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Volume 107, Issue 1
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Michio TAKEDA, Hitoshi ENDOU1996 Volume 107 Issue 1 Pages 1-8
Published: 1996
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSThe incidence of drug-induced nephrotoxicity (DIN) has recently been increasing. Based on developments in molecular biology and cell biology, cultured cells have become a very useful tool for investigating DIN. Especially, the immortalized cell lines derived from well-defined nephron segments are ideal for such studies. As indicators to detect DIN, myosin light chain phosphorylation in glomerular mesangial cells, enzymes of proximal tubule origin such as glycine-amidinotransferase, cytosolic free calcium concentration and intracellular ATP content may be useful. The involvement of nitric oxide and heat shock protein in DIN has been reported. Therapeutic effects of growth factors such as HGF or EGF for DIN have been identified. The direct evidence for the involvement of reactive oxygen species and the molecular basis for redox regulation in DIN is reguired. Cisplatin has been shown to induce apoptosis, and the role of apoptosis in DIN remains to be further clarified. Thus, in parallel with in vivo studies, cultured cells provide an opportunity for clarifying the intracellular mechanism for DIN more precisely and establishing an efficient screening system to develop drugs to prevent DIN.View full abstractDownload PDF (7183K) -
Hideyuki YAMAMOTO1996 Volume 107 Issue 1 Pages 9-19
Published: 1996
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSMany of the extracellular signals such as neurotransmitters and hormones regulate the intracellular concentration of second messengers such as cAMP, cGMP, and calcium ion (Ca2+), diacylglycerol and IP3 Accumulating evidence indicates that protein phosphorylation-dephosphorylation is an important mechanism by which second messengers act to regulate a variety of cellular processes. Ca2+/calmodulin-dependent protein kinase II, cAMP-dependent protein kinase and protein kinase C are three major classes of protein kinases in the central nervous system. In an attempt to elucidate the physiological roles of the protein kinases, I have been studying the substrate proteins and functional significance of the enzymes and phosphorylated proteins. For these purposes, I investigated the phosphorylation-dephosphorylation of cytoskeletal proteins such as microtubule-associated protein 2 and tau, which are involved in the assemblydisassembly of microtubules and the production of abnormally phosphorylated forms of tau in neurofibrillary tangles in Alzheimer's disease brain. As the natural consequence, studying the protein phosphatases is significant for elucidating the switch-off mechanism of protein phosphorylation. Thus, I have been investigating the functional significance of protein phosphorylation-dephosphorylation for the elucidation of signal transduction in the brain, which is widely involved in the regulation of brain functions.View full abstractDownload PDF (9705K) -
Yoshinobu YAMAZAKI, Hiroo TAKEDA, Masuo AKAHANE, Atsushi TSUBAKI, Yuki ...1996 Volume 107 Issue 1 Pages 21-31
Published: 1996
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSThe effects of KSG-504 after intravenous administration on behavior and other central functions were studied. KSG-504 did not affect the general behavior of dogs up to the dose of 30 mg/kg, but the drug (100 mg/kg, i.v.) caused vomiting in 3 out of the 5 dogs. Moreover, KSG-504 (1-30 mg /kg, ix.) had no effects on spontaneous motility, thiopental-induced sleep, acetic acid-induced writhing in mice and satiety in rats. A high dose of CCK-8 (100 μg/kg or more) suppressed spontaneous motility, writhing and satiety, and prolonged sleep when administered subcutaneously. The behavioral changes induced by CCK-8 were antagonized by KSG-504 in a dose-dependent manner (1-30 mg/kg, i.v.). When KSG-504 was administered intravenously to rabbits at the dose of 10 mg/kg or 0.5 mg/kg/min for 120 min, we could not detect the drug in the cerebrospinal fluid, indicating that KSG-504 does not cross the blood-brain barrier after peripheral administration of the drug. Thus, the inhibitory effect of KSG-504 on CCK-8-induced behavioral changes may be the result of antagonism at peripheral CCK-A receptors.View full abstractDownload PDF (8414K) -
Yoshinobu YAMAZAKI, Masuo AKAHANE, Mamoru KOBAYASHI, Kazuhiko SHINAGAW ...1996 Volume 107 Issue 1 Pages 33-44
Published: 1996
Released on J-STAGE: February 06, 2007
JOURNAL FREE ACCESSWe investigated the interaction of KSG-504 with CCK-8 or pentagastrin-induced gallbladder and gastrointestinal responses in vitro and in vivo. KSG-504 (10-7-10-4 M) inhibited CCK-8-induced contractions of both isolated guinea pig gallbladder and rabbit terminal cavity of the bile duct in a concentration-dependent manner. Furthermore, intravenous administration of KSG-504 also dose-dependently inhibited CCK-8-induced gallbladder contraction in anesthetized guinea pigs with an IC50 value of 0.23 mg/kg. In conscious mice, KSG-504 inhibited both CCK-8 and egg yolkstimulated gallbladder emptying in a dose-dependent manner (IC50 : 13.3 and 9.6 mg/kg, respectively). The CCK-8-induced delay of gastric emptying in conscious rats was also antagonized by KSG-504 with an IC50 value of 3.78 mg/kg, i.v., whereas pentagastrin-stimulated gastric acid secretion in anesthetized rats was not affected by KSG-504 at all. KSG-504 (1 mg/kg, i.v.) also inhibited CCK-8-induced duodenal and jejunal contractions in anesthetized rabbits. These results indicate that KSG-504 exerts an antagonistic effect on CCK-A receptors in the gastrointestinal tract, but not on gastrin receptors in the stomach.View full abstractDownload PDF (9245K)
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