The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 76, Issue 4
Displaying 1-12 of 12 articles from this issue
Review
  • Takashi Yamamoto, Takatoshi Nagai, Tsuyoshi Shimura, Yasunobu Yasoshim ...
    1998 Volume 76 Issue 4 Pages 325-348
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    Recent advances in neural mechanisms of taste are reviewed with special reference to neuroactive substances. In the first section, taste transduction mechanisms of basic tastes are explained in two groups, whether taste stimuli directly activate ion channels in the taste cell membrane or they bind to cell surface receptors coupled to intracellular signaling pathways. In the second section, putative transmitters and modulators from taste cells to afferent nerves are summarized. The candidates include acetylcholine, catecholamines, serotonin, amino acids and peptides. Studies favor serotonin as a possible neuromodulator in the taste bud. In the third section, the role of neuroactive substances in the central gustatory pathways is introduced. Excitatory and inhibitory amino acids (e.g., glutamate and GABA) and peptides (substance P and calcitonin gene-related peptide) are proved to play roles in transmission of taste information in both the brainstem relay and cortical gustatory area. In the fourth section, conditioned taste aversion is introduced as a model to study gustatory learning and memory. Pharmacobehavioral studies to examine the effects of glutamate receptor antagonists and protein kinase C inhibitors on the formation of conditioned taste aversion show that both glutamate and protein kinase C in the amygdala and cortical gustatory area play essential roles in taste aversion learning. Recent molecular and genetic approaches to disclose biological mechanisms of gustatory learning are also introduced. In the last section, behavioral and pharmacological approaches to elucidate palatability, taste pleasure, are described. Dopamine, benzodiazepine derivatives and opioid substances may play some roles in evaluation of palatability and motivation to ingest palatable edibles.
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  • Noboru Toda, Tomio Okamura
    1998 Volume 76 Issue 4 Pages 349-367
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    The vascular tone, vascular resistance and blood flow in the brain are regulated by neural and humoral factors in quite a different way from those of peripheral organs and tissues. In contrast to the dominant vasoconstrictor control in the periphery, the intracranial vascular tone is predominantly influenced by vasodilator mediators over vasoconstrictor ones. Recent studies have revealed that nitroxidergic vasodilator nerve and endothelium-derived hyperpolarizing factor (EDHF) or K+ channel opening substance appear to play important roles in the regulation of cerebral arterial and arteriolar tone in primate and subprimate mammals, in addition to the accepted information concerning the crucial contribution of endothelium-derived relaxing factor (EDRF) or nitric oxide (NO), polypeptides, prostanoids, etc. This article summarizes characteristic properties of vasodilator factors in controlling the cerebral arterial and arteriolar tone that undoubtedly contribute to circulatory homeostasis. The content includes vasodilator nerve, endogenous vasodilator substances, and vasodilator interventions such as hypoxia, hypercapnia and hyperosmolarity.
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Regular Papers
  • Kumi Satoh, Atsuko Yamamoto, Katsuji Hoshi, Kazuo Ichihara
    1998 Volume 76 Issue 4 Pages 369-376
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    Effects of azelnidipine, a dihydropyridine derivative, on stunned myocardium were examined in anesthetized open-chest dogs. The left anterior descending (LAD) coronary artery was ligated for 20 min and then released for 60 min. Dimethyl sulfoxide (DMSO), the solvent of azelnidipine, or azelnidipine (0.03, 0.1 or 0.3 mg/kg) was injected i.v. 20 min before ligation. Segment shortening was determined by sonomicrometry. The levels of high-energy phosphate were measured in 60-min reperfused hearts. Azelnidipine at 0.1 and 0.3 mg/kg significantly decreased diastolic blood pressure and increased % segment shortening. The increase in % segment shortening due to azelnidipine appeared to be abolished by propranolol and atropine pretreatment. Ischemia significantly decreased % segment shortening in all groups. The % segment shortening that had been decreased by ischemia recovered during reperfusion, but did not reach its preischemic level in each group. In the 0.1 and 0.3 mg/kg of azelnidipine-treated dogs, a significant enhancement of % segment shortening recovery during reperfusion was observed, as compared with that in the DMSO-treated dogs. Azelnidipine did not affect the high-energy phosphate levels in 60-min reperfused hearts. In conclusion, azelnidipine improved the contractile dysfunction in stunned myocardium, without any preservation of high-energy phosphate.
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  • Yasuo Oyama, Lumi Chikahisa, Kaori Kanemaru, Mami Nakata, Sachi Noguch ...
    1998 Volume 76 Issue 4 Pages 377-385
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    Effects of FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1, 3-propanediol HCl), a novel immunosuppressant, were examined on neurons and thymocytes respectively dissociated from rat brains and thymus glands using a flow cytometer to see if FTY720 exerts cytotoxic actions not only on spleen cells as previously reported but also on the other cells. FTY720 at a concentration of 10 μM deteriorated almost all of the thymocytes, while it was not the case for brain neurons. FTY720 increased the intracellular concentration of Ca2+ ([Ca2+]i) of thymocytes in both the presence and absence of external Ca2+, although the [Ca2+]i increased by FTY720 in the presence of external Ca2+ was much greater than that in the absence of external Ca2+. Thus, FTY720 may increase the membrane permeability of Ca2+ and release Ca2+ from intracellular Ca2+ stores in thymocytes. Furthermore, the number of thymocytes stained with ethidium, a dye impermeant to intact membranes, time-dependently increased after drug application. Therefore, FTY720 at concentrations of 3 – 10 μM non-specifically increases the membrane permeability of thymocytes, resulting in necrotic cell death, although FTY720 at micromolar concentrations was reported to induce apoptosis of spleen cells.
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  • Kenjiro Fukao, Toshihiko Momiyama, Kumatoshi Ishihara, Hisamitsu Ujiha ...
    1998 Volume 76 Issue 4 Pages 387-396
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    The effects of muscimol, a γ-aminobutyric acid (GABA)A-receptor agonist, and aminooxy-acetic acid (AOAA), an inhibitor of GABA-converting enzyme, on tonic and absence-like seizures in spontaneously epileptic rats (SER: zi/zi, tm/tm) were investigated to elucidate whether GABAergic function operates normally in these animals. Muscimol at doses of 1 and 3 mg/kg (i.p.) induced high-voltage slow waves in the cortical and hippocampal EEG of SER, although the behavioral observation suggested inhibition of absence-like seizures. Similar high-voltage slow waves were also observed in the cortical and hippocampal EEG of normal rats with muscimol (1 and 3 mg/kg). Tonic convulsions in SER were dose-dependently inhibited by muscimol. AOAA (3 and 10 mg/kg, i.v.) inhibited both tonic and absence-like seizures in SER, although there were no obvious changes in EEG pattern. The inhibitory effects of AOAA on tonic convulsions appeared more slowly and lasted longer than those on absence-like seizures. Cerebral, hippocampal and cerebellar GABA levels were significantly higher in SER than the normal Kyo:Wistar and zitter rat (zi/zi), which were both the parent strains. These findings suggest that GABA receptors and GABAergic neurons are functional in SER and that the GABA system is involved in the inhibition of both seizures.
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  • Junichi Onaya, Mamoru Kyogashima, Atsuko Sunose, Satoshi Miyauchi, Syo ...
    1998 Volume 76 Issue 4 Pages 397-404
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    Effects of dermatan sulfate (DS) on the endotoxin-induced disseminated intravascular coagulation (DIC) rat model were compared with those of low-molecular weight heparin (LMWH), nafamostat mesilate (NM) and argathroban (AR). At doses of 5, 10 or 20 mg/kg/4 hr, DS significantly ameliorated the decrease of fibrinogen (Fbg), the increase of fibrin-fibrinogen degradation products (FDP) and except at the highest dose (20 mg/kg/4 hr), the prolongation of thrombin clotting time (TCT). It also decreased the glomerular fibrin deposits (%GFD) at doses of 10 or 20 mg/kg/4 hr. LMWH suppressed the decrease of Fbg and the increase of FDP at doses of 1.4 or 2.8 mg/kg/4 hr. Only the highest dose of LMWH suppressed the decrease of the platelet count (PL), the prolongation of prothrombin time, and improved the %GFD. AR suppressed the decrease of PL and improved the %GFD. At the dose required to improve the %GFD, DS (5, 10 mg/kg/4 hr) significantly suppressed the prolongation of TCT, which is related to the bleeding frequency, while LMWH and AR further increased the prolongation of the TCT. These results suggest that DS has potential as a therapeutic drug with a lower hemorrhagic risk as compared with LMWH and AR in the treatment of DIC.
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  • Shun-suke Takahashi, Martin A. Denvir, Lisbet Harder, David J. Miller, ...
    1998 Volume 76 Issue 4 Pages 405-413
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    Doxorubicin is an anthracycline antibiotic that is used widely as a chemotherapeutic agent. However, the usefulness of this agent is limited due to its cardiotoxic effects. The mechanisms associated with this cardiotoxicity remain essentially unknown, despite numerous studies describing a range of structural and functional abnormalities. The purpose of the present study was to determine the in vivo and in vitro effects of doxorubicin exposure on sarcoplasmic reticulum (SR) Ca2+-content and contractile protein function. The Ca2+-content of SR is shown to have a biphasic response to in vivo and in vitro doxorubicin exposure that is time- and dose-dependent. In vitro doxorubicin exposure initially reduces the SR Ca2+-content, but the predominant action to block the SR Ca2+-release channel increases SR Ca2+-content within 60 min. Similar results are observed with in vivo doxorubicin exposure: it leads to Ca2+-overload. These data are consistent with the view that doxorubicin acts in a similar manner to ryanodine and results in cardiomyopathy due to Ca2+-overload.
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  • Toshiaki Imagawa, Mariko Shida, Kaori Matsuzawa, Shunji Kaya, Kazuya T ...
    1998 Volume 76 Issue 4 Pages 415-423
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    To ascertain whether ouabain binding to human α1-subunit influences coexpression of rat α1-subunit, the ouabain-sensitive profiles of Na+, K+-ATPase activity and 86Rb+ uptake activity and ouabain binding capacity were measured in HeLa cells stably expressing rat α1-subunit. The ouabain-sensitive profile of ATPase and 86Rb+ uptake activity seemed to be the sum of two components, one with high and one with low apparent affinity to ouabain, which were similar to that observed in HeLa and NRK-52E cells derived from human and rat, respectively. The ATPase activity with low sensitivity to ouabain increased in simple proportion to the amount of the rat α1 mRNA derived from transfected cDNA, which was determined by the reverse transcription-polymerase chain reaction method. The turnover number of the human Na+, K+-ATPase activity obtained from the ratio of the Na+, K+-ATPase activity to the ouabain binding capacity is about 150/sec. The expression of the rat α1-subunit had no effect on the turnover numbers of the Na+, K+-ATPase activity with high affinity to ouabain estimated from the ouabain binding capacity as the active site concentration. These results suggested that the ouabain bound to human α1-subunit did not inhibit the ATPase activity of the coexpressing rat α1 in these cells.
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Short Communications
  • Tohru Masukawa, Kunio Nakanishi, Reiko Natsuki
    1998 Volume 76 Issue 4 Pages 425-429
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    Effects of nitric oxide (NO) synthase inhibitors on the enoxacin-induced convulsions were examined in mice pretreated with fenbufen. 7-Nitroindazole markedly suppressed the incidence of convulsions, whereas L-arginine did not modify the convulsions at all. The suppression of the convulsions by 7-nitroindazole was not reversed by the pretreatment of L-arginine. Brain NO synthase activity was significantly raised at 30 min after enoxacin when combined with fenbufen. The increased NO synthase activity was found to be suppressed by the pretreatment of 7-nitroindazole. These findings suggest that endogenous NO may be involved as a proconvulsant substance in the development of enoxacin-induced convulsions in mice pretreated with fenbufen.
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  • Koh-ichi Sugimoto, Akio Fujimura
    1998 Volume 76 Issue 4 Pages 431-434
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    We examined the effects of icatibant, a specific bradykinin B2-receptor antagonist, on the regression of left ventricular mass (LVM) induced by angiotensin converting enzyme (ACE) inhibitors, ramipril and imidapril, in spontaneously hypertensive rats. Both ramipril and imidapril lowered blood pressure equally, which were not influenced by icatibant. Icatibant did not alter the regressive effect of imidapril, while it showed a tendency to increase LVM in the ramipril-treated rats. The changes of LVM induced by icatibant were significantly different between the ramipril- and the imidapril-treated rats, suggesting that the role of bradykinin in the antihypertrophic effect might differ among ACE inhibitors.
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  • Manoj Lakhe, Yasuyuki Furukawa, Takanori Yonezawa, Masamichi Hirose, Y ...
    1998 Volume 76 Issue 4 Pages 435-439
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    To investigate whether a Ca2+ sensitizer increases sinus rate, we studied the effects of racemic thiadiazinone, EMD 53998 (a Ca2+ sensitizer with phosphodiesterase inhibitory action) and its (+)-enantiomer EMD 57033 (a relatively pure Ca2+ sensitizer) on isolated, blood-perfused spontaneously beating right atria and paced left ventricles of the dogs. EMD 53998 increased sinus rate dose-dependently, but EMD 57033 did not. Both substances increased atrial and ventricular contractile force. Propranolol did not affect the responses to each substance. These results suggest that the Ca2+ sensitizing action induced by EMD 57033 does not affect pacemaker currents directly.
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  • Hiraku Akiho, Akihiko Iwai, Mika Katoh-Sudoh, Shin-ichi Tsukamoto, Kaz ...
    1998 Volume 76 Issue 4 Pages 441-444
    Published: 1998
    Released on J-STAGE: April 26, 2001
    JOURNAL FREE ACCESS
    We studied the effects of orotic acid and YM-39558 (2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-carboxylic acid ethyl ester), orotic acid ethylester, on delayed neuronal death of hippocampal CA1 neurons induced by transient forebrain ischemia. Our data indicated that YM-39558 had high permeability across the blood brain barrier and was hydrolyzed to orotic acid, the active substance, in the brain. The neuronal damage was reduced significantly in animals intraperitoneally treated with YM-39558 (100 mg/kg×3) after ischemia, but not with orotic acid in the same way. The results also suggested that the maintenance of a few ten micromolar orotic acid in cerebrospinal fluid were needed for its neuroprotective effects.
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