The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 80 , Issue 1
Showing 1-14 articles out of 14 articles from the selected issue
Reviews
  • Yuji Imaizumi, Yoshiaki Ohi, Hisao Yamamura, Susumu Ohya, Katsuhiko Mu ...
    1999 Volume 80 Issue 1 Pages 1-8
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Ca2+ spark is a local and transient Ca2+ release from sarcoplasmic reticulum (SR) through the ryanodine receptor Ca2+-releasing channel (RyR). In cardiac myocytes, Ca2+ spark is an elementary unit of Ca2+-induced Ca2+ release (CICR) by opening of RyR(s) in junctional SR (jSR), which is triggered by Ca2+-influx through L-type Ca2+ channels to the narrow space between a transverse tubule and jSR. Ca2+ spark has, therefore, been described as the evidence for “the local control of excitation-contraction coupling”. In contrast, Ca2+ sparks in smooth muscle have been reported in relation to Ca2+-dependent K+ (KCa) channel activation and muscle relaxation. A spontaneous Ca2+ spark in a superficial area activates 10 - 100 KCa channels nearby and induces membrane hyperpolarization, which reduces Ca2+ channel activity. In several types of smooth muscle cells, which have relatively high membrane excitability, an action potential (AP) elicits 5 - 20 Ca2+ hot spots (evoked sparks with long life) in the early stage via CICR in discrete superficial SR elements and activates KCa-channel current highly responsible for AP repolarization and afterhyperpolarization. CICR available for contraction may occur more slowly by the propagation of CICR from superficial SR to deeper ones. The regulatory mechanism of ion channel activity on plasma membrane by superficial SR via Ca2+ spark generation in smooth muscle cells may be analogously common in several types of cells including neurons.
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  • Kiyofumi Yamada, Xiuhai Ren, Toshitaka Nabeshima
    1999 Volume 80 Issue 1 Pages 9-14
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    Alzheimer's disease (AD) is the most common cause of progressive decline of cognitive function in aged humans, and it is characterized by the presence of numerous senile plaques and neurofibrillary tangles accompanied by neuronal loss. The senile plaques are composed of amyloid β-peptides (Aβ), 40 - 42 amino acid peptide fragments of the β-amyloid precursor protein. Genetic, molecular biological and neuropharmacological evidence support the 'amyloid cascade hypothesis' for the pathogenesis of the disease. We review the in vivo effects of various compounds on behavioral and neuropathological changes in the non-transgenic animal models of AD produced by continuous i.c.v. infusion of Aβ. These results support therapeutic strategies such as cholinergic therapy, anti-inflammatory agents, antioxidants and estrogen replacement therapy, as well as other cognition enhancers for the treatment of AD. In addition, the amyloid cascade hypothesis offers a number of potential targets for novel therapeutic strategies in AD. We believe that our non-transgenic animal model, as well as transgenic animal models, are useful for developing novel pharmacotherapeutics in AD.
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Regular Papers
  • Michiko Nojiri, Kouichi Tanonaka, Ken-ichi Yabe, Ken-ichiro Kawana, Ta ...
    1999 Volume 80 Issue 1 Pages 15-23
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    A possible mechanism for hypoxic preconditioning of adult rat cardiomyocytes was pharmacologically investigated. Isolated cardiomyocytes in all experimental groups were incubated for 120 min under hypoxic conditions followed by 15-min reoxygenation (sustained H/R). Sustained H/R decreased rod-shaped cells. Exposure of the cardiomyocytes to 20-min of hypoxia/30-min reoxygenation (hypoxic preconditioning) attenuated the sustained H/R-induced decrease in rod-shaped cells. The effects of hypoxic preconditioning were abolished by treatment with the protein kinase C (PKC) inhibitor polymyxin B, but abolished by neither the adenosine A1/A2-antagonist sulfophenyl theophylline (SPT) nor the ATP-sensitive potassium channel (KATP channel) blocker glibenclamide. In another series of experiments, cardiomyocytes were incubated without hypoxic preconditioning in the presence of either the PKC activator PMA, adenosine or KATP-channel opener nicorandil and then subjected to sustained H/R. Treatment of the cells with PMA, adenosine or nicorandil mimicked the effects of hypoxic preconditioning. The effects of treatment with adenosine and nicorandil were abolished by polymyxin B treatment. Combined treatment with both SPT and glibenclamide abolished the effects of hypoxic preconditioning, whereas it failed to abolish PMA-induced cytoprotection. These results suggest that the activation of PKC in hypoxic preconditioned cardiomyocytes coupled independently with stimulation of adenosine receptor or opening of KATP channel, either of which is fully enough to exert the cytoprotective effects.
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  • Akio Ozaki, Yuko Fujishima, Takayuki Sukamoto
    1999 Volume 80 Issue 1 Pages 25-32
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    5-Hydroxytryptamine3 (5-HT3)-receptor blocking activities of KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) were assessed in vivo and in vitro. Intravenous administration of KB-R6933, granisetron, ondansetron and azasetron inhibited 5-HT-induced bradycardia (von Bezold-Jarisch reflex) in anesthetized rats, with ED50 values of 0.071, 0.71, 4.0 and 0.82 μg/kg, respectively. The inhibitory effect of KB-R6933 at a dose of 0.3 μg/kg lasted for at least 8 hr, whereas those of granisetron at 30 μg/kg, ondansetron at 100 μg/kg and azasetron at 30 μg/kg nearly disappeared within 2 - 4 hr. Oral administration of KB-R6933 and granisetron also inhibited the bradycardia, with ED50 values of 0.41 and 76.3 μg/kg, respectively. In guinea pig ileum, KB-R6933 concentration-dependently antagonized 5-HT-evoked contraction and reduced the maximal contraction (pKB=8.75). Granisetron, ondansetron and azasetron shifted the dose-response curve for 5-HT to higher concentrations with no reduction of maximal contraction, and their pKBs were 7.65, 7.00 and 6.29, respectively. In a radioligand receptor binding study, KB-R6933, granisetron, ondansetron and azasetron displaced [3H]GR65630 binding to rat entorhinal cortex membrane, with Ki values of 0.066, 0.99, 2.70 and 2.5 nM, respectively. On the other hand, KB-R6933 exhibited negligible affinities for other receptors or binding sites tested, except for a weak affinity for the cholinergic M1-receptor, even at concentrations up to 10 μM. These results suggest that KB-R6933 is a potent and selective 5-HT3-receptor antagonist with a longer duration of action than those of existing 5-HT3-receptor antagonists.
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  • Yuko Takaoka, Satoko Matsuura, Keiko Boda, Hiroichi Nagai
    1999 Volume 80 Issue 1 Pages 33-40
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    This study was conducted to investigate a mechanism of the anti-inflammatory action of mesoporphyrin, especially the effect on the production of cytokines by some cultured inflammatory cells. Mesoporphyrin had no effect on lipopolysaccharide-induced tumor necrosis factor-α production by RAW 264.7 cells (murine macrophage-like cells). Mesoporphyrin inhibited interferon-γ production by 1E10.H2 cells (murine T helper-1 cells), but not interleukin-4 production by D10.G4.1 cells (murine T helper-2 cells). Mesoporphyrin inhibited interleukin-6 production by human osteoblast-like MG-63 cells. This inhibition of interleukin-6 production is closely related to the suppression of prostaglandin E2 generation by interfering cyclooxygenase 1 and 2 enzyme activities. These data suggest that the inhibition of cytokine production is one of the anti-inflammatory mechanisms of mesoporphyrin.
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  • Shin-ichi Satoh, Teruki Kobayashi, Asako Hitomi, Ichiro Ikegaki, Yoshi ...
    1999 Volume 80 Issue 1 Pages 41-48
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    This study investigated the therapeutic potential of agents that inhibited neutrophil infiltration in cerebral ischemic infarction. The migration of neutrophils elicited by N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor, C5a or platelet-activating factor was potently inhibited by fasudil, an inhibitor of protein kinases including rho kinase, protein kinase C and myosin light chain kinase, and hydroxy fasudil, a metabolite of fasudil, in vitro. In a microembolism model in rats, myeloperoxidase-quantified neutrophil accumulation in the ischemic brain was observed 24 hr after embolization. Intravenous administration of fasudil prevented the accumulation of neutrophils. In rats given fasudil, myeloperoxidase activity in the ipsilateral hemisphere (0.04±0.01 unit/g wet tissue) was significantly lower than that in ischemic rats (0.11±0.02 unit/g wet tissue). Fasudil also significantly reduced the size of the infarct area and improved neurological functions. These results suggest that neutrophil infiltration into the ischemic brain is involved in the pathogenesis of ischemic injury and that inhibiting neutrophil infiltration may provide an effective therapeutic intervention to reduce ischemic injury.
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  • Toyoko Arimoto, Toshikazu Yoshikawa, Hirohisa Takano, Masahiro Kohno
    1999 Volume 80 Issue 1 Pages 49-54
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The generation of the reactive oxygen species during the interaction of diesel exhaust particles (DEP) with NADPH-cytochrome P450 reductase (P450 reductase) was investigated by electron spin resonance using the spin-trap 5, 5'-dimethyl-1-pyrroline-N-oxide (DMPO). Addition of DEP extract to an incubation mixture of mouse lung microsomes in the presence of NADPH resulted in a time-dependent NADPH oxidation and acetylated-cytochrome c reduction. Using purified P450 reductase as the enzyme source, superoxide radicals which were detected as the spin adduct (DMPO-OOH) while metabolized by P450 reductase were dependent upon both DEP and enzyme concentrations. The ELISA method using a specific monoclonal antibody revealed that DEP produced 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is formed from deoxyguanosine in DNA by hydroxyl radicals, in the culture medium of L1210 cells. Active oxygen scavengers such as superoxide dismutase and catalase effectively blocked the formation of 8-OHdG in culture medium, and deferoxamine, which inhibits hydroxyl radicals production by chelating iron, was also effective in inhibiting the DEP-produced 8-OHdG formation. These results indicate that DEP components produce 8-OHdG through the hydroxyl radical formation via superoxide by redox cycling of P450 reductase.
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  • Hiromi Sugawara, Masao Endoh
    1999 Volume 80 Issue 1 Pages 55-65
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    EMD 53998 (5-[1-(3, 4-dimethoxybenzoyl)-1, 2, 3, 4-tetrahydro-6-quinolyl]-6-methyl-3, 6-dihydro-2H-1, 3, 4-thiadiazin-2-one), the racemic mixture of (+)-enantiomer EMD 57033 and (-)-enantiomer EMD 57439, is a prototype of Ca2+ sensitizers that act via a central and/or down-stream mechanism in cardiac E-C coupling. In rabbit ventricular cardiomyocytes loaded with indo-1/AM, EMD 53998 and EMD 57033 shifted the relationship between Ca2+ transients and cell shortening (systolic function) to the left to the same extent as compared with that of elevation of [Ca2+]o. EMD 57439 did not elicit a positive inotropic effect (PIE). The PIE of EMD 57033 was associated with a more pronounced decrease in the diastolic cell length than that of EMD 53998, whereas the systolic effects of these compounds were equivalent. These results indicate that weak phosphodiesterase (PDE) III inhibition may exert a differential action on diastolic and systolic function. Thus, EMD 57439 antagonizes the Ca2+-sensitizing effect of EMD 57033 on diastolic function with no effect on systolic function, which may lead to a decease in diastolic cell length of a lesser extent with the racemate EMD 53998 compared with (+)-enantiomer EMD 57033.
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  • Yasuhiro Akiyama, Kuniko Hara, Masatoshi Kobayashi, Takashi Tomiuga, T ...
    1999 Volume 80 Issue 1 Pages 67-74
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    To clarify how vitamin K2 prevents bone loss in vivo, it was given to ovariectomized 20-week-old rats for 2 weeks. Bone mineral density (BMD) in the whole femur and in 7 specific portions (F1 to F7 from the proximal to the distal end) was determined by dual-energy X-ray absorptiometry, and histomorphometry was also performed in proximal tibial metaphysis. Ovariectomy (OVX) resulted in significant decreases in the BMD in the whole femur and the F1, F2, F6 and F7 portions. Histomorphometrical analysis of the tibia showed that the bone volume / tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) were decreased, while trabecular separation (Tb.Sp) and osteoclast number / bone surface (Oc.N/BS) were increased by OVX. The parameters for bone formation were not changed by OVX. These data indicate that the bone loss within 2 weeks is due to the enhancement of bone resorption. Vitamin K2 at 50 mg/kg inhibited the decrease in the BMD of the whole femur together with the F6 and F7 portions. Vitamin K2 also inhibited the decrease in Tb.N and the increases in Tb.Sp, Oc.N/BS and osteoclast surface / bone surface (Oc.S/BS) caused by OVX. These results suggest that vitamin K2 prevents bone loss through the inhibition of bone resorption and osteoclast formation in vivo.
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Short Communications
  • Pao-Li Wang, Mitsuko Shinohara, Noboru Murakawa, Masaki Endo, Shigeki ...
    1999 Volume 80 Issue 1 Pages 75-79
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    We examined the effect of cysteine protease of Porphyromonas gingivalis (P. gingivalis) on cell adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) of human gingival epithelial cells. The cells were incubated for 48 hr with or without P. gingivalis protease. Their cell adhesion molecule expression levels were increased at 12 hr, but decreased at 18 - 48 hr. This result suggests that protease degrades cell adhesion molecules. After the stimulation with protease for 12 hr, P. gingivalis fimbrial binding to a monolayer of the cells was effectively inhibited by the addition of the cell adhesion molecules, suggesting the fimbrial binding to the cells occurred through cell surface adhesion molecules.
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  • Yukimasa Azuma, Jiro Seto, Katsutoshi Ohno, Hiroshi Mikami, Toshihiro ...
    1999 Volume 80 Issue 1 Pages 81-84
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The effect of NTE-122 (trans-1, 4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on cholesterol absorption was investigated. NTE-122 inhibited whole-cell ACAT activity in CaCo-2 cells, a human intestinal cell line, with an IC50 value of 4.7 nM. In CaCo-2 cells cultured on a membrane filter, NTE-122 pronouncedly inhibited the basolateral secretion of newly synthesized cholesteryl esters, and significantly reduced the basolateral secretion of newly synthesized triglycerides without influencing the cellular triglyceride synthesis. Furthermore, NTE-122 (1 mg/kg, p.o.) inhibited [14C]cholesterol absorption in rats. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing the absorption of dietary cholesterol.
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  • Takao Shimazoe, Miyuki Maetani, Sachiko Nakamura, Shiro Yamanouchi, Sh ...
    1999 Volume 80 Issue 1 Pages 85-88
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The entrainment function in the suprachiasmatic nucleus (SCN) of young non-diabetic Otsuka Long Evans Tokushima Fatty (OLETF) rats was studied. OLETF rats significantly needed more days for re-entrainment to a new light-dark cycle than control Long Evans Tokushima Otsuka (LETO) rats. We also assessed Fos expression in the SCN induced by dim light exposure. The number of Fos-immunoreactive cells was significantly decreased in 5- to 13-week-old OLETF rats compared with LETO rats. Moreover, the effect of glutamate on neuronal activity in the SCN of OLETF rats were investigated. In young non-diabetic OLETF rats, the phase delay in the SCN neuronal firing rhythm induced by 1 μM glutamate was significantly less than that in LETO rats. These results suggested that the entrainment function is reduced in OLETF rats before the onset of diabetes.
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  • Shinji Takai, Denan Jin, Kazuyoshi Kirimura, Junko Ikeda, Masato Sakag ...
    1999 Volume 80 Issue 1 Pages 89-92
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    We investigated whether a lipoxygenase inhibitor, panaxynol, affected the vascular contraction induced by angiotensin (Ang) II and the mean arterial pressure in spontaneously hypertensive rats (SHR). Panaxynol suppressed dose-dependently the contractile responses induced by 30 nM Ang II in isolated intact and endothelial cell-denuded aorta in the hamster. IC50 values in the intact and endothelial cell-denuded aorta were 23 and 20 μM, respectively. In SHR, the mean arterial pressure after injection of 30 and 60 mg/kg panaxynol was reduced, and the maximum hypotensive values were 23 and 48 mmHg, respectively. Thus, lipoxygenase products may affect the renin-angiotensin system.
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  • Akio Ozaki, Mikio Yoshidomi, Takayuki Sukamoto
    1999 Volume 80 Issue 1 Pages 93-96
    Published: 1999
    Released: March 31, 2001
    JOURNALS FREE ACCESS
    The effects of a 5-hydroxytryptamine3 (5-HT3)-receptor antagonist KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) on experimental diarrhea and on intestinal fluid secretion stimulated by cholera toxin were examined and compared with those of ramosetron and loperamide. KB-R6933 and ramosetron (0.03 - 1 mg/kg, p.o.) inhibited the diarrhea induced by 5-HT, but not that by castor oil or prostaglandin E2 (PGE2), in mice. Loperamide significantly inhibited the diarrhea induced by 5-HT, castor oil and PGE2. All drugs tested inhibited the diarrhea induced by restraint stress and the intestinal fluid secretion stimulated by cholera toxin in rats. The results suggest the possibility that KB-R6933 may have clinical efficacy in the treatment of diarrhea.
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