Folia Pharmacologica Japonica
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
Volume 83, Issue 5
Displaying 1-11 of 11 articles from this issue
  • Tomitaro KITA, Taeko HATA, Noriko HARADA, Eiji ITOH
    1984 Volume 83 Issue 5 Pages 373-382
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    Male ddY mice were loaded with restraint and water immersion stress (RWIS) for 1 hr, and their ECG was measured by lead II. A considerable decrease of heart rate and remarkable prolongations of PQ, QT and QRS intervals were observed in the ECG of RWIS mice. Then experimental arrhythmias were induced by methacholine or adrenaline (Adr) on RWIS mice, and their frequencies of appearance were examined. The appearances of methacholine-induced ventricular extrasystole, atrio-ventricular (A-V) block, sino-atrial (S-A) block and sinus standstill were higher in RWIS mice than in normal mice, and the appearances of sinus arrhythmia and supraventricular extrasystole were similar to normal mice. The appearance of Adr-induced arrhythmia of any type was significantly higher in RWIS mice than in normal mice. Then protective effects of 3 β-blockers, oxprenolol, propranolol and carteolol, on the worsening of Adr-induced arrhythmias on RWIS mice were studied. A single administration of 5 or 10 mg/kg of oxprenolol or 5 mg/kg of propranolol inhibited the appearance of extrasystole and A-V block. The effectiveness of three-times administrations of 1 ?? 10 mg/kg of oxprenolol was similar to that of the single administration. These results suggest that oxprenolol shows a strong antiarrhythmic effect by continuous administrations on chronic syndromes in SART mice, and it shows an immediate effect by a single administration on acute syndromes in RWIS mice.
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  • Shohei HIGUCHI, Yuuko OSADA, Yoko SHIOIRI, Shiro NAKAIKE, Makoto MURAM ...
    1984 Volume 83 Issue 5 Pages 383-394
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    Anti-inflammatory activity and mode of action of oxaprozin, a new non-steroidal anti-inflammatory agent, were investigated in experimental animal models and in vitro tests. Anti-inflammatory potency of oxaprozin was almost equal to that of aspirin in acetic acid vascular permeability, carrageenin hind paw edema, cotton pellet granuloma and adjuvant arthritis tests in rats. On the other hand, in mice, oxaprozin was more potent than aspirin, ibuprofen and phenylbutazone, and it was as potent as sulindac and fenbufen in acetic acid vascular permeability and carrageenin hind paw edema tests. In adrenalectomized rats, the anti-edema activity of oxaprozin in the carrageenin hind paw edema test was the same as that in intact rats. Oxaprozin inhibited erythema formation induced by ultra-violet rays in guinea pigs. The inhibitory potency of oxaprozin against prostaglandin E2 biosynthesis in vitro was equal to that of ibuprofen. Oxaprozin showed a concentration-dependent inhibition of heat-induced denaturation of bovine serum albumin and lysis of rabbit erythrocytes in vitro. However, oxaprozin did not inhibit rat hind paw edemas induced by dextran, formalin and serotonin. It was suggested from these results that the mode of action of oxaprozin is similar to those of other acidic non-steroidal anti-inflammatory drugs. Ulcerogenicity of oxaprozin was weaker than those of phenylbutazone and aspirin in rats. Species differences in the metabolic rate of oxaprozin were shown. The blood concentration of oxaprozin in rats is extremely low because the metabolic rate of oxaprozin is rapid in rats. Therefore, in rats, oxaprozin exhibited a weak anti-inflammatory effect. However, in mice, oxaprozin had a low metabolic rate, and the effect of oxaprozin was as potent as sulindac and fenbufen. The elimination half-life of oxaprozin is extended, 49 to 69 hr, in humans. It was suggested from these findings that oxaprozin is a potent and long acting anti-inflammatory drug in clinical use.
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  • Jun GOTO, Makoto MURAMATSU, Kazuaki HOSODA, Susumu OTOMO, Hironaka AIH ...
    1984 Volume 83 Issue 5 Pages 395-400
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    The inhibitory effects of oxaprozin, a new non-steroidal anti-inflammatory drug, on platelet aggregation and prostaglandin (PG) synthetase activity were studied. In arachidonic acid (AA)-induced rabbit platelet aggregation in vitro, oxaprozin exhibited a dose-dependent inhibitory effect, and its median inhibitory concentration was 124.2, μM. The effect of oxaprozin was less potent than that of indomethacin and piroxicam, equipotent as that of aspirin and phenylbutazone, and 2 times as potent as that of ibuprofen. In collagen-induced rat platelet aggregation ex vivo, oxaprozin showed a weak but significant inhibitory effect with oral dose of 300 mg/kg. Indomethacin, aspirin and ibuprofen exhibited an inhibitory effect with 100 mg/kg. Although phenylbutazone also exhibited an inhibitory effect with 300 mg/kg, the effect was more potent than that of oxaprozin. ADP-induced platelet aggregation both in rabbit in vitro and rat ex vivo was not affected by oxaprozin. Moreover, oxaprozin administered orally inhibited dose-dependently AA-induced pulmonary thrombotic mortality in mice, and its median effective dose was 56.4 mg/kg. The effect of oxaprozin was less potent than of sulindac, piroxicam and ibuprofen, equipotent as that of aspirin, and 5 times as potent as that of phenylbutazone. On the other hand, oxaprozin inhibited dose-dependently PG synthetase activity. The inhibitory effect of oxaprozin was less potent than that of indomethacin and piroxicam, almost equipotent as that of ibuprofen, and more potent than that of phenylbutazone and aspirin. These results suggest that oxaprozin, like many other acidic non-steroidal anti-inflammatory drugs, suppresses platelet aggregation by mainly inhibiting PG synthetase activity.
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  • Kazuo NAKAMURA, Tetsuo HAYASHI, Keiji NAKAMURA
    1984 Volume 83 Issue 5 Pages 401-412
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    The [14C]2-deoxy-D-glucose technique has been applied to examine glucose utilization rate (GUR), as a measure of neuronal activity, of 42 cerebral nuclei, hypophysis and adrenals in male Wistar rats. Restraint and water-immersed stress for a 10 min period significantly increased GUR in the cortex frontalis, nucleus (n.) amygdaloideus centralis and lateralis, n. ventromedialis, substantia nigra, n. reticularis lateralis, n. ambiguus, lobus anterior of hypophysis, and adrenals. The elevation was predominant in the n. amygdaloideus centralis, n. ambiguus and lobus anterior of hypophysis. Bromazepam significantly prevented these elevations at the non-muscle relaxant dose of 1 mg/kg, p.o. Further prolongation (55 min) of stress caused a marked and non-selective increase of GUR in all cerebral nuclei and glands examined. In spontaneously hypertensive rats in the conscious, resting state, the pretreatment with bromazepam (3 mg/kg, p.o.) abolished the stress-induced pressor response and the release of epinephrine, norepinephrine and dopamine β-hydroxylase into the circulation. These results suggest that the n. amygdaloideus centralis is mostly a sensitive site to stress and one of the major action sites of bromazepam.
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  • Taeko HATA, Tomitaro KITA, Eiji ITOH, Noriko HARADA
    1984 Volume 83 Issue 5 Pages 413-424
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    Protective effects of β-blockers (oxprenolol, propranolol and carteolol) on the abnormal ECG of the sympathicotonia type were studied in male ddY SART stressed mice. Oxprenolol and carteolol were observed to have mild effects on the abnormal ECG as compared with propranolol. Experimental arrhythmias were induced by drugs in SART mice, and their frequencies of appearance were examined. The types of arrhythmias used as indices were sinus arrhythmia, supraventricular and ventricular extrasystole, the 1st and 2nd degrees of atrio-ventricular (A-V) block, sino-atrial (S-A) block and sinus standstill. The frequency of appearance of arrhythmia of any type induced by adrenaline was lower in SART mice than in normal mice. The frequency of appearance of methacholine (MCh)-induced arrhythmia of any type was significantly higher in SART mice than in normal mice. Protective effects of the 3 β-blockers on the worsening of MCh-arrhythmias in SART mice were studied. With a single dose of 5 or 10 mg/kg, the drugs were effective on supraventricular extrasystole and S-A block. Continuous administrations of oxprenolol and carteolol inhibited the occurrence of supraventricular extrasystole, A-V block and S-A block, but not the occurrence of ventricular extrasystole. Continuous administrations of propranolol were effective on any type of arrhythmias except for sinus arrhythmia. These results further support our viewpoint that the SART mouse is of the sympathicotonia type with respect to the heart, and they suggest that oxprenolol and carteolol may be effective clinically on arrhythmias caused by autonomic imbalance.
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  • Kazuma FUJIMOTO, Toshiie SAKATA, Koichi ARASE, Koichiro TSUTSUI, Masat ...
    1984 Volume 83 Issue 5 Pages 425-432
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    To clarify suppressive effects of mazindol on food intake in rats, changes in body weight, meal patterns as well as 24-hr food intake, and endogenous chemical substances were investigated following the intra-ventricle III infusion of 0.03 pmole mazindol. Experiments were carried out under the condition of a 12: 12 light-dark cycle (light: 0800 ?? 2000 hr). Mazindol decreased food intake as well as body weight after a 12 hr starvation. Reduced food consumption was observed during 12 hr following the injection. Weight reduction, however, lasted over all 3-tested days. When food was available ad. lib., mazindol decreased meal size during the 4 hr after injection and prolonged postprandial intermeal interval during the 4 hr period starting 2 hr after the injection. The infusion of mazindol also produced relative hyperglycemia and decreased free fatty acids, which was not accompanied with hyperinsulinemia. These findings, together with other reports, indicates that mazindol, unlike amphetamine and fenfluramine, possesses inhibitory actions on the hypothalamic feeding center.
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  • (V) Effect of different administration routes of trypan blue in rats
    Makoto EMA, Seizaburo KANOH
    1984 Volume 83 Issue 5 Pages 433-440
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    The teratogenicity of trypan blue (TB) after both maternal and intrauterine administrations was studied in Wistar rats, and the following results were obtained: 1) The teratogenic dose of TB by maternal subcutaneous injection was found to be greater than 50 mg/kg, and the critical period was until day 10 of pregnancy (sperm=day 0). No teratogenicity was detected by oral administration of 250mg/kg TB. 2) TB (250 μg/uterine horn) was injected into the uterine cavity on day 4 or 6 of pregnancy. An increase of intrauterine death without malformations was observed in both TB-treated groups. 3) TB was injected into the exocoelom. The incidences of malformed fetuses were 53% in the group injected with 2.5 μg/embryo TB on day 10 and 32% and 57% in the groups injected with TB at 1.0 and 2.5 μg/embryo on day 11, respectively. An increase of intrauterine death was observed in these groups. Types of malformations observed in these groups were abnormal tail, spina bifida and deformity of vertebrae, and were almost similar to those observed by maternal subcutaneous injection of TB. 4) A trace of TB was found microscopically in the frozen section of embryo after both subcutaneous and intraexocoelom injections of TB. These results suggest that TB acts directly on embryos to produce malformations.
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  • Shuji INOUE, Masato EGAWA, Shinobu SATOH
    1984 Volume 83 Issue 5 Pages 441-449
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    The present study investigated the effects of mazindol on the metabolic abnormalities of ventromedial hypothalamic-lesioned (VMH) rats. About 200g female Sprague-Dawley rats were divided into VMH and sham-operated rats. Two weeks later the feeding of a mazindol-containing diet (50 mg/kg) was started in half of each group. Eight weeks after mazindol treatment, rats were sacrificed, and various parameters were determined. Food intake was measured between the 4th and 5th week. In VMH-lesioned rats, mazindol decreased food intake remarkably and restored body weight, Lee Index, organ weights (liver, parametrial fat pad and lung), serum insulin, serum lipids (cholesterol, triglyceride, phospholipid and free fatty acids), serum GOT GPT, total lipid in the liver and findings of liver history to normal. Mazindol did not change these parameters, except for serum triglyceride, in sham-operated rats and had no effect on food intake. The results suggested that normalization of these abnormalities in VMH-lesioned rats depends mainly on the reduction of food intake due to overresponse to mazindol by VMH lesions.
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  • Kiyoko KAJI, Masahiro MIYASHITA, Yoshiyuki SEYAMA, Saburo YAMASHITA
    1984 Volume 83 Issue 5 Pages 451-457
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    The anti-hyperlipidemic effect of the iodine egg was found to be in the neutral lipid (NL) fraction in its yolk. For the purpose of clarifying the hypolipidemic effect of the iodine-containing NL fraction, the effect of clofibrate (CPIB) was investigated. CPIB was found to lower TC, atherogenic index C(TC-HDL cholesterol)/HDL cholesterol), TG and FFA, but not FC; while NL lowered TC, FC and the atherogenic index, but not TG and FFA. Cholesterol metabolites, probably metabolized in the liver, were examined. Hepatic cholesterol level was increased by NL and CPIB. The ratio of fecal bile acid of the excretion type, lithocholic acid (LCA) to deoxycholic acid (DCA), increased when NL and CPIB were administered, but the hepatic HMG-CoA reductase activity, responsible for the endogenous cholesterol synthesis, was not altered. Thus, the anti-hyperlipidemic mechanism of NL may be the mobilization of peripheral cholesterol to the liver, probably for the disposal by excretion as bile acids.
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  • (VI) Teratogenic effect of trypan blue and its related compounds in rats
    Makoto EMA, Hironoshin KAWASAKI, Yoshiyuki OGAWA, Takafumi ITAMI, Seiz ...
    1984 Volume 83 Issue 5 Pages 459-465
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    The teratogenicity of trypan blue and its related compounds was studied in Wistar rats and the following results were obtained: 1) οo-Tolidine, 1-amino-8-naphthol-3, 6-disulfonic acid or 1-nitronaphthalene-3, 6-disulfonic acid was injected subcutaneously on day 7 of pregnancy (sperm=day 0). No fetotoxicity was observed in any group. 2) The main fractions, blue fraction (blue fr.) and red fraction (red fr.), were separated from commercial trypan blue (C-TB) by silica gel column chromatography. C-TB, blue fr. or red fr. was injected into pregnant rats subcutaneously on day 7 of pregnancy. The incidence of malformed fetuses after injection of blue fr. was higher than that of C-TB, and the types of malformations induced by C-TB and blue fr. were similar. However, no fetotoxicity was detected after injection of red fr. 3) Blue fr. or red fr. was injected into the exocoelom on day 11 of pregnancy. The incidence of malformed fetuses in the group injected with blue fr. (2.5 μg/embryo) was 39%, and the types of malformations were abnormal tail and vertebrae, which were also observed after injection of C-TB or blue fr. into pregnant rats. No significant teratogenic effect was observed after injection of red fr. From these data, it was concluded that the teratogenic effect of C-TB might be due to the blue fr., but not the red fr.
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  • Shin John PACK
    1984 Volume 83 Issue 5 Pages 467-478
    Published: 1984
    Released on J-STAGE: March 07, 2007
    JOURNAL FREE ACCESS
    A communication box paradigm which can eliminate the influence of the physical noxious stimuli such as electrical foot-shock from the conditioned emotional stimuli has recently been developed for producing gastric mucosal lesions (GML) in mice. In this situation, the unshocked animals (NE group) were exposed to affective stimuli such as visual, auditory and olfactory sensations from the shocked conspecifics (E group). The present study was conducted to investigate an experimental procedure that can be applied to rats. When the communication box paradigm was applied to rats, the incidence of GML was very low: E group (38%) and NE group (13%). Marked augmentation of the incidence of GML was obtained in both E and NE groups by reserpine pretreatment at the dose of 1 mg/kg which did not produce GML. Various kinds of GML were defined endoscopically using a narrow fibre scope. The manifestation of the GML in both E and NE groups was completely suppressed by vagotomy, whereas pyloroplasty was ineffective. The procedure for eliciting GML in rats was established by a combination of the communication box paradigm with reserpine pretreatment. The endoscopic technique may provide a clue for investigating the time-dependent healing process of GML, especially for evaluating the therapeutic effect of a drug.
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