implications of the kinin-kallikrein system should be clearly distinguished from the many, mostly endothelium-mediated protective effects which occur during ACE inhibition due to the potentiation of kinin effects. Finally, a view shall also be cast upon newly discovered targets of action, which could be exploited for therapeutically altering the kinin-kallikrein system.
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  • Akihiro Nakamura, Hirohito Shiomi
    1999 Volume 79 Issue 4 Pages 427-431
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Cutaneous nociceptors are peripheral receptive endings of primary sensory neurons activated by noxious stimuli. Nociceptors detect and signal the presence of tissue-damaging stimuli or the existence of tissue damage. In this short review, we will focus on the molecular mechanism of maintenance, activation, inhibition and sensitization in cutaneous nociceptors. Neurotrophic factors are essential to the development of nociceptors during embryogenesis. Recent evidences have indicated that nociceptors in the adult are maintained by either nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF). A selective activator of nociceptors is capsaicin, natural product of capsicum peppers. Recently, the receptor for capsaicin (the vanilloid receptor 1: VR1) has been cloned, identified and characterized. VR1 seems to play an important role in the activation and sensitization of nociceptors. In contrast, peripheral endogenous cannabinoids such as anandamide are novel candidates for mediators that inhibit the excitation of nociceptors. Intracellular messengers and the mechanisms of signal transduction in nociceptors have also been studied. Our recent findings provide evidences demonstrate that an activation of both cAMP- and cGMP-second messenger systems is required to induce the sensitization of nociceptors. Such emerging evidences reviewed here would make a significant contribution to further understanding of the molecular mechanism of nociceptors.
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Regular Papers
  • Carlos Goicoechea, Esther Porras, María José Alfaro, Mar ...
    1999 Volume 79 Issue 4 Pages 433-437
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The antinociceptive effect of alendronate was studied. The bisphosphonate was i.p. administered and two tests were carried out: acetic acid in mice and formalin test in rats. In the acetic acid test, alendronate induced a dose-dependent antinociceptive effect that was statistically significant for the doses of 10, 20 and 40 mg/kg, and could be detected 48 hr after its administration. In the formalin test, however, alendronate, at the doses of 10 and 20 mg/kg, did not modify the pain score nor the number of flinches, when it was administered either 30 or 60 min before the test. However it must be noted that doses inducing analgesic effect are close to those inducing toxicity.
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  • Naofumi Murakami, Shizuhiko Aihara, Kazumi Iwata, Takako Saito, Tomohi ...
    1999 Volume 79 Issue 4 Pages 439-446
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    We evaluated the effects of a new non-steroidal anti-inflammatory drug (NSAID), d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), and indomethacin on the production of arachidonate metabolites and pro-inflammatory cytokines in male Sprague-Dawly rats with monosodium urate crystal (MSU)-induced pleurisy. Levels of tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 in the pleural exudate were determined by biological assays, while prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and cytokine-induced chemoattractant-1 (CINC-1) levels were quantified by enzyme immunoassays. Orally administered M-5011 (5 mg/kg) decreased the pleural exudate volume at 3 and 4 hr after MSU injection. Indomethacin (10 mg/kg) decreased the volume at 3 - 5 hr. These drugs reduced the number of leukocytes in the pleural cavity at 6 hr. Both NSAIDs also reduced the content of PGE2 in the exudate without affecting LTB4 levels. Increased productions of both IL-6 and CINC-1 in the exudate were reduced by pretreatment with M-5011 or indomethacin, and TNF levels in the exudate were increased by pretreatment of these drugs. Thus, M-5011 inhibits the production of both IL-6 and CINC-1 at lower doses than those of indomethacin, and the inhibitory effect of M-5011 on CINC-1, but not IL-6, may partly contribute to the inhibition of leukocyte infiltration in rats with MSU-induced pleurisy.
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  • Ryo-ich Takei, Ichiro Ikegaki, Katsushi Shibata, Gozoh Tsujimoto, Tosh ...
    1999 Volume 79 Issue 4 Pages 447-454
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The pharmacological profiles of the α1-adrenoceptor antagonists naftopidil, tamsulosin and prazosin were studied in an anesthetized dog model that allowed the simultaneous assessment of their antagonist potency against phenylephrine-mediated increases in prostatic pressure and mean blood pressure. The intravenous administration of each of these compounds dose-dependently inhibited phenylephrineinduced increases in prostatic pressure and mean blood pressure. To further assess the ability of the three compounds to inhibit phenylephrine-induced responses, the doses required to produce a 50% inhibition of the phenylephrine-induced increases in prostatic and mean blood pressure and the selectivity index obtained from the ratio of those two doses were determined for each test compound. Forty minutes after the intravenous administration of naftopidil, the selectivity index was 3.76, and those of tamsulosin and prazosin were 1.23 and 0.61, respectively. These findings demonstrated that naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure in the anesthetized dog model. The selectivity of naftopidil for prostatic pressure was the most potent among the test compounds. In addition, using cloned human α1-adrenoceptor subtypes, naftopidil was selective for the α1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the α1a- and α1b-adrenoceptor subtypes, respectively. The selectivity of naftopidil for prostatic pressure may be attributable to its high binding affinity for α1a- and α1d-adrenoceptor subtypes.
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  • Mizuo Miyazaki, Naotaka Shiota1, Hiroshi Sakonjo, Shinji Takai
    1999 Volume 79 Issue 4 Pages 455-460
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    We investigated the effect of an angiotensin (Ang) II antagonist, (+/-)-1-(cyclohexyloxy- carbonyloxy)-ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116), on neointima formation in dog artery injured by a balloon catheter. Dogs were orally treated with 10 mg/kg TCV-116 or placebo twice a day for 5 weeks. After treatment with these drugs for 1 week, the right carotid artery was injured by a balloon catheter. The left carotid artery was regarded as the control. In the group treated with placebo, neointima formation in the injured arteries was observed. The activities of angiotensin converting enzyme (ACE) and chymase in the injured carotid arteries were increased 2.56- and 3.26-fold compared with those in the non-injured arteries, respectively. The neointimal area in dogs treated with placebo and TCV-116 were 0.51±0.07 and 0.21±0.07 mm2, respectively, and this difference was significant. In conclusion, an Ang II antagonist, TCV-116, prevented neointima formation by blocking the action of Ang II generated by both ACE and chymase in the injured arteries.
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  • Xiao-Ping Yang, Shigetoshi Chiba
    1999 Volume 79 Issue 4 Pages 461-466
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Using a cannula insertion method, periarterial nerve electrical stimulations were performed at 1 and 10 Hz in the isolated, perfused canine splenic artery. Electrical nerve stimulation readily caused double-peaked vasoconstrictions. The 1st-peak response at 1 Hz was not influenced by treatment with imipramine but the 2nd one was significantly enhanced by it. The 2nd-peak response was markedly blocked by prazosin. An additional treatment with α, β-methylene ATP, a P2X-purinoceptor desensitizer, abolished electrical stimulation-induced vascular responses that remained. At 10 Hz, the responses to electrical stimulation were not significantly influenced by imipramine. On the other hand, the imipramine treatment inhibited the tyramine-induced vasoconstriction but potentiated the noradrenaline-induced one. ATP-induced responses were not modified by imipramine. From these results, it is concluded that 1) the 1st-peaked constriction is mainly due to a P2X-purinoceptor-dependent mechanism, 2) the 2nd one is mainly due to an α1-adrenoceptor-dependent mechanism, and 3) presynaptic uptake mechanisms may perform an important role in the regulation of vascular reactivity, especially at a low frequency.
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  • Ken-ichi Fujita, Kiyoshi Nagata, Eriko Watanabe, Miki Shimada, Yasushi ...
    1999 Volume 79 Issue 4 Pages 467-475
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    At least three forms of phenol sulfotransferase (ST) ST1B1, ST1A1 and ST1C1 are contained in rat livers. To identify the form contributing to the metabolism of 3, 3′, 5-triiodothyronine (T3), functional characterization of these forms was performed by expression in Escherichia coli. ST1B1 and ST1C1 were shown to be active on sulfation towards T3 with high affinity (Km: 44.4 and 25.8 μM, respectively), whereas ST1A1 had low affinity. In Western blotting using antibodies raised against the individual ST, hepatic contents of each ST were quantitatively determined. ST1B1 showed no clear sex-difference, whereas the level of ST1C1 was higher in adult males than adult females. The content of ST1B1 was 1.4, 6.8 and 10 times higher than that of ST1C1 in adult males, adult females and both sexes of immature rats, respectively. The developmental pattern of ST1B1 was similar to that of ST1A1, but differed from that of ST1C1. These results indicate that ST1B1 and ST1C1 are involved in T3 metabolism in rats and ST1B1 is the constitutive form across sexes and ages.
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  • Yoshihiro Waki, Takashi Horita, Ken-ichi Miyamoto, Keiichi Ohya, Shohe ...
    1999 Volume 79 Issue 4 Pages 477-483
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    We have reported that denbufylline, a phosphodiesterase 4 (PDE4) inhibitor, inhibits bone loss in Walker256/S tumor-bearing rats, suggesting therapeutic potentiality of a PDE4 inhibitor in osteopenia. In the present study, effects of a new PDE4 inhibitor, 1-n-butyl-3-n-propylxanthine (XT-44), in bone were evaluated in cell cultures and animal experiments. In rat bone marrow culture, XT-44 stimulated mineralized-nodule formation, whereas it inhibited osteoclast-like cell formation in mouse bone marrow culture. In Walker256/S-bearing rats (6-week-old female Wistar Imamichi rats), rapid decrease in bone mineral density (BMD) was prominent, and oral administration of XT-44 (0.3 mg/kg, every 2 days) inhibited the decrease in BMD. In the second animal experiment, female Wistar rats (6-week-old) were sciatic neurectomized, and XT-44 was orally administered to these rats every 2 days for 4 weeks. XT-44 administration (0.3 mg/kg) recovered BMD in these neurectomized animals. Furthermore, 19-week-old, female Wistar rats were ovariectomized (OVX), and 15 weeks after surgery, these rats were orally administered XT-44 every 2 days for 8 weeks. XT-44 treatment (1 mg/kg) increased the BMD of OVX rats. These results indicate that XT-44 could be a candidate as a therapeutic drug for treating osteopenia including osteoporosis.
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Short Communications
  • Toshihiro Okamoto, Yuji Hitomi, Atsuko Hara
    1999 Volume 79 Issue 4 Pages 485-488
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The effect of cyclosporine A (CsA) on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibody (250 μg/kg) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 hr. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with CsA (10, 30 and 100 mg/kg) in a dose-dependent manner. Anti-Fas antibody administration elevated CPP32-like protease activity at 3 hr in mouse liver, and this elevation of CPP32-like activity was inhibited by treatment with CsA. The present results show that CsA treatment inhibits the anti-Fas antibody-induced apoptotic process of hepatitis, at least in part, by affecting a reaction upstream of CPP32-like protease activation.
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  • Masako Okazaki, Mayumi Tsuji, Yukako Yamazaki, Yuko Kanda, Shinichi Iw ...
    1999 Volume 79 Issue 4 Pages 489-492
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The effects of Sasa senanensis Rehder extract (SE) by alkaline hydrolysis on histamine release from rat peritoneal exudate cells (PECs) were examined. Preincubation with SE for 5 min suppressed calcium-ionophore A23187-induced histamine release in a concentration-dependent manner. A23187 evoked a quick increase in cytoplasmic free calcium ([Ca2+]i) levels in the presence of extracellular calcium. Preincubation with SE also had an inhibitory effect on calcium influx increases induced by A23187. These results indicate that SE prevents degranulation from rat PECs by inhibiting [Ca2+]i level elevation.
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  • Yasuko Sakurai-Yamashita, Kohei Takada, Keiko Takemura, Kimihiro Yamas ...
    1999 Volume 79 Issue 4 Pages 493-496
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    Ability of mosapride, a gastrokinetic agent, to bind to 5-HT4 receptor was examined in the stomach of human and guinea pig by in vitro receptor autoradiography. [125I]SB207710 binding sites were detected in the muscle layer including the myenteric plexus of the stomach from both humans and guinea pigs, although the binding was observed more clearly and densely in the stomach of guinea pigs than humans. Mosapride as well as SB204070 inhibited the binding of [125I]SB207710. Thus, mosapride possesses the ability to bind to 5-HT4 receptors of human stomach and may modulate the motility, as in the case of guinea pig stomach.
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  • Hooi Hoon Ang, Hung Seong Cheang
    1999 Volume 79 Issue 4 Pages 497-500
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The anxiolytic effect of Eurycoma longifolia Jack in mice was examined. Fractions of E. longifolia Jack extract produced a significant increase in the number of squares crossed (controls=118.2±10.2 squares), but significantly decreased both the immobility (controls=39.4±4.0 sec) and fecal pellets (controls=12.3±2.1 fecal pellets) when compared with control mice in the open-field test; they significantly increased the number of entries (controls=6.7±0.5 entries) and time spent (controls=42.9±0.1 sec) in the open arms, but decreased both the number of entries (controls=13.2±0.7 entries) and time spent (controls=193.4±0.7 sec) when compared with the control mice in the closed arms of the elevated plusmaze test. Furthermore, fractions of E. longifolia Jack extract decreased the fighting episodes significantly (controls=18.0±0.4 fighting episodes) when compared with control mice. In addition, these results were found to be consistent with anxiolytic effect produced by diazepam. Hence, this study supports the medicinal use of this plant for anxiety therapy.
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  • Michitaka Shichijo, Yasuo Shimizu, Kenju Hiramatsu, Michinori Togawa, ...
    1999 Volume 79 Issue 4 Pages 501-504
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    The effect of suplatast tosilate (IPD-1151T), which is known to suppress interleukin (IL)-4 release from T cells, on the release of IL-4 and IL-13 from human peripheral basophils was investigated. Basophils were obtained from 16 mite-sensitive atopic asthmatic patients. IPD-1151T clearly inhibited the antigen-induced release of IL-13 but not IL-4. These results suggest that IPD-1151T possesses different activity for the regulation of cytokine release in basophils and T cells.
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  • Kazuki Nakamura, Yu Yamaguchi, Satomi Kagota, Kazumasa Shinozuka, Masa ...
    1999 Volume 79 Issue 4 Pages 505-508
    Published: 1999
    Released on J-STAGE: March 31, 2001
    JOURNAL FREE ACCESS
    We investigated the effect of water extracts of Cordyceps sinensis (WECS) on Kupffer cell function in rats. Rats were received a single i.v. injection of a colloidal carbon solution and then the clearance rate from the blood were measured. The rats had been daily administered with WECS, p.o. at a dose of 200 mg/kg for 25 days until the day before the injection of colloidal carbon. The half-life of the colloidal carbon in the blood of rats administered WECS 200 mg/kg was significantly shorter than that of the control rats. This suggests that accelerated function of Kupffer cells is partially involved in the anti-metastatic action of WECS.
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