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Volume 72 (1996)
- Issue 4 Pages 261-
- Issue 3 Pages 195-
- Issue 2 Pages 83-
- Issue 1 Pages 1-
Volume 72, Issue 2
Displaying 1-10 of 10 articles from this issue
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Yasuo Mori, Gabor Mikala, Gyula Varadi, Tsutomu Kobayashi, Sheryl Koch ...1996 Volume 72 Issue 2 Pages 83-109
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSVoltage-dependent Ca2+ channels serve as the only link to transduce membrane depolarization into cellular Ca2+-dependent reactions. A wide variety of chemical substances that have the ability to modulate Ca2+ channels have been demonstrated both for their clinic utility and for importance in elucidating the molecular basis of various biological responses. Recently, introduction of molecular biology to pharmacology has brought a great deal of information about the molecular basis of drug action in Ca2+ channels. In this review, we attempt to overview recent progress in understanding the interactions between Ca2+ channels and their blockers, namely Ca2+ antagonists, from a molecular and structural point of view.View full abstractDownload PDF (2392K) -
Bo-Kyung Kim, Hiroshi Ozaki, Masatoshi Hori, Hideaki Karaki1996 Volume 72 Issue 2 Pages 111-118
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSActivation of voltage-dependent Ca2+ channels by high K+ (40 mM) increased the cyiosolic Ca2+ level ([Ca2+]i) (estimated by fura-PE3 fluorescence ratio) and force in myometrium isolated from pregnant (21 days after gestation) and non-pregnant (estrus) rats. 12-Deoxyphorbol 13-isobutyrate (DPB, 1 mM) decreased the high K+_stimulated [Ca2+]i and force in a concentration-dependent manner. The inhibitory effect was stronger in the pregnant myometrium than in the non-pregnant myometrium. In the pregnant myometrium, the increase in Ca2+ permeability by ionomycin (1 μM) greatly increased [Ca2+]i and force, which were only partially inhibited by verapamil (10 μM). DPB (1 μM) inhibited the verapamil-insensitive component of the increases in [Ca2+]i and muscle tension. Oxyiocin (100 nM) and thapsigargin (1 μM) also induced a verapamil-insensitive increase in [Ca2+]i and force, and DPB (1 μM) inhibited these increments. Ca2+ sensitivity of contractile elements, estimated from the relationships between Ca2+ and muscle force in intact and α-toxin permeabilized muscle, was not significantly changed by DPB (1 μM). In summary, DPB inhibits the increase in [Ca2+]i more strongly in myometrium isolated from pregnant rats than that from non-pregnant rats without any change in the [Ca2+]i/tension relationship. Since DPB decreased [Ca2+]i-rise induced by three different mechanisms, DPB may activate Ca2+ extrusion, rather than to inhibit a specific influx pathway, to decrease [Ca2+]i.View full abstractDownload PDF (478K) -
Kumiko Ishida-Tokuda, Yukihiro Ohno, Hideki Sakamoto, Tadashi Ishibash ...1996 Volume 72 Issue 2 Pages 119-126
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSWe studied the effects of perospirone (SM-9018), a novel serotonin-2 (5-HT2) and dopamine-2 (D2) receptor antagonist (SDA), on conditioned fear stress (CFS)-induced freezing behavior in rats and compared its actions with those of other antipsychotics. Exposure of rats to the environment previously paired with foot shock induced marked freezing behavior, which was reduced by the anxiolytic diazepam (0.1 minus; 3 mg/kg, p.o.) or antidepressants, desipramine and imipramine (10 minus; 100 mg/kg, p.o.). Perospirone at 0.3 minus; 3 mg/kg, p.o. significantly attenuated the CFS-induced freezing behavior in a dose-dependent manner, while the effect was reduced at the higher dose of 6 mg/kg. Other SDA-type antipsychotics, clozapine (1 minus 30mg/kg, p.o.) and risperidone (0.03 minus; 1 mg/kg, p.o.), and selective 5-HT2 antagonists, ritanserin (0.1 minus; 1 mg/kg, p.o.) and ketanserin (0.3 minus; 1 mg/kg, p.o.), all reduced the freezing behavior with U-shaped dose-response curves. However, neither conventional antipsychotic, haloperidol (0.1 minus; 3 mg/kg, p.o.), chlorpromazine (3 minus; 100 mg/kg, p.o.), thioridazine (3 minus; 100 mg/kg, p.o.), mosapramine (3 minus; 100 mg/kg, p.o.) nor tiapride (30 minus; 1000 mg/kg, p.o.) reduced the CFS-induced freezing behavior. In addition, subacute treatment of rats with perospirone (1 minus; 10 mg/kg/day) or imipramine (30 mg/kg/day) for 2 weeks prevented the induction of the freezing behavior by CFS. These findings suggest that SDA-type antipsychotics including perospirone are effective for the treatment of mood disturbances such as anxiety and depressive mood associated with schizophrenia and have a broader efficacy profile as compared with the conventional antipsychotics.View full abstractDownload PDF (590K) -
Hisayuki Yokokura, Yohei Okada, Osamu Terada, Hiroyoshi Hidaka1996 Volume 72 Issue 2 Pages 127-135
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSOur objective is to describe the basic chemical and biological properties of the new calmodulin antagonist HMN-709 (2-[N-(2-aminoethyl)-N-(4-chlorobenzenesulfonyl)]amino-N-(4-fluorocinnamyl)-N-methylbenzylamine). This newly synthesized compound was found to inhibit the Ca2+/calmodulin-dependent activation of calmodulin kinase I, smooth muscle myosin light chain kinase and Ca2+-phosphodiesterase with IC50 Values of 1.57±0.21, 2.29±0.09 and 0.30±0.08 μM (mean±S.E.), respectively. This compound showed little or no effect on the Ca2+/calmodulin-independent activation of protein kinase A, protein kinase C and basal phosphodiesterase. In addition, HMN-709 inhibited calmodulin kinase I competitively with respect to calmodulin (Ki=0.88 μM) and non-competitively with respect to ATP. Affinity chromatography, with HMN-709-coupled Sepharose HP, showed that the compound bound to calmodulin in a Ca2+-dependent manner and did not bind to calmodulin kinase I. These results suggest that HMN-709 antagonizes calmodulin by binding to Ca2+/calmodulin. HMN-709 inhibited collagen-induced platelet aggregation with an IC50 value of 11.80±0.86 μM (mean±S.E.) without inhibiting phorbol 12, 13-dibutyrate-induced aggregation at doses up to 12 μM. HMN-709 appears to be a new, membrane-permeable calmodulin antagonist that may be used for studying the involvement of calmodulin in cellular processes.View full abstractDownload PDF (654K) -
Izumi Murakami, Hiroshi Satoh, Shoichi Asano, Rika Maeda1996 Volume 72 Issue 2 Pages 137-147
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe mucosal protective effect of lansoprazole, a proton pump inhibitor, was examined in ethanol- and acidified taurocholate-induced rat gastric lesion models. The formation of gastric lesions was markedly inhibited by prostaglandin E2 but hardly inhibited by cimetidine, ranitidine and famotidine. Lansoprazole (3 minus; 30 mg/kg, p.o.) inhibited the formation of gastric lesions in a dose-dependent manner, with ID50 Values of 8.5 (ethanol) and 4.1 mg/kg, p.o. (acidified taurocholate). The protective effect of lansoprazole was significantly decreased by functional ablation of capsaicin-sensitive sensory neurons or prior administration of indomethacin or Nγ-nitro-L-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide (NO) synthesis. The inhibitory effect of L-NAME was antagonized by prior administration of L-arginine, a substrate of endogenous NO, but not D-arginine. The antisecretory effect of lansoprazole on the basal acid secretion in pylorus-ligated rats was not affected by any of these treatments. Lansoprazole (5 and 15 mg/ml) administered directly into the gastric chamber obviously increased both the production of NO in the mucosa and mucosal blood flow, which was prevented by pretreatment with L-NAME. These results suggest that capsaicin-sensitive sensory neurons, NO and prostaglandins are involved in the mucosal protection afforded by lansoprazole possibly via an increase in mucosal blood flow, but are not involved in the antisecretory action of lansoprazole.View full abstractDownload PDF (672K) -
Keiko Suzuki, Shoji Yamada1996 Volume 72 Issue 2 Pages 149-159
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSAscites sarcoma 180 (S180A) is a transplantable tumor that induces hypercalcemia in tumorbearing mice and stimulates bone resorption in cultured neonatal mouse calvaria without parathyroid hormone (PTH)-like activity. The serum-free conditioned media of S180A cell cultures (S180A-CM) stimulated [3H]thymidine incorporation (178.3% of the control) and inhibited alkaline phosphatase activity (39.0% of the control) in the osteoblastic osteosarcoma cell line UMR 106-01, contrary to PTH. To investigate signal transduction by S180A-CM, we determined the levels of intracellular free calcium ([Ca2+]i), inositol 1, 4, 5-triphosphate (IP3), 1, 2-diacylglycerol (DAG), phosphatidylcholine (PC) and protein kinase (PK) C activity in UMR 106-01 cells. PTH and PTH-related protein (PTHrP), both potent bone-resorbing factors (BRFs), caused an increase in [Ca2+]i and stimulated IP3 production, whereas S180A-CM had little or no effect on these parameters. On the other hand, S180A-CM stimulated DAG production, accompanied by PC breakdown, and the translocation of PKC activity from the cyiosol to the membrane fraction. Sphingosine, a specific PKC inhibitor, inhibited bone-resorbing activity (BRA) in S180A-CM more effectively than PTH or PTHrP-stimulated resorption. H-7, an inhibitor of both cAMP-dependent PKA and PKC, completely inhibited BRA in S180A-CM. These results suggest that BRFs of Sl80A-CM stimulate osteoblastic cell proliferation and bone resorption via two signal transduction pathways, which are different from those of PTH: 1) activation of PKC by DAG resulting from PC hydrolysis and 2) activation of PKA subsequent to prostaglandin E2 production by bone.View full abstractDownload PDF (749K) -
Zhong-Fang Lai, Jie Liu, Katsuhide Nishi1996 Volume 72 Issue 2 Pages 161-174
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSUsing ion-selective microelectrode techniques, we investigated the effects of 4-acetamido-4''-isothiocyanatostilbene-2, 2''-disulfonic acid (SITS) and 4, 4''-diisothiocyanostilbene-2, 2''-disulfonic acid (DIDS), which are known as Cl¯-HC03¯ exchange blockers, on action potentials and intracellular pH (pHi) in guinea pig ventricular papillary muscles subjected to simulated ischemia. Simulated ischemia was produced by stopping the flow of superfusing solution and then covering the preparations with mineral oil. Simulated ischemia induced a progressive decrease in the maximum upstroke rate and resting membrane potentials, shortened action potential duration, and resulted in cessation of action potentials within 10minus;12 min after the onset of simulated ischemia. The pHi-measurements revealed progressive intracellular acidosis during the period of simulated ischemia. SITS (0.5 mM) or DIDS (O.1 mM) delayed the onset of ischemia-induced deterioration of action potentials and prolonged the time to cessation of action potentials. SITS or DIDS (0.1minus;0.5 mM) induced an increase in pHi in HC03¯-buffered solution and suppressed the development of intracellular acidosis during ischemia. Under the external Cl¯-free condition, the time to cessation of action potentials caused by ischemia was significantly delayed, and the development of intracellular acidosis during ischemia was attenuated. The present results indicate that activation of the Cl¯-HC03¯ exchange system would be involved, in part, in the development of intracellular acidosis during cardiac ischemia.View full abstractDownload PDF (851K) -
Masato Yonamime, Yoko Aniya, Takahiro Yokomakura, Tomoyuki Koyama, Tat ...1996 Volume 72 Issue 2 Pages 175-181
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSEffect of acetaminophen on glutathione (GSH) S-transferase and related drug metabolizing enzymes was studied in vivo. Rats were given acetaminophen (250 mg/kg, i. p.) 24 hr after the treatment with 3-methylcholanthrene (25 mg/kg, i. p.) and killed by decapitation at indicated times. Liver microsomal GSH S-transferase activity was increased to 331%, 193% and 158% of the control level at 3, 6 and 12 hr, respectively, after the administration of acetaminophen, while GSH content in the liver was markedly decreased at 3 and 6 hr. The increase in the transferase activity was not recovered by the treatment with dithiothreitol. Microsomal GSH peroxidase activity was significantly enhanced at 3 hr. Cyiosolic GSH S-transferase and aniline hydroxylase in microsomes were gradually decreased with the increase in the time after administration of acetaminophen. Vmax values of both GSH S-transferase and GSH peroxidase activities in microsomes were increased at 3 hr. Two Km values were obtained for the peroxidase in the control, while only one was observed after the acetaminophen treatment. These results indicate that acetaminophen is converted via cytochrome P-450 to the reactive intermediate N-acetyl-p-benzoquinone imine, which binds to microsomal GSH S-transferase, resulting in the activation of the enzyme.View full abstractDownload PDF (453K) -
Yozo Hori, Kunihiro Odaguchi, Hirokuni Jyoyama, Kiyoshi Yasui, Takuji ...1996 Volume 72 Issue 2 Pages 183-190
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSWe compared the effects of an anti-ulcer agent, benexate hydrochloride betadex (BHB), on prostaglandin (PG) levels in gastric tissue and inflammatory exudate in untreated and indomethacintreated rats. BHB (100, 300 and 1000 mg/kg, p. o.) showed dose-dependent inhibition of gastric mucosal lesions induced by indomethacin (30 mg/kg, p. o.). Sustained decrease of PGS (PGE2 and 6-keto-PGF1α) in the gastric wall was observed from 0.5 to 6 hr after indomethacin treatment. BHB (300 and 1000 mg/kg) dose-dependently led to recovery of the indomethacin-induced decrease of gastric PGS at 1 and 6 hr after dosing. It did not antagonize the indomethacin-induced decrease of PG levels in the pleural exudate of carrageenin pleurisy nor did it affect the anti-inflammatory effects of indomethacin. BHB (100 to 1000 mg/kg) alone increased gastric PGE2 by 61% to 113%, while it decreased PGE2 levels in the pleural exudate by 9% to 71% at 6 hr after dosing. These results suggest that sustained increase of gastric PGE2 by BHB could be responsible for protection against indomethacin-induced gastric mucosal lesions and that BHB is a suitable anti-ulcer agent for NSAIDs without compromising their anti-inflammatory effects.View full abstractDownload PDF (523K) -
Ryuichi Hattori, Yoshiki Yui, Eiji Shinoda, Reiko Inoue, Takeshi Aoyam ...1996 Volume 72 Issue 2 Pages 191-193
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe inhibition of nitric oxide synthase (NOS) by ebselen, 2-phenyl-1, 2-benzisoselenazole-3(2H)-one, was reversed by the addition of 10View full abstractDownload PDF (177K)
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