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Volume 106, Issue 1
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Kazushige TOUHARA1995 Volume 106 Issue 1 Pages 1-9
Published: 1995
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSA pleckstrin homology (PH) domain is an approximately 100 amino acid region of sequence homology present in numerous proteins involved in signal transduction and growth control. The three dimensional structures of several PH domains demonstrate that they consist of a β-barrel of seven antiparallel β-sheets and a carboxyl-terminal amphiphilic α-helix. Several ligands capable of binding to PH domains have been identified including phosphatidylinositol 4, 5bisphosphate and the βγ subunits of heterotrimeric G proteins, which bind to the amino and carboxyl-termini of the PH domain, respectively. Furthermore, several isoforms of protein kinase C appear to bind to some PH domains. A general function of PH domains may be to anchor PH domain-containing proteins to the appropriate membrane-compartment. The membrane localization of PH domain-containing proteins may require cooperative multiple ligand binding to the PH domain. Finally, the heterogeneity of sequences among various PH domains may prove to be the basis for differences in the regulation and specificity of PH domain-ligand interaction in a fashion similar to SH2 and SH3 domains. The function of the PH domain and the mechanisms of PH domain action seem to be quite complex.View full abstractDownload PDF (8239K) -
Masahiro NOMOTO1995 Volume 106 Issue 1 Pages 11-18
Published: 1995
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSApplication of the common marmoset to pharmacological studies was reviewed, especially employment of the animal as a model of Parkinson's disease were presented. The common marmoset is one of the New World monkeys with a body weight of 300-350 g. It is small enough to be easily handled and to be kept as a group in a room. In the fields of pharmacology, it has been used in studies of plasma renin acitivity inhibitors, lipoprotein, memory/learning, obsterics, transplantation, toxicology, anxiolytic agents and virology/immunology. We showed that the common marmoset was a useful animal for studies on Parkinson's disease, dopamine metabolism by microdialysis and nausea/vomiting. The common marmoset was sensitive to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine (MPTP) and developed permanent parkinsonism after MPTP injection. MPTP-treated common marmosets showed tremor and akinesia, and it remarkably responded to antiparkinsonian agents. A dopamine D 1 agonist, which caused stereotyped behavior in rats, did not reverse parkinsonism in humans. We showed this agent did not have any antiparkinsonian effects on MPTP-treated common marmosets. MAO has subtypes, A and B, that have differences of distribution in different species. MAO type B inhibitors were applied for the treatment of Parkinson's disease. MAO subtype B inhibitors do not cause any change in behavior or extracellular concentration of dopamine or its metabolites in rodents. In MPTP-treated common marmosets, however, administration of a MAO type B inhibitor increased the antiparkinsonian effects of levodopa and decreased dopamine metabolites. The common marmoset is a suitable animal for the study of MAO type B inhibitors.View full abstractDownload PDF (6345K) -
Masakuni NISHIKAWA, Tomio OKAMURA, Noboru TODA1995 Volume 106 Issue 1 Pages 19-29
Published: 1995
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSThe effect of AE0047 on contractile responses to high K+ and agonists and to perivascular nerve stimulation was investigated using isolated dog cerebral, coronary and mesenteric arteries and mesenteric veins. AE0047 inhibited concentration-dependent contractions induced by KCl, norepinephrine, prostaglandin (PG) F2α and serotonin. The inhibition of contractions caused by PGF2α and serotonin was greater in cerebral arteries than in mesenteric arteries. The inhibitory effect of AE0047 on norepinephrine-induced mesenteric arterial contraction persisted for 24 hr or longer even though the strips were repeatedly washed. Greater inhibition was obtained in the arteries contracted with K+ than in those contracted with agonists. AE0047 reduced Ca2+-induced contraction in K+-depolarized mesenteric artery strips to a greater extent than those in PGF2α-stimulated strips. The relaxation induced by transmural electrical stimulation in coronary arteries treated with phentolamine was reduced by AE0047, whereas the norepinephrine-induced relaxation was unaffected. In cerebral arteries treated with superoxide dismutase, AE0047 reduced nicotine-induced relaxation but not NO-induced relaxation. These findings suggest that AE0047 selectively inhibits vasocontractions via voltage-dependent Ca channels and preferentially inhibits cerebroarterial contraction, these actions being long-lasting. AE0047 appears to reduce the release of neurotransmitter from adrenergic and nitroxidergic nerve terminals in blood vessels.View full abstractDownload PDF (7740K) -
Bunsho LEE, Kazuhiko TAKASAKI, Akinori MOCHIZUKI, Norihiko TAMURA, Yas ...1995 Volume 106 Issue 1 Pages 31-40
Published: 1995
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSThe pharmacological effects of N-[2-(4-(bezhydryloxy)piperidino)ethyl] -3-hydroxy-5-(3pyridylmethoxy)-2-naphthamide (F-1322), a novel anti-asthmatic agent, was investigated in vitro. The results obtained were as follows: 1) In the isolated trachea of guinea pigs, F-1322 showed a markedly potent antagonistic action against the contraction induced by histamine, while it had little or no effect on 5-hydroxytryptamine-, acetylcholine-, leukotriene D4- or U-46619-induced contractions. 2) In rabbit platelets, F-1322 did not affect the platelet aggregation induced by platelet activating factor. 3) F-1322 significantly inhibited the thromboxane (TX) A2 synthetase (IC50 value: 1.7 × 10-8 M) and 5-lipoxygenase (IC50 value: 9 × 10-7 M) activities. 4) F-1322 had no effect on phospholipase A2, cyclooxygenase, Ca2+/calmodulin-dependent phosphodiesterase and phosphodiesterase activities. These in vitro studies suggest that the anti-asthmatic action of F-1322 is associated with histamine antagonism and an inhibitory action on TXA2 synthetase and 5-lipoxygenase activities.View full abstractDownload PDF (7808K) -
Kiyoshi SAITOH, Toshio MORI, Hirotaka KASAI, Takashi NAGAYAMA, Akiko T ...1995 Volume 106 Issue 1 Pages 41-50
Published: 1995
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSAnti-atheromatous effects of fenofibrate were studied in cholesterol-fed rabbits. Rabbits in the control group (HCD) and fenofibrate group (F-HCD) were fed the 0.5% cholesterol diet and the 0.5% cholesterol plus 0.11 % fenofibrate diet (corresponding to ca. 30 mg/kg/day), respectively, for 2, 4 or 10 weeks. Fenofibrate did not change serum levels of total cholesterol, HDL-choelsterol and triglyceride during the feeding period. The percentage of plaque area (PPA) formation in the thoracic aorta was time-dependently increased. PPA values were reduced in the rabbits treated with fenofibrate for 2 and 4 weeks, but not in those treated for 10 weeks. Fenofibrate had no effect on the plaque thickness. The percentage of circulating free platelets in the HCD group was reduced at the 4th week of feeding, but that in the F-HCD group was not. The anti-platelet effect of fenofibrate might cause the anti-atheromatous effect. Fenofibric acid, an active metabolite of fenofibrate, had no inhibitory effect on LDL peroxidation in vitro. From these results, we conclude that fenofibrate manifests an anti-atheromatous effect independent of the hypolipidemic effect in cholesterol-fed rabbits and that it may inhibit an early event in the atherogenesis.View full abstractDownload PDF (7966K) -
Kiyoshi SAITOH, Toshio MORI, Hirotaka KASAI, Takashi NAGAYAMA, Shigeo ...1995 Volume 106 Issue 1 Pages 51-60
Published: 1995
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSAnti-atheromatous effects of fenofibrate were studied in KHC rabbits with a hereditary deletion in LDL receptors, a defect similar to that in Watanabe heritable hyperlipidemic rabbits. KHC rabbits (10-weeks-old) were given a dietary admixture of fenofibrate (ca. 30 or ca. 100 mg/kg/day) for 20 weeks. Fenofibrate did not change serum total cholesterol, high density lipoprotein and triglyceride levels. Fenofibrate decreased the percent of plaque area formation in the thoracic aorta, but not the degree of foam cell formation, fibrosis and edematous change, and thickness of the intima. Furthermore, fenofibrate markedly inhibited the medial damage with foam cell formation in the aorta at week 20. From these results, we conclude that fenofibrate manifested the antiatheromatous effect in KHC rabbit and also the previous model of cholesterol-fed rabbits, particularly against the medial damage in KHC rabbits, independent of the hypolipidemic effect.View full abstractDownload PDF (8820K)
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