Journal of Pharmacobio-Dynamics
Online ISSN : 1881-1353
Print ISSN : 0386-846X
ISSN-L : 0386-846X
Volume 9, Issue 7
Displaying 1-10 of 10 articles from this issue
  • MASAHIRO KOIKE, RYO NORIKURA, TAKEO YOSHIMORI, SHINYA FUTAGUCHI, KOICH ...
    1986 Volume 9 Issue 7 Pages 563-569
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    5-[(2-Aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a sleep inducer, is a ring-opened derivative of 1, 4-benzodiazepine and has been reported to be activated by intestinal aminopeptidases. In order to determine the biopharmaceutical significance of 450191-S as the ring-opened derivative of 1, 4-benzodiazepine, we examined plasma levels of active metabolites in rats following oral administration of 450191-S or its primary active metabolite, 8-chloro-6-(2-chlorophenyl)-N, N-dimethyl-4H-1, 2, 4-triazolo [1, 5-a] [1, 4] benzodiazepine-2-carboxamide (M-1). By increasing the dose of 450191-S, the plasma level of the active metabolites increased dose-dependently, which appeared to be due to saturation of hepatic elimination. The areas under the plasma concentration-time curves of active metabolites at a dose of 30 mg/kg of 450191-S were 2-to 20-fold higher than those at the same dose of M-1 administration per se. These results appeared to be attributable to the presence of a labile precursor of M-1, desglycylated 450191-S, which could avoid extensive first-pass extraction by the liver. In conclusion, the results suggested that 450191-S is superior to M-1, since the former maintained higher plasma levels of the active metabolites.
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  • KOUICHI TAKAHASHI, YUTAKA HIGASHI, NOBORU YATA
    1986 Volume 9 Issue 7 Pages 570-577
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    Hepato-biliary transport of amaranth (AM) in normal and carbon tetrachloride (CCl4) or α-naphthylisothiocyanate (ANIT) treated rats was studied using single pass liver perfusion. CCl4-intoxicated rats were prepared by two different methods. One was a subcutaneous injection (CCl4 s.c.) and the other was an oral administration (CCl4p.o.). Though AM had been recognized to be non-metabolized in the liver, AM has been reported to be metabolized via azo-reduction by intestinal microflora and/or in the liver to yield naphthionic acid (1-amino-4-naphthalene sulfonic acid) (NSA) after oral administration. In the present investigation, AM was metabolized also in the perfused rat liver to yield NSA, which was not excreted in the bile, but effluxed into the effluent. The hepatic clearance of AM was significantly decreased in all intoxicated livers compared with the untreated livers. The concentration of NSA effluxed in the effluent was decreased in CCl4s.c.-intoxicated livers. However, in other intoxicated livers, there was no significant difference from the untreated livers in the concentration of NSA in the effluent. The amount of AM excreted in the bile was significantly decreased in CCl4s.c.-or CCl4p.o.-intoxicated livers. In ANIT-intoxicated livers, no bile excretion was observed because of the biliary stagniation. From the results of pharmacokinetic analysis using a five-compartment model, the metabolism was not altered by all treatments investigated in the present study. Subcutaneous administration of CCl4, which caused a mild intoxication, affected only the permeability of the plasma membrane of the liver to AM, but oral administration of CCl4, which caused a severe intoxication, decreased the biliary excretion of AM as well as increased the permeability. ANIT-intoxication increased the permeability of plasma membrane of the liver to AM.
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  • MASAHIRO KOIKE, MINORU MIZOBUCHI, SHIRO TAKAHASHI
    1986 Volume 9 Issue 7 Pages 578-584
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    5-[(2-Aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S) is a ring-opened derivative of 1, 4-benzodiazepine, which is activated by desglycylation and subsequent cyclization. After 450191-S administration, rat bile contained three novel conjugates which released active metabolites possessing the 1, 4-benzodiazepine structure through β-glucuronidase hydrolysis. Since the released metabolites have no functional groups to conjugate with glucuronic acid, we speculated that the aglycone might be the ring-opened form of 1, 4-benzodiazepine which spontaneously cyclizes after the release of glucuronic acid. This possibility was tested by chemically reducing the ketone group of the ring-opened 1, 4-benzodiazepine glucuronate conjugates, which would prevent the spontaneous ring closure reaction after the release of the glucuronic acid moiety. The NaBH4 reduction of the ketone of the benzophenone moiety of the conjugates and subsequent treatment with β-glucuronidase allowed identification of the reduced aglycones with authentic samples using gas chromatography-mass spectrometry.
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  • TAKAMASA YAMAGUCHI, SUSUMU KURIHARA, MASAHIKO IKEKITA, KAZUYUKI KIZUKI ...
    1986 Volume 9 Issue 7 Pages 585-592
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    In the present investigation, the occurrence of angiotensin I converting enzyme (EC 3. 4. 15. 1 ; ACE) was first demonstrated in the kidney of bullfrog (Rana catesbeiana). Namely, a large amount of hydrolyzing activity toward Nα-hippuryl-L-His-L-Leu-OH (HHL), a synthetic substrate of ACE, was detected in a 100000×g pellet fraction of the bullfrog kidney. The renal HHL hydrolyzing enzyme was solubilized from the 100000×g pellet with sodium deoxycholate. The solubilized bullfrog renal enzyme liberated H-His-Leu-OH from HHL. The enzyme activity was strongly activated by NaCl and slightly activated by cobalt sulfate in the presence of NaCl. These properties of the bullfrog renal enzyme agreed well with those of mammalian ACE previously reported. The bullfrog renal HHL hydrolyzing activity was completely inhibited by typical ACE inhibitors, ethylenediamine tetraacetic acid (10-3M), captopril (10-5M), SA-466 (10-5M) and MK-422 (10-6M). Furthermore, [Ile5]-angiotensin I converting activity was also detected in this enzyme fraction of bullfrog kidney and this converting activity was completely inhibited by MK-422 (10-6M). Thus, enzyme activities having characteristics of ACE were detected in the 100000×g pellet of bullfrog kidney. We also detected [Val5, Asn9]-angiotensin I (bullfrog angiotensin I) converting activity in the bullfrog renal extract. This converting activity was also completely inhibited by MK-422 (10-6M).
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  • NAOHITO OHNO, YOSHIYA ARAI, IWAO SUZUKI, TOSHIRO YADOMAE
    1986 Volume 9 Issue 7 Pages 593-599
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    The correlation between murine lymphocytes blastoid transformation and alkaline phosphatase (AL-P) activity was examined. When murine spleen cells were stimulated with lipopolysaccharide, a B cell mitogen, for 48 h, the AL-P activity was induced in a dose dependent manner. Similarly, stimulation of the spleen cells with Concanavalin A (Con A), a T cell mitogen, induced the AL-P activity. However, when the thymocytes were treated with Con A, only the [3H] dThd uptake was increased. Other B cell mitogens, such as lipid A and fungal B cell mitogens, and T cell mitogen, Pusum sativum agglutinin (PSA) also induced the AL-P activity of spleen cells. Kinetics of [3H] dThd uptake and induction of AL-P was similar. Correlation coefficients between [3H] dThd uptake and AL-P activity were r=0.98789, p<0.01 for LPS, r=0.99530, p<0.01 for lipid A and r=0.62595, p<0.001 for the fungal B cell mitogens. The AL-P activity of the spleen cell was also induced by treatment with Con A sup, which was a supernatant fluid prepared by spleen cell cultured with Con A for 48 h, containing various lymphokines. These findings suggest that the AL-P activity was induced in the case of B lymphocyte blast transformation when stimulated directly with B cell mitogen or indirectly via lymphokines with T cell mitogen. Measurement of the AL-P activity would be a useful method to assay murine blastoid lymphocytes.
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  • NAGAO SUZUKI, YUTAKA KASUYA
    1986 Volume 9 Issue 7 Pages 600-606
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    Effects of cocaine and tetraethylammonium (TEA) on the spike potential induced by transmural nerve stimulation were investigated with microelectrodes in smooth muscle cells of rat vas deferens. Resting membrane potential was not changed by 10-5M cocaine. 10-5M cocaine reduced the amplitudes of spontaneous excitatory junction potentials and diminished generation of excitatory junction potentials induced by nerve stimulation. However, cocaine did not affect the electrophysiological parameters of spike potentials ; overshoot potential, threshold potential and duration of spikes were not changed by cocaine. Cocaine slightly inhibited the twitch contractions to transmural nerve stimulation. In contrast, 1-5 mM TEA increased the overshoot potentials and prolonged the duration of spikes dosedependently without changing the resting membrane potential. Twitch contractions to transmural nerve stimulation were greatly enhanced by 2.5 mM TEA. These results suggest that TEA, but not cocaine, may increase the Ca-influx which is believed to occur during spike generation in the smooth muscle cells of vas deferens.
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  • HITOSHI OHMORI, TOSHIHIKO YAMAUCHI, ITARU YAMAMOTO
    1986 Volume 9 Issue 7 Pages 607-612
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    When murine lymphocytes were cultured in a cystine-deficient RPMI-1640 medium containing 10% fetal calf serum, approximately 70% of the cells died in 48 h. In the presence of 5×10-4ML-cystine, 70-80% of the lymphocytes remained viable under the same condition. The decrease of the viability was also effectively inhibited when cystine was replaced by the following thiol compounds ; 2-mercaptoethanol (2-ME), dithiothreitol (DTT), cysteamine and glutathione (GSH). Oxidized DTT, an intramolecular disulfide that was resistant to the reduction by the lymphocytes, did not show a protective effect in contrast to DTT. On the other hand, 2-hydroxyethyldisulfide was readily reduced to 2-ME by the lymphocytes and improved lymphocyte viability as effectively as 2-ME. These observations suggest that thiol groups are responsible for the improvement of lymphocyte viability under a cystine-deficient condition. The viabilities of both T cells and B cells were equally improved by 2-ME. The intracellular level of GSH remained constant in the presence of cystine but dropped rapidly in its absence. 2-ME could not reverse this decrease of GSH level. These protective effects of thiol compounds on lymphocyte viability are discussed in relation to their capacities to activate murine lymphocytes.
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  • AKIRA SAITO, KATSUTOSHI GOTO
    1986 Volume 9 Issue 7 Pages 613-619
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    Effects of capsaicin in vivo and in vitro on calcitonin gene-related peptide (CGRP)-containing nerves were examined in cerebral arteries. CGRP-like immunoreactive (CGRP-I) nerves were demonstrated in cerebral arteries of rats, guinea pigs and rabbits. The overall distribution of CGRP-I nerves was similar to that of substance P-containing nerves. Since the distribution of CGRP-I nerves of cerebral arteries among these species was the densest in guinea pigs, this animal was used to study the effect of several treatments on CGRP-I nerves. Catecholamine (CA)-fluorescence but not CGRP-I nerves was abolished by surgical sympathectomy or reserpine pretreatment. Pretreatment of the animal with capsaicin abolished CGRP-I nerves of cerebral arteries. CGRP-like immunoreactivity disappeared from cerebral arteries by in vitro incubation with capsaicin. Capsaicin treatment in vivo and in vitro did not affect CA-fluorescence nerves in these arteries. Since capsaicin selectively affects primary afferent nerves, it is suggested that CGRP is contained in sensory nerves. Capsaicin may be a valuable tool in elucidating the physiological or pathophysiological role of CGRP in cerebral circulation.
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  • SHIZUO YAMADA, YOSHIYUKI KAGAWA, HIDETO USHIJIMA, NORIYASU TAKAYANAGI, ...
    1986 Volume 9 Issue 7 Pages 620-625
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    The effect of piperidine and related alicyclic amines on central nicotinic and muscarinic cholinoceptors was investigated by measuring specific binding of [3H] nicotine and [3H] cismethyldioxolane (CD) in rat cerebral cortical membranes. Piperidine, pyrrolidine, 4-hydroxypiperidine and piperazine at concentrations of 1μM-30 mM completed dosedependently with [3H] nicotine and [3H] CD for the binding sites. Among these compounds, piperidine was the most potent competitor of brain [3H] nicotine binding sites. Piperidine and pyrrolidine showed a greater affinity for [3H] nicotine binding sites in the rat cerebral cortex than of [3H] CD binding sites. In contrast, 4-hydroxypiperidine and piperazine displayed approximately 10 times greater affinity for [3H] CD binding sites. Pipecolic acid had little effect on these cholinoceptor agonist binding sites. The inhibitory effect of brain [3H] nicotine binding by piperidine did not differ between brain regions or during development. In addition, there was little difference in the piperidine-induced inhibition of brain [3H] nicotine binding between species such as rat, mouse, guinea-pig and rabbit. Thus, the present study demonstrates a high affinity of piperidine for nicotinic cholinoceptors in the mammalian brain.
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  • TAKAO KUBO, MINORU KIHARA
    1986 Volume 9 Issue 7 Pages 626-629
    Published: 1986
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    The purpose of this study was to examine, using pentobarbital-anesthetized rats, whether vasopressin contributes to hypertension caused by denervation of baroreceptors, in comparison to the contribution of vasopressin to hypertension caused by nucleus tractus solitarius (NTS) lesions. Bilateral baroreceptor denervation caused acute hypertension which was inhibited by intravenous injection of an antagonist of the vasoconstrictor action of vasopressin. Lesions of the NTS also produced an increased in blood pressure which was reduced by the vasopressin antagonist. The magnitude of the antagonist-induced hypotension was significantly greater in NTS hypertension than that in baroreceptor denervation hypertension. It is concluded, that in rats, vasopressin contributes to the neurogenic hypertension caused by baroreceptor denervation and NTS lesions. Thus, it appears that interruption of baroreceptor afferents at the NTS level is responsible for the vasopressin-mediated hypertension caused by NTS lesions but that it is not the only factor involved.
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