The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 68 , Issue 3
Showing 1-15 articles out of 15 articles from the selected issue
  • Mariko Nishiyama, Kayoko Moroi, Li-Hua Shan, Masao Yamamoto, Chikahisa ...
    1995 Volume 68 Issue 3 Pages 235-243
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    To study endothelin receptor subtypes that mediate venous smooth muscle contraction, effects of some endothelin receptor agonists and antagonists on the rabbit lateral saphenous vein were examined and compared with those on the saphenous artery. In the artery, endothelin (ET)-1 elicited concentration-dependent contractions, while selective ETB-receptor agonists, IRL1620 (Suc-[Glu9, Ala11, 15]ET-1(8-21)) and sarafotoxin 6c (S6c) had almost no effect. The ET-1-induced responses shifted in parallel to the right by BQ-123 (cyclo (-D-Trp-D-Asp-Pro-D-Val-Leu-)), an ETA-receptor antagonist, or PD142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp), an ETA/ETB-receptor antagonist, indicating the involvement of the ETA receptor in this response. In the saphenous vein, not only ET-1 and ET-3, but also ETB-receptor agonists, IRL1620, S6c and [Glu9jsarafotoxin 6b ([Glu9]S6b), produced concentration-dependent, BQ-123-insensitive contractions. PD142893 did not affect the ET-1-induced contraction, but it shifted greatly the IRL1620-induced concentration-response curve in parallel to the right. The major components of ET-3-, S6c- and [Glu9]S6b-induced contractions were resistant to PD142893. These results indicate that two different vasoconstrictive ETB-receptor subtypes, ETB, (sensitive to IRL 1620 and PD 142893) and ETB2 (insensitive to IRL 1620 and PD 142893), are located on the smooth muscle of the saphenous vein.
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  • Masashi Iida, Naomi Fujita, Makoto Hosono, Yoshikazu Sukenaga
    1995 Volume 68 Issue 3 Pages 245-253
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    The bronchodilator and cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride) were evaluated. In anesthetized guinea pigs, i.v. bolus injections of NKH477 (1-100 μg/kg) inhibited the bronchoconstriction induced by inhaled leukotriene D4, increased the heart rate (HR) and decreased the diastolic arterial blood pressure (DBP) in a dose-dependent manner. The bronchodilator effect of NKH477 was 1500 times more potent than that of aminophylline and 17 times less potent than that of isoproterenol. The selectivity of NKH477 for bronchodilation vs an increase in HR was 15 times higher than that of isoproterenol and similar to that of aminophylline; and vs a decrease in DBP, the selectivity was 4 times higher than that of aminophylline and similar to that of isoproterenol. I.v. infusion of NKH477 (0.1-3 μg/kg/min) for 2 hr dose-dependently inhibited the bronchoconstriction induced by i.v. histamine. Isoproterenol (0.1 μg/kg/min, i.v.) enhanced the bronchoconstriction after termination of the infusion, whereas NKH477 did not. In conscious guinea pigs, inhalation of NKH477 (0.1- 5 mg/ml) concentrationdependently inhibited the bronchoconstriction induced by inhaled histamine, and a high concentration of NKH477 (35.4 mg/ml) increased the HR. The bronchodilator effect of inhaled NKH477 was 15 times less potent than that of isoproterenol. The selectivity of inhaled NKH477 was similar to that of isoproterenol. These results indicate that NKH477 may be useful as a bronchodilator.
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  • Akifumi Togari, Michitsugu Arai, Shigeki Nakagawa, Akira Banno, Masako ...
    1995 Volume 68 Issue 3 Pages 255-261
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    Rats with hereditary defects in ascorbic acid (AsA) synthesis (ODS rats) subjected to AsA-deficiency for 3 weeks showed reductions of plasma alkaline phosphatase and dry and ash weights of the tibia, but no body weight alteration. In accordance with the chemical changes, bone loss and decrease of bone formation by AsA deficiency but not by malnutrition were observed in contact microradiographs of the tibia and by a tetracycline double labeling technique, respectively. The mechanical properties of femora measured by a three point-bending procedure were also altered by AsA deficiency for 3 weeks and showed decreases of 59% in toughness, 32% in strength, 32% in ductility and 22% in stiffness. The biomechanical changes by AsA deficiency were greater than the chemical changes in bone, indicating the usefulness of measuring mechanical properties as a sensitive method for the evaluation of the bone status. The second moment of the area of the femur was not changed by AsA deficiency. These results suggest that AsA deficiency in ODS rats causes marked bone loss and reduction in bone formation, which is accompanied by a greater reduction in biomechanics of the femur without causing macroarchitectural changes.
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  • Tatsuya Kurobane, Shuji Kojima, Motoaki Yoshimura, Takeshi Icho, Yoshi ...
    1995 Volume 68 Issue 3 Pages 263-269
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    Neopterin is an 2-amino-4-hydroxypteridine derivative and a precursor of biopterin, which is derived from guanosine triphosphate. Previously, we have reported that 5, 6, 7, 8-tetrahydroneopterin (NPH4), a reduced form of neopterin, possesses an antioxidant activity in various systems. In this study, we investigated the activity in more detailed manner and discussed the possible applications of this antioxidant. Analysis by electron spin resonance spectrometry indicated that NPH4 scavenged superoxide anion radicals and hydroxyl radicals as well. Moreover, NPH4 protected the rat brain homogenate from autoxidation. Next, we examined the effect of NPH4 on the cell injury induced by cumene hydroperoxide (CHP) in cultured bovine artery endothelial cells. The activity of lactate dehydrogenase, a marker enzyme of cell injury, was elevated by CHP in a dose-dependent manner, and this elevation was dose-dependently suppressed by NPH4. The elevation of lipid peroxide content was also inhibited by NPH4 in the same fashion. These data suggest that NPH4 would be effective against various diseases whose pathogenesis is active oxygenrelated.
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  • Shizuhiko Aihara, Naofumi Murakami, Takako Tomita, Tomohiro Naruse, Ka ...
    1995 Volume 68 Issue 3 Pages 271-277
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    The effects of indomethacin on the production of cytokines at inflammatory sites were investigated in the monosodium urate (MSU) pleurisy model characterized by both cellular influx and edema. Indomethacin (10 mg/kg) orally administered 0.5 hr prior to MSU injection into the pleural cavity significantly inhibited MSU-induced neutrophil accumulation in the cavity. In addition, the drug slightly enhanced the level of MSU-induced tumor necrosis factor production without affecting interleukin-1 production. Furthermore, indomethacin inhibited both the levels of MSU-induced rat cytokine-induced neutrophil chemoattractant (CINC/gro) and interleukin-6 (IL-6) production by 78.3% at 3 hr and 45.8% at 4 hr post-injection, respectively. Although intrapleural injection of CINC/gro induced neutrophil infiltration in a dose-dependent manner, IL-6 did not affect the action of CINC/gro on neutrophil influx. These findings suggest that the inhibitory action of indomethacin on neutrophil infiltration is, at least, partly mediated by a decrease in the MSU-induced CINC/gro content in this model.
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  • Yosuke Murata, Kengo Harada, Fumio Nakajima, Joji Maruo, Tominori Mori ...
    1995 Volume 68 Issue 3 Pages 279-285
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    The effects of amiloride and its analogues (3'', 4''-dichlorobenzamil (DCB), 2'', 4''-dimethylbenzamil (DMB), 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and 5-(N-methyl-N-isobutyl)amiloride (MIBA)) on cardiac ion transporters (Na+/Ca2+ exchanger, Na+/H+ exchanger, Na+ pump and Ca2+ pump) and their cytotoxicities were tested in cardiac myocytes. All the tested compounds showed concentration-dependent inhibitory effects on the ion transporters studied in canine cardiac sarcolemmal vesicles. The concentrations (μM) of amiloride, DCB, DMB, EIPA and MIBA required to produce 50% inhibition were > 1000, 19, 10, 83 and 84, respectively, for the Na+/Ca2+ exchanger; 130, 73, 63, 16 and 14 for the Na+/H+ exchanger; > 1000, 72, > 300, > 300 and > 300 for the Na+ pump; and > 1000, 37, 93, 90 and 70 for the Ca2+ pump, respectively. Furthermore, these agents induced cell death in isolated rat cardiac myocytes and the 50% lethal concentrations (μM) were > 1000, 9.2, 30, 16 and 17, respectively. These findings demonstrate that amiloride and its analogues have non-selective inhibitory effects on cardiac ion transporters and cytotoxicity in cardiomyocytes. When these drugs are employed as experimental tools to investigate the involvement of ion transporters in cell functions, the results must be interpreted with caution.
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  • Mikio Ito, Kazuhide Inaguma, Yoshinori Suzuki, Tetsuya Segami, Yoshio ...
    1995 Volume 68 Issue 3 Pages 287-295
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    We investigated the effect of the zinc-cimetidine complex on the healing of acetic acidinduced gastric ulcers in rats. When the effects of test drugs were assessed on the 15th day after acetic acid injection, the zinc-cimetidine complex at oral doses of 15.0 (11.4 mg as cimetidine), 30.0 and 60.0 mg/kg twice daily promoted the ulcer healing in a dose-dependent manner. Cimetidine was effective at oral doses of over 45.4 mg/kg twice daily. ZnCl2 was ineffective on all ulcer parameters. The effect of the combination of cimetidine and ZnCl2 was similar to that of cimetidine alone. The zinc-cimetidine complex had already inhibited the increase in thiobarbituric acid reactants in the ulcerated region before the ulcer-healing effect of this compound was recognized. A single oral administration of the complex at 15 and 30 mg/kg to normal rats was ineffective in inhibiting acid secretion and in increasing serum gastrin levels, although cimetidine was markedly effective on both parameters. These results indicate that the zinc-cimetidine complex at about 1/4 the dose of cimetidine was as effective as cimetidine when the ulcer-healing effects of both compounds were compared with the same dose of cimetidine. In addition, the ulcer-healing effect of this complex may be due, at least in part, to the inhibition of lipid peroxidation but not due to the inhibition of acid secretion or the trophic effect of gastrin.
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  • Haruko Sugino, Hideyo Shimada
    1995 Volume 68 Issue 3 Pages 297-303
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    N-{3-[4'' (2", 6"-Dimethylheptyl)phenyl]butanoyl}ethanolamine (E5050), a newly synthesized compound, was shown recently to induce uricosuria in humans via inhibition of the postsecretory reabsorption of urate. We examined the effects of this compound on urate excretion in rats loaded with oxonate and compared these effects with those of the uricosuric drugs trichlormethiazide and probenecid. When administered i.p., E5050 (0.3 - 15 mg/kg) increased the urinary excretion rate of urate and the ratio of urate clearance to inulin clearance in a dose-dependent manner, while the urine volume increased only slightly, and the glomerular filtration rate and plasma urate level were not changed. No paradoxical effect on urate excretion was observed. In contrast, trichlormethiazide and probenecid had a biphasic effect on urate excretion. In a pyrazinoic acid suppression test, the uricosuric effect of E5050 was completely inhibited by pretreatment with pyrazinoic acid. In a phenolsulfonphthalein (PSP) test, E5050 did not affect urinary PSP excretion, while probenecid strongly decreased such excretion. Thus, E5050 also appears to be uricosuric in rats.
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  • Takushi X. Watanabe, Yukako Itahara, Hisaya Kuroda, Yun-Neng Chen, Ter ...
    1995 Volume 68 Issue 3 Pages 305-313
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    activities of synthetic calciseptine and FS2, a homologous peptide from snake venom, were determined using in vitro and in vivo preparations. Calciseptine and FS2 produced dosedependent relaxation in pre-constricted rat aorta, pulmonary artery and trachea. The onset and duration pattern of these relaxing effects were similar to those caused by nifedipine, an L-type Ca2+ channel blocker. Calciseptine relaxed the contraction of rat aorta provoked by an L-type channel agonist, Bay K 8644. This relaxation was not affected by NG-nitro-L-arginine, indomethacin or propranolol. Calciseptine and FS2 inhibited the contraction caused by acetylcholine in guinea pig ileal longitudinal muscle. In case of in vivo study using anesthetized rats, calciseptine, FS2 and nifedipine showed depressor effects. The hypotensive effects of the two peptides were more potent and sustained than that of nifedipine. These findings show that both synthetic calciseptine and FS2 have similar biological activities like nifedipine, an L-type Ca2+ channel blocker. In addition, these two peptides with large molecular weights may be unique and useful tools for studying the Ca2+ channel.
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  • Masatoshi Ohnishi, Yasuo Watanabe, Takeshi Shibuya
    1995 Volume 68 Issue 3 Pages 315-321
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    The neuroprotective functions of glia cells in the presence of excessive amounts of extracellular glutamate (Glu) were examined using glia-rich and glia-poor cultured cerebellar granule cells that contained the same number of neurons. In order to focus on the metabolic enzyme glutamine synthetase (GS) and the uptake system in glia cells, selective inhibitors such as L-methionine sulfoximine (MSO) and 4-acetamido-4''-isothiocyanostilbene-2, 2''-disulfonic acid (SITS) were used as pharmacological tools. The increased amount of lactate dehydrogenase (LDH) leakage induced by 50 μM Glu and SITS was equivalent to that of 1 mM Glu. However, the simultaneous treatment with 50 μM Glu and 5 μM MSO did not increase the LDH leakage. The larger quantities of extracellular Glu were sustained in both glia-rich and glia-poor cultures. After the administration of Glu and MSO, however, the larger quantities of Glu were not sustained. Taking these results into consideration, the Glu uptake system in glia cells seems to be more important than the Glu metabolic enzyme system in the regulation of neuronal protection from Glu toxicity.
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  • Yoko Aniya, Kun Fan Fong, Akira Naito, Matao Sakanashi
    1995 Volume 68 Issue 3 Pages 323-329
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    The antioxidative effects of β-adrenoceptor antagonists and related compounds were investigated. Among the β-adrenoceptor antagonists, the agents with a potent membrane-stabilizing activity such as bopindolol and propranolol strongly inhibited the hydrogen peroxide (H2O2)-induced lipid peroxidation of liver microsomes. Fifty percent inhibition concentration values for the lipid peroxidation of bopindolol, 18-502 (metabolite of bopindolol) and propranolol were calculated to be 1.8 μM, 10 μM and 2.3 μM, respectively. The same potency order of the agents for the inhibition of lipid peroxidation was observed in rat heart homogenates. Furthermore, cytochrome P-450-catalyzing lipid peroxidation in microsomes and H2O2-induced lipid peroxidation in coronary arteries or cardiac muscles of pigs were also inhibited by bopindolol, whereas propranolol was less effective. Bopindolol and 18-502, but not propranolol, scavenged a stable free radical 1, 1-diphenyl-2-picrylhydrazyl. Thus it was concluded that bopindolol that has membrane-stabilizing and radical scavenging activities is a more potent antioxidant than propranolol and may produce a beneficial effect for the treatment of ischemic cardiac diseases.
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  • Takashi Akata, Kenji Kodama, Shosuke Takahashi
    1995 Volume 68 Issue 3 Pages 331-343
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    Employing the isometric tension recording method, we studied the role of endothelium or endothelium-derived relaxing factor (EDRF) in the generation of rhythmic oscillations observed in contractile responses to various receptor agonists in isolated rabbit small mesenteric and epicardial coronary arteries. Norepinephrine (NE, 0.1-10 μM) generated oscillatory contraction in endothelium-intact strips from the mesenteric arteries. Similarly, acetylcholine (ACh, 10 μM), histamine (10 μM) and serotonin (10 μM) generated oscillatory contraction in endothelium-intact strips from the coronary arteries. These agonistinduced oscillations in both arteries were consistently eliminated by either endothelial denudation or EDRF pathway inhibitors including NG-nitro L-arginine (30 and 100 μM), oxyhemoglobin (3 and 10 μM) and methylene blue (3 and 10 μM). In contrast, EDRF releasers such as ACh or A23187 augmented the oscillations in the endothelium-intact strips. SNP (0.03 - 30 μM) failed to generate oscillations in NE (10 μM)-preconstricted endothelium-denuded strips from the mesenteric arteries. In conclusion, these agonist-induced oscillations are probably mediated through EDRF. The inability of SNP to generate oscillations suggests the obligatory role of the endothelium in generation of the oscillations. The oscillatory release of EDRF by endothelial cells may be responsible for generation of the oscillations.
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  • Tomihiko Chihara, Shigeki Nakamura, Toshiyuki Onogawa, Tatsuya Yamashi ...
    1995 Volume 68 Issue 3 Pages 345-347
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    We studied the antagonistic actions of OPC-21268 (1-{1-[4-(3-acetylaminopropoxy)-benzoyl]-4-piperidyl}-3, 4-dihydro-2(1H)-quinolinone) on the arginine vasopressin (AVP)-induced vasoconstrictor response in the spinally-anesthetized dog. OPC-21268 at doses of 0.3, 1.0 and 3.0 mg/kg, i.v. produced a rightward parallel shift of the dose-response curves for AVP in a dose-dependent manner. The doses of OPC-21268 were similar to those that inhibited the AVP-induced vasoconstrictor response in the rat. This observation suggests that OPC-21268 acts as a V1-AVP-receptor antagonist in peripheral resistance vessels in dogs as well as in rats.
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  • Mei-Yu Geng, Hiroshi Saito, Hiroshi Katsuki
    1995 Volume 68 Issue 3 Pages 349-352
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    The effects of treatment with thiamine (Vitamin B1) alone or together with its antagonist oxythiamine on the survival of brain neurons in primary culture were investigated. Treatment with thiamine significantly promoted the survival of hippocampal neurons in high cell density culture, but had no effects on the neuronal survival in low cell density culture. In addition, the survival-promoting activity exerted by thiamine was remarkably decreased by the co-application of oxythiamine, although oxythiamine used alone revealed neither a trophic nor toxic effect on the neurons of examined brain regions. The neurotrophic function of thiamine may be due to its coenzymatic role in a biochemical reaction and/or its specific function on neurotransmission and nerve conduction.
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  • Koichi Yokota, Noriko Yamamoto, Yuji Obata, Minoru Oda
    1995 Volume 68 Issue 3 Pages 353-357
    Published: 1995
    Released: April 07, 2006
    JOURNALS FREE ACCESS
    We devised a method for evaluating polymorphonuclear leukocyte (PMN) infiltration in vivo employing an air bleb technique combined with measurement of myeloperoxidase (MPO) activity, and the effects of some anti-platelet agents were evaluated. KBT-3022 (ethyl 2-[4, 5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate) and cilostazol inhibited the increase in MPO activity in the connective tissue around the air bleb induced by leukotriene B4 (LTB4) and formyl-methionyl-leucyl-phenylalanine (fMLP). Indomethacin inhibited only the fMLP-induced increase in MPO activity, but ticlopidine hydrochloride and acetylsalicylic acid had no effect. Histologic observation confirmed the inhibition of PMN infiltration by KBT-3022. These results indicate that KBT-3022 may be a potent inhibitor of both LTB4- and fMLPinduced infiltration of PMNs.
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