The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
Volume 17 , Issue 2
Showing 1-24 articles out of 24 articles from the selected issue
  • YOSHIO IWASAWA, AKIO KIYOMOTO
    1967 Volume 17 Issue 2 Pages 143-152
    Published: June 01, 1967
    Released: February 02, 2007
    JOURNALS FREE ACCESS
    For many years the synthesis of isoquinoline derivatives has been carried out in our Organic Chemistry Research Laboratory. In the process of pharmacological screening tests, 1-(3, 4-dihydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline was found to have significant bronchodilating as well as hypotensive actions, as briefly communicated in the previous report (1). This compound ha d been synthesized by Pyman in 1909 (2) and its hypotensive action was reported by Laidlaw in the following year (3). While our work was in progress, Holtz and his co-workers (4) demonstrated the formaton of this compound as a condensation product of dopamine and its enzymatically deaminated product, 3, 4-dihydroxyphenyl-acetaldehyde. They also reported its hypotensive and bronchodilating activities, which were interpreted as a β-sympathomimetic action of this compound. In reference to these studies 1-aralkyl derivatives of tetrahydroisoquinoline (THI) were synthesized and tested their bronchodilating activities. Among the compounds tested, 1-(3, 4, 5-trimthoxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (IX) was observed to be the most active bronchodilator hitherto described in the literature. The relationship between the chemical structure and the bronchodilating activity was investigated in this paper.
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  • MASANORI SATO, ISAO YAMAGUCHI, AKIO KIYOMOTO
    1967 Volume 17 Issue 2 Pages 153-163
    Published: June 01, 1967
    Released: February 02, 2007
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    In the preceding paper, it was reported that 1-(3', 4', 5'-trimethoxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (III) was the most potent bronchodilator of all the tetrahydroisoquinoline derivatives tested. Its bronchodilating activities in vitro and in vivo were about 10 times and 5 times stronger respectively than those of isoproterenol (1). In view of the general correlation between the bronchodilating and cardiovascular actions exhibited by adrenergic β-stimulants, it is interesting to study the effects of this compound on the cardiovascular system. In addition to III, we also tested two other tetrahydroisoquinoline derivatives, 1-benzyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (I) and 1-(3', 4'-ethylenedioxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (II), for their effects on the cardiovascular system of variuos experimental animals in comparison with the actions of isoproterenol on the same system. Of the three compounds, compound III was pharmacologically the most active. Compound I having the basic structure in the chemical sense belonged to the least active group. Compound II, in which both 3'- and 4'-hydroxy groups of tetrahydroisoquinoline are masked through formation of the ethylenedioxy linkage, had an intermediate pharmacological potency.
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  • AKIRA HOSHIKA
    1967 Volume 17 Issue 2 Pages 164-173
    Published: June 01, 1967
    Released: February 02, 2007
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    The oxidation of pharmacological amines such as histamine, 5-hydroxytryptamine and catecholamines is catalyzed by amine oxidizing enzymes from various origins (1, 2). These enzymes were classified into monoamine oxidase (2-5) and diamine oxidase (1, 6-10) according to their substrate specificity and susceptibility to inhibitors such as iproniazid and isoniazid. However, purified enzyme preparations were recently obtained from bovine plasma (11, 12), hog plasma (13) and pea seedlings (14, 15). They all have been often designated as amine oxidase, apart from the conventional classification, since these enzymes show properties of monoamine oxidase in their substrate specificity, and often behave also like diamine oxidase in substrate specificity and inhibition by isoniazid. It has been generally accepted that amine oxidases from various origins can take only molecular oxygen as hydrogen acceptor (1, 6, 16). However, there still remain many unsolved problems about the mechanism of electron transport to the acceptors via amine oxidases. The present paper reports evidences for the occurrance of transport of electron from histamine and some other amines to cytochrome c via diamine oxidase prepared from hog kidney or crystalline amine oxidase from Aspergillus niger. The latter enzyme was recently isolated by Yamada et al. (17) and was known to have the substrate specificity and susceptibility to inhibitors like diamine oxidase from hog kidney (18, 19). A preliminary report on these findings has been published earlier (32).
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  • AKIRA HOSHIKA
    1967 Volume 17 Issue 2 Pages 174-180
    Published: June 01, 1967
    Released: February 02, 2007
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    In the previous report (1) it has been demonstrated that hydrogen or electron from reduced amine oxidase is transferred not only to molecular oxygen but also to cytochrome c in the oxidation process of histamine and some other biological amines. It has also been shown that although ethylenediamine is generally considered not to be qualified as the substrate of amine oxidizing enzyme, it can serve as a hydrogen donor and induces the cytochrome c reduction under both aerobic and anaerobic conditions. Hill et al. (2) reported that ethylenediamine does not serve as the substrate for amine oxidase from pea seedlings. However, they found that when the enzyme is incubated with ethylenediamine under anaerobic conditions, there occur changes in the absorption spectrum. These changes were not restored by oxygenation unlike in the case of other substrates such as putrescine. The present paper describes the result of kinetic and stoichiometric studies on the reduction of cytochrome c induced by ethylenediamine, using amine oxidase from Aspergillus niger purified by Yamada et al. (3). A preliminary short communication of this paper has been published earlier (10).
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  • RYUICHI KATO
    1967 Volume 17 Issue 2 Pages 181-198
    Published: June 01, 1967
    Released: February 02, 2007
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    It is well documented that the activities of many microsomal enzymes which metabolize foreign compounds are markedly stimulated by administration of phenobarbital and other drugs. The mechanism of the increased activity of these enzymes is likely due to de novo synthesis of microsomal enzymes (1-4). In a previous communication the author reported a marked increae in the activities of N-demethylation of aminopyrine and hydroxylation of aniline in liver microsomes of fasted female rats (5). On the other hand, recently Pitot and Peraino (6) reported that the administration of glucose suppressed the induction of threonine dehydrase after the forced feeding with casein hydrate. It is therefore interesting to investigate a possible interaction in the increase in activities of some microsomal NADPH-dependent enzymes between phenobarbital treatment and starvation or sucrose feeding. The results reported here indicated that the activities of NADPH-dependent enzymes are increased or not altered by starvation, however these activities are markedly depressed by sucrose feeding. Moreover, the stimulation of the activities of the microsomal enzymes by phenobarbital was not prevented in the sucrose fed female rats and indeed the phenobarbital effect was potentiated in the fasted female rats.
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  • MOTOO OKA, TAKESHI OHUCHI, HIROSHI YOSHIDA, REIJI IMAIZUMI
    1967 Volume 17 Issue 2 Pages 199-207
    Published: June 01, 1967
    Released: February 02, 2007
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    It is well known that catecholamine is stored within specific granules in various tissues and when it is released from these granules it displays its physiological effects. Therefore, the mechanisms of storage and release of catecholamine have recently become a topic of interest. It was reported by Kirshner (1) and Carlsson et al. (2) that the uptake of 14C-catecholamine into the granules of the adrenal medulla was stimulated by ATP and Mg2+. Euler and Lishajko also showed ATP-Mg2+ dependent uptake of catecholarnine by the granules of adrenergic nerves (3, 4). The effect of ATP and Mg2+ on the uptake and release of catecholamine in the granules of adrenal medulla was also studied in this laboratory. It was found that on the addition of ATP and Mg2+, there was only slight or no inhibition of the release of catecholamine from the granules when they were incubated in sucrose solution, while when they were incubated in saline solution catecholamine release was greatly stimulated. This report gives further details of the stimulatory effect of ATP and Mg2+ on the release of catecholamine from the granules of adrenal medulla. A preliminary report of this work has been published (5, 6).
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  • RYUICHI KATO, AKIRA TAKANAKA
    1967 Volume 17 Issue 2 Pages 208-217
    Published: June 01, 1967
    Released: February 02, 2007
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    The enzymes which metabolize lipid soluble compounds are localized in microsomes of liver and reduced NADP and molecular oxygen are required as cofactors. It was recently demonstrated that the activities of drug-metabolizing enzymes are an important factor for controling the action and toxicity of drugs (1-9). The activities of drugmetabolizing enzymes were altered by several factors, such as administration of some drugs, anabolic hormone, alloxan diabetes, hyperthyroidism and starvation (1-15). In previous papers, it was reported that the activity of drug-metabolizing enzymes of liver microsomes in male rats was markedly decreased by starvation, while the activity in female rats was increased (14). The starvation caused a decrease in liver weight as well as body weight and the blood flow of liver. On the other hand, studies on electron microscopy showed that endoplasmic reticulum in liver of fasted rats was markedly altered in their fine structure by starvation (16, 17). Moreover, it has been considered that microsomes are artifacts during the homogenization of liver and they are likely derived from the endoplasmic reticulum. Thus, there is a possibility that the alternations in the enzyme activities in female and male rats may be artifacts during the homogenization. The purpose of the present investigation is to establish the correlation between the in vivo metabolism and activity of drugs and the in vitro metabolism of drugs in fasted female and male rats.
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  • YOSHIHIRO MATSUDA, IZURU MATSUOKA, SHUJI TAKAORI, KIRO SHIMAMOTO
    1967 Volume 17 Issue 2 Pages 218-227
    Published: June 01, 1967
    Released: February 02, 2007
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    It has been demonstrated by several investigators that the cardiac effects of alkyldisulfide derivatives of thiamine are considerably different from those of thiamine HCl. Misu et al. (1) in this laboratory have observed the effects of thiamine derivatives on the spontaneous contraction and transmembrane potentials of the isolated rabbit's atria. Thiamine tetrahydrofurfuryl disulfide (TTFD) prolonged the repolarization phase of the action potential and antagonized the shortening of the same phase caused by hypoxia. Furthermore, TTFD prolonged the time length required to abolish the spontaneous contraction of the atria induced by hypoxia, but thiamine HCl did not so. The positive inotropic effect and prolongation of the repolarization time in the isolated guinea-pig's atria have been confirmed by Nakazawa and Ueno (2) and Kanno (3) in TTFD and thiamine propyldisulfide but not in thiamine HCl. The blocking effects of thiamine derivatives on the neuro-muscular junction (4-6) and the sympathetic ganglion (7, 8) have been reported. Thiamine was also described to inhibit the activity of cholinesterase (9). These findings indicate the possibility that thiamine derivatives, especially the alkyldisulfides, exert cholinergic excitement in the central nervous system. The present report deals with effects of thiamine derivatives on the spontaneous EEG of rabbits, when these drugs are administered into the ear marginal vein, common carotid artery or lateral ventricle.
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  • HIDEMASA YAMASAKI, KOITI ENDO
    1967 Volume 17 Issue 2 Pages 228-239
    Published: June 01, 1967
    Released: February 02, 2007
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    Compound 48/80 releases histamine from mast cells with accompanying morphological changes characterized by degranulation. These actions are considered to be dependent on energy harnessing processes in mast cells, because the histamine release or degranulation of mast cells was inhibited by anoxia or inhibitors of oxidative phosphorylation when the medium was devoid of glucose, and glucose blocked these inhibitions (1-6). Since, however, evidences for the energy dependent processes involved in the histamine release action of 48/80 have been obtained from the experiments on only limited animal species, such as rat (2-9), cat (1) or hamster (10), despite the fact that not all the species are equally susceptible to the action of 48/80, further investigations on this point are to be extended over other animal species. Mongar and Schild (11) reported that the in vitro histamine release by 48/80 from guinea-pig lung tissue was not inhibited by anoxia and metabolic inhibitors while the histamine release induced by antigen was clearly inhibited. Sinomenine releases histamine from rat mast cells in a very similar fashion to 48/80 (12). In vitro histamine release from guinea-pig lung by this compound was also not inhibited by anoxia like the release by 48/80 (13). In the present study, in vitro histamine release by compound 48/80 as well as sinomenine from chopped skin of different animal species including guinea pig was compared under aerobic and anaerobic conditions, and it was found that the release of histamine in all these species consisted of two different types of release: the one which is dependent on energy-yielding processes and the other which does not depend on the processes. Concerning the mechanism of the latter type of histamine release further studies were made.
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  • TAKESHI SHIMADA
    1967 Volume 17 Issue 2 Pages 240-246
    Published: June 01, 1967
    Released: February 02, 2007
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    It is well-known that the adrenal glucocorticoids produce the electroencephalographic abnormalities such as paroxysmal bursts and seizures in human (1-3). Feldman et al. (4) have reported that hydrocortisone activates the evoked multisynaptic potentials in the brainstem reticular formation of the intact and adrenalectomized cats. In the rats, Woodbury et al. (5) have demonstrated that desoxycorticosterone acetate (DOCA) elevates the threshold for the electroshock seizure but hydrocortisone lowers it significantly. Further, Woodbury (6) and Vernadakis et al. (7) have suggested that the increased brain excitability by hydrocortisone relates to depletion of gamma-aminobutyric acid in the central nervous system. The behavioral and electroencephalographic studies on dexamethasone in rabbits have already been described elsewhere (8). The intravenously administered dexamethasone produced a considerable alertness both in behavior and spontaneous EEG lasting for about 20 minutes. The compound activated the reticular and thalamic arousal responses, but did not modify the recruiting response. The present report is also an attempt to study the effects of hydrocortisone and DOCA on the EEG as well as on the responses of the EEG to physostigmine and strychnine in the unanesthetized but restrained rabbits.
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  • HIDENORI OHASHI, YOSHIAKI NONOMURA, AKIRA OHGA
    1967 Volume 17 Issue 2 Pages 247-257
    Published: June 01, 1967
    Released: February 02, 2007
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    There have been published a number of papers dealing with the action of pharmacologically active polypeptides such as angiotensin, bradykinin and oxytocin on the visceral smooth muscle (1-9). However, no one has investigated into their effects on the membrane potential. Since the work of Evans and Schild (10, 11) it has been generally accepted that the effect on the spike generating mechanisms of smooth muscle is not only one way through which drugs can exert their actions on the contractility of smooth muscle. In other words, drugs would influence the contraction of smooth muscle without direct relationship to the spike discharges. Therefore it is highly desirable to observe the effect of these polypeptides on the membrane potential of smooth muscle simultaneously with their effect on the mechanical activity. The present studies were carried out along this line with the taenia coli of the guinea pig by recording changes in the membrane potential and spike discharges concurrently with the tension change. In the present article, it is also intended to decide the site of action of these polypeptides as it is uncertain whether they would act on smooth muscle directly or indirectly through nervous elements in smooth muscle. In contrast with some of the previous reports (1, 3, 4), which insisted on the participation of the indirect mechanism, it was revealed that all the three polypeptides act directly on the smooth muscle cells. Some of the results have been reported in brief (12).
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  • NORIMOTO URAKAWA, HIDEAKI KARAKI, MIYOSHI IKEDA
    1967 Volume 17 Issue 2 Pages 258-266
    Published: June 01, 1967
    Released: February 02, 2007
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    It was reported that high-potassium caused a rapid rise of tension which gradually declined to a new steady state level in strips of guinea pig taenia coli, and that the K-induced contracture was composed of phasic and tonic responses (1, 2). When the sucrose gap technique was used, a brief burst of spike discharges was recorded to correspond to the phasic response of K-induced contracture in taenia coli and membrane depolarization was correlated to the tonic response (3). It was proposed that in the phasic contraction, tissue calcium was released to initiate contraction, whereas in the tonic contraction, external calcium crossed the membrane to initiate it and that the transmembrane calcium transport involved in the tonic response was dependent on metabolism (1, 2). In the tonic response the Ca transport process was possibly coupled to an active Na efflux (2, 4). On the other hand, contracture studies on single fiber of frog skeletal muscle showed that the anion substitutions with NO3 and SCN lowered the threshold concentration of potassium required for contracture and increased the contracture tension only at potassium concentrations below the level required for maximum tension development (5). Another contracture potentiating anion, Br, had similar effects on K-induced contracture in the frog toe muscle (6). The present experiments were undertaken to investigate the possibility of these anions, having a potentiating effect on skeletal muscle, differently modifing the phasic response and the tonic one, in contracture of taenia coli with high-potassium.
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  • TAKEHIKO DEGUCHI
    1967 Volume 17 Issue 2 Pages 267-278
    Published: June 01, 1967
    Released: February 02, 2007
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    Tetrodotoxin known as a powerful neurotoxin blocks electrical excitation of nerve and muscle cell membranes at very low concentrations (1, 2). The mechanism of its action is shown to be specific blockage of sodium conductance increase in excitation of membranes leaving delayed increase in potassium conductance almost intact (2-6). This specificity and intensity in action has attracted attention of physiologists and pharmacologists in the world, and many investigators are now utilizing the toxin as an interesting pharmacological tool (e.g. 7-14). This toxin has varieties of pharmacological effects in both conscious and anesthetized animals, e.g., blood pressure reduction, respiratory depression, nausea and vomiting, motor disorder, loss of various sensations (cf. 13). The respiratory failure is believed to cause death in animals received given high dosages. Recently, chemical structures of tetrodotoxin and related substances were clarified by great efforts of researchers in Japan and the United States using the advanced physical techniques in the field of natural products chemistry (15-18). It is of interest to investigate the pharmacological properties of the compounds structurally related to tetrodotoxin in view of the powerful and specific action of tetrodotoxin on membrane excitation and its relation to the unique structure. The author wishes to present here observations upon some of the pharmacological properties of nine related compounds and discussions on the structure-activity relationship in tetrodotoxin.
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  • SHIGERU MATSUO
    1967 Volume 17 Issue 2 Pages 279-286
    Published: June 01, 1967
    Released: February 02, 2007
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    It has already been established that imipramine clinically available as an antidepressant potentiates the pressor response to noradrenaline (1-4), but depresses the same responses to tyramine, amphetamine and phenetylamine (3, 5, 6). The mechanism of the potentiation or the depression has been discussed to derive from the interference with the uptake of catecholamine into the binding site as cocaine (7-10) or from the change in the sensitiveness of effector organs caused by a depletion of the endogeneous catecholamine in a similar manner to reserpine. Furthermore, there is another possibility that imipramine potentiates the pressor response due to its adrenergic β-blocking mechanism. In the present experiments the effects of imipramine, propranolol and pronethalol on the adrenergic mechanism of the isolated rabbit's atria were comparatively investigated. The parameter used was the transmembrane potentials recorded from the right atrium and the S-A node. Responses of the potentials to the test compounds as well as the effects of the test compounds on the responses of the potentials to noradrenaline, adrenaline and isopropylnoradrenaline were observed.
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  • HIKARU OZAWA, KAZUNOBU SUGAWARA
    1967 Volume 17 Issue 2 Pages 287-297
    Published: June 01, 1967
    Released: February 02, 2007
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    The pharmacological studies of the puffer fish poison, so called Fugu poison, has been reported by many investigators for years. Recently, the review concerned to tetrodotoxin was published by Kao (1). Since the main reason of death by puffer poison is a respiratory paralysis, the effects of tetrodotoxin on respiratory system and on skeletal muscle preparation have been noticed. Since 1952 when the crystalline tetrodotoxin was isolated from the puffer fish (2), the pharmacological actions of this purified crystalline tetrodotoxin have been studied and in 1964 the chemical structure was established (3). There have been also several studies on the smooth muscle preparations: in earlier times, it had been studied by Ishihara (4), Kimura (5), and Takahashi et al. (6, 7), and recently, on the cat's nictitating membrane by Kao (8), on guinea-pig taenia coli by Toida et al. (9, 10), and on visceral smooth muscles by Ogura (11) and Hamada (12). In the present paper, authors investigated to clarify the sites of action of crystalline tetrodotoxin on the smooth muscle preparations innervated by the sympathetic nerve.
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  • YOSHITSUGU OSUMI, YASUKO AMANO, KIRO SHIMAMOTO
    1967 Volume 17 Issue 2 Pages 298-307
    Published: June 01, 1967
    Released: February 02, 2007
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    There have been numerous biochemical and histological studies on the diffusely developed fatty liver regard as the model of disturbance of the liver function. However, the single oral administration of carbon tetrachloride (CCl4) in relatively larger doses produces the diffuse fatty degeneration of liver within 24 hours after the treatment. Moreover, the degree of the fatty liver is not reliable to the doses of CCl4 and the recovery from the degeneration is subjected to much individual variation. The present experiment is a device to establish a dose-response relationship in the development of fatty liver by the repeated oral administration of the doses of CCl4, which did not affect the activity of liver enzyme such as GOT in the single doses. The effects of CCl4 on lipid metabolism of the liver and blood as well as histological changes of the parenchymatous organs were observed at various term after the treatment.
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  • SHUNJI KOZAWA, KATSUMI NAITO, AKIFUMI YASUI
    1967 Volume 17 Issue 2 Pages 308-316
    Published: June 01, 1967
    Released: February 02, 2007
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    The fact that separated mammalian cerebral cortical tissues, suitably maintained in vitro, show remarkable respiratory and metabolic responses to adequate electrical stimulation has already been published frequently (1) ; recently it was shown that such respiratory and metabolic responses to adequate electrical stimulation were dependent only on the concentration of external sodium, approximately in Michaelis Menten fashion, but potassium by itself was inert to this metabolism, and calcium was independent of such responses (2). Meanwhile, a number of studies are being made everywhere at present in order to elucidate the exact mechanism of linkage between active cation transport and metabolism. One of the experimental approaches to the mechanism by which the energy from metabolism is supplied to active transport, would be to examine the action of metabolic inhibitors. It seems to be necessary to investigate whether or not the respiratory and metabolic responses stated above have any connection with the active transport; therefore, the effects of ouabain and 2, 4-dinitrophenol on the respiratory and metabolic responses of a rat's cerebral cortical slices to electrical stimulation have been studied in this paper.
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  • YOSHIO IMAI, TOSHIMI USUI, TOICHIRO MATSUZAKI, HAJIME YOKOTANI, HIROYU ...
    1967 Volume 17 Issue 2 Pages 317-324
    Published: June 01, 1967
    Released: February 02, 2007
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    Cutolo and Larriza (1) synthesized 3-phosphoryl-L-ascorbic acid, and they noted that some amount of the compound was excreted as ascorbic acid (AsA) in the guinea pig urine after oral or intraperitoneal administration, however, its antiscorbutic activity is not yet estimated. The authors studied the antiscorbutic activity of the compound as well as its percutaneous absorption in guinea pigs.
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  • TADAATSU NUKADA, NORIO ANDOH
    1967 Volume 17 Issue 2 Pages 325-326
    Published: June 01, 1967
    Released: February 02, 2007
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  • YOSHIHIRO KINOSHITA, HIDEYO OHSHIKA, KENGO NAKAI
    1967 Volume 17 Issue 2 Pages 326-327
    Published: June 01, 1967
    Released: February 02, 2007
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  • KENICHI KOGA, TAKAO MIZUGUCHI, YOSHIO OHMIYA, KENGO NAKAI
    1967 Volume 17 Issue 2 Pages 327-328
    Published: June 01, 1967
    Released: February 02, 2007
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  • HEITAROH IWATA, KIMIO KARIYA, SEIGO FUJIMOTO
    1967 Volume 17 Issue 2 Pages 328-329
    Published: June 01, 1967
    Released: February 02, 2007
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  • YOSHIO IMAI, HARUKI MATSUMURA, YOSHITOMO ARAMAKI
    1967 Volume 17 Issue 2 Pages 330-331
    Published: June 01, 1967
    Released: February 02, 2007
    JOURNALS FREE ACCESS
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  • TSUNE ENOMOTO, SATORU MINESHITA, SACHIKO OH-ISHI, TATSURO SHIGEI
    1967 Volume 17 Issue 2 Pages 331-332
    Published: June 01, 1967
    Released: February 02, 2007
    JOURNALS FREE ACCESS
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