Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 92, Issue 3
Displaying 1-15 of 15 articles from this issue
Current Perspective
  • Naoki Hattori
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 171-177
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    Hyperprolactinemia is not only seen in pregnancy but also in several pathological conditions such as prolactin (PRL) secreting pituitary adenoma (prolactinoma), intracranial tumors compressing the pituitary stalk or hypothalamus, and PRL stimulative drugs. However, some patients with hyperprolactinemia are diagnosed as having idiopathic hyperprolactinemia because the causes are unknown. They are subjected to repeated radiological examinations to find a microadenoma, to a long-term treatment with bromocriptine, and even to a surgical intervention. There is accumulating evidence that macroprolactinemia, in which most circulating PRL forms large protein complexes (more than 150 kDa), is a major cause of idiopathic hyperprolactinemia. The patients with macroprolactinemia are clinically characterized by the lack of hyperprolactinemia-related symptoms such as amenorrhea and galactorrhea. We found that anti-PRL autoantibody is a leading cause of macroprolactinemia that might be heterogeneous in nature. Most patients with anti-PRL autoantibodies were symptom-free and pregnancy was possible despite a marked hyperprolactinemia. Identification of macroprolactinemia is clinically important to prevent unnecessary examinations and treatments in patients with idiopathic hyperprolactinemia.
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Critical Review
  • Taizo Kita, George C. Wagner, Toshikatsu Nakashima
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 178-195
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    Methamphetamine (METH)-induced neurotoxicity is characterized by a long-lasting depletion of striatal dopamine (DA) and serotonin as well as damage to striatal dopaminergic and serotonergic nerve terminals. Several hypotheses regarding the mechanism underlying METH-induced neurotoxicity have been proposed. In particular, it is thought that endogenous DA in the striatum may play an important role in mediating METH-induced neuronal damage. This hypothesis is based on the observation of free radical formation and oxidative stress produced by auto-oxidation of DA consequent to its displacement from synaptic vesicles to cytoplasm. In addition, METH-induced neurotoxicity may be linked to the glutamate and nitric oxide systems within the striatum. Moreover, using knockout mice lacking the DA transporter, the vesicular monoamine transporter 2, c-fos, or nitric oxide synthetase, it was determined that these factors may be connected in some way to METH-induced neurotoxicity. Finally a role for apoptosis in METH-induced neurotoxicity has also been established including evidence of protection of bcl-2, expression of p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), activity of caspase-3. The neuronal damage induced by METH may reflect neurological disorders such as autism and Parkinson’s disease.
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Full Papers
  • Kazuhide Nishimaru, Yoshio Tanaka, Hikaru Tanaka, Koki Shigenobu
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 196-202
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    The intracellular signalling pathway for α-adrenoceptor-mediated negative inotropy was studied pharmacologically in isolated adult mouse ventricle. The negative inotropy was inhibited by GF-109203X, a nonselective protein kinase C inhibitor. Phorbol 12-myristate 13-acetate also produced sustained negative inotropy, which was inhibited by KB-R7943, a Na+/Ca2+ exchanger inhibitor. The α-adrenoceptor-mediated negative inotropy was augmented by RHC-80267, a diacylglycerol lipase inhibitor, but was inhibited either by C2-ceramide, a phospholipase D inhibitor, and high concentration of propranolol (50 μM), which inhibits phosphatidate phosphohydrolase. The inotropy was not affected by U-73122, a phospholipase C inhibitor. Lavendustin-A, a tyrosine kinase inhibitor, also inhibited the negative inotropy. These findings suggest that α-adrenoceptor-mediated negative inotropy in adult mouse ventricle is mediated by activation of tyrosine kinase, the phospholipase D-phosphatidate phosphohydrolase pathway, and protein kinase C.
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  • Chiu-Yin Kwan, Wen-Bo Zhang, Joanna Miller, Paul H.M. Harrison, Salina ...
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 203-208
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    The vascular effects of a newly discovered anti-fungal agent, pramanicin (PMC), and its two analogues, PMC-A, in which the epoxy group is replaced by a – HC = CH – bond, and PMC-B, on which the diene is converted to the saturated (CH2)4-derivative, respectively, were investigated in rat aorta. All three compounds caused an initial endothelial-dependent relaxation, which is prevented either by removal of endothelium or inclusion of the nitric oxide synthase inhibitor L-NAME. Upon prolonged incubation with the aortic rings, they also caused endothelial cell dysfunction characterized as reduced relaxation to carbachol (CCh). These effects were the strongest for PMC, being completely inhibitory at 20 μM after 30 min incubation, whereas those of PMC-A and PMC-B were smaller and comparable with each other, causing 30 – 40% inhibition at 20 μM. PMC and its analogues had no effect on KCl-induced contraction and also had no effect on relaxation induced by sodium nitroprusside, suggesting that these compounds had no effect on the basic mechanisms of the contractile elements. Phenylephrine (PE)-induced contraction, however, was significantly reduced in the presence of these compounds, the inhibitory effect being strongest with PMC, but this inhibitory action was rapidly reversible and not of the competitive mode with respect to PE. We conclude that the epoxy group in PMC is required for the optimal vascular effects. We have discussed and speculated upon the possible mechanisms of action of PMC. The potent, selective, and irreversible inhibitory effect of PMC on the endothelial function points to its potential development into an anti-angiogenic drug.
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  • Hiroyasu Hirose, Jian Jiang, Masaru Nishikibe
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 209-217
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    To investigate whether the inhibition of muscarinic M2 receptors results in the enhancement of reflex bronchoconstriction under airway hyperresponsiveness, we evaluated the effects of muscarinic antagonists with or without M2 antagonist activity on methacholine (MCh)- and SO2-induced airway responses in ovalbumin (OVA)-sensitized and -challenged mice. In this model, similar airway hyperresponsiveness to MCh (12 mg/ml) was observed on Days 31 and 37 (2.2-fold and 2.7-fold, respectively). However, airway hyperresponsiveness to SO2 (0.05 l/min) on Day 37 was less than that on Day 31 (4.0- and 2.7-fold on Days 31 and 37), indicating reflex bronchoconstriction was enhanced on Day 31 in comparison to Day 37. Ipratropium (0.03 – 0.3 mg/ml, inhalation) and Compound A (0.1 – 3 mg/kg, p.o.) inhibited MCh-induced responses on Days 31 and 37. Although ipratropium (0.03 – 1 mg/ml) dose-dependently inhibited SO2-induced responses on Day 31, ipratropium at a dose of 0.1 mg/ml significantly increased SO2-induced responses on Day 37 (162.2% of the corresponding control). On the other hand, Compound A (0.03 – 0.3 mg/kg, p.o.) inhibited SO2-induced responses without any increases on Days 31 and 37. These results suggest that two different conditions of reflex bronchoconstriction are presented in this model: 1) SO2-induced responses are enhanced by dysfunctional M2 receptors on Day 31; 2) the dysfunctional M2 receptors are partially restored on Day 37. In addition, the inhibition of the restored M2 receptors further enhance reflex bronchoconstriction.
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  • Yang-Su Park, Sung-Eun Yoo, Hwa-Sup Shin, Yong-Ri Jin, Yeo-Pyo Yun
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 218-227
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    This study was designed to characterize vasorelaxant effects of BMS-180448 ((3S-trans)-N-(4-chlorophenyl)-N'-cyano-N''-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)), a prototype cardioselective ATP-sensitive potassium channel opener, in rat aorta. BMS-180448 relaxed phenylephrine-precontracted endothelium-intact aortic rings (IC50: 0.97 ± 0.29 μM), the effect being significantly attenuated by removal of functional endothelium (IC50: 1.95 ± 0.23 μM) and pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) or methylene blue. BMS-180448 completely relaxed endothelium-denuded aorta contracted with phorbol 12,13-dibutyrate, PGF2α, and U46619 with a significantly greater potency (IC50: 0.069 ± 0.002, 0.055 ± 0.002, and 0.068 ± 0.008 μM, respectively, P<0.05) than that contracted with phenylephrine (1.95 ± 0.23 μM) or KCl (0.25 ± 0.08 μM), indicating potency change with the type of vasoconstrictor. BMS-180448 (1 – 3 μM) inhibited Ca2+ (0.5 – 2.5 mM)-induced contraction of endothelium-denuded aorta evoked in the presence of high KCl (65.4 mM), but had no effect on contraction induced by phenylephrine in Ca2+-free buffer. BMS-180448 (10 μM) increased cAMP level in aorta by approximately two-fold compared with the control, comparable to forskolin, an adenylate cyclase activator. These findings suggest that cardioselective BMS-180448 still exerts significant vasorelaxant activity in rat aorta contracted with various vasoconstrictors via multiple mechanisms including the blockade of extracellular Ca2+ influx through voltage-dependent channels and activation of the adenylate cyclase and nitric oxide pathway, with the possibility of hemodynamic implications in certain clinical conditions such as myocardial infarction and hypertension.
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  • Yoshihisa Kitamura, Atsushi Miyamura, Kazuyuki Takata, Masatoshi Inden ...
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 228-236
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    Recently, it has been shown that endoplasmic reticulum (ER) stress causes apoptosis. However, the mechanism of the ER stress-dependent pathway is not fully understood. In human neuroblastoma SH-SY5Y cells, we detected a caspase-12-like protein that has a molecular mass (approximately 60 kDa) similar to that of mouse caspase-12. Thapsigargin, an inhibitor of ER-associated Ca2+-ATPase, induced the degradation of caspase-12-like protein. In addition, the degradation of caspases-9 and -3, cleavage of poly(ADP-ribose) polymerase, DNA fragmentation, and cell death were also observed. Pretreatment with phorbol-12-myristate-13-acetate, which induces the expression of antiapoptotic Bcl-2, inhibited thapsigargin-induced degradation of caspases-9 and -3, but not caspase-12-like protein degradation. A caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(OCH3)-CH2F, inhibited the degradation of caspase-12-like protein, but not that of caspases-9 and -3. These results suggest that thapsigargin may induce the activation of both ER- and mitochondria-dependent pathways in human SH-SY5Y cells.
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  • Mototaka Nakama-Kitamura, Nobutaka Doe
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 237-244
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    The response latencies of the biting response in the tail-pinch test and step-through response in the passive avoidance test were measured in mice. 1) Scopolamine decreased the latency of the step-through response in the passive avoidance test, but diazepam did not. 2) Morphine (5 mg/kg, i.p.) was given 30 min before the test for 4 consecutive days in novel environments by sessions. The decrease in biting response latency was attenuated and delayed in the groups in which contexts were changed daily compared to the groups that were maintained in the same context throughout the conditioning period. The latency of step-through response was increased with morphine in both groups regardless of the change or lack of change in context. 3) Morphine was repeatedly administered to animals in the same environment and then the context was changed. The decreased latency in the tail-pinch test was significantly reversed by the change in context, but the response in the passive avoidance test maintained a longer latency. These findings indicate that morphine develops associative and nonassociative antinociceptive tolerance, indicating that antinociceptive tolerance to morphine has contextual specificity, but the facilitation of memory does not. The results indicate that the facilitation of memory with morphine may contribute to associative learning in antinociceptive tolerance to morphine.
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  • Yoshitoku Yoshida, Nagisa Matsumoto, Remi Tsuchiya, Mitsuhiro Morita, ...
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 245-251
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    The distribution of group I metabotropic glutamate receptors in rat hippocampal cells in culture was examined by calcium imaging and immunocytochemistry. To distinguish different cell types in the culture, the effects of t-ACPD ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid) and of NMDA (N-methyl-D-aspartate) were examined. About 40% of the cultured cells showed either a transient increase or a sustained or oscillatory increase in the intracellular calcium concentration ([Ca2+]i) during t-ACPD administration, while about 60% of the cells showed a sustained [Ca2+]i increase in response to NMDA. Cells that showed an oscillatory [Ca2+]i change during t-ACPD administration did not respond to NMDA administration, while cells that showed a sustained [Ca2+]i increase during NMDA administration did not show any oscillatory response to t-ACPD. After pharmacological examination using those two agonists, the cultured cells were subjected to immunocytochemistry using anti-GFAP and ant-MAP-2 antibodies to distinguish, respectively, astrocytes and neurons. All cells responding to NMDA with a sustained [Ca2+]i increase were MAP-2-positive, whereas all cells showing either oscillatory or sustained [Ca2+]i increase in response to t-ACPD were GFAP-positive. The present results show that, in these cultures, group I metabotropic glutamate receptors are mainly expressed on glial cells and contribute to dynamic [Ca2+]i changes in astrocytes.
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  • Katsuhiko Muraki, Yuji Imaizumi
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 252-258
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    Palmitoyl-L-carnitine (palcar), which accumulates in ischemic heart, affects cellular functions of vascular endothelium in the ischemic area. The aim of this study was to examine the effects of palcar on intracellular Ca2+ concentration ([Ca2+]i) in vascular endothelial cells in comparison with those of sphingosine-1-phosphate (S1P) and to investigate the underlying mechanisms. Application of palcar at a concentration range between 0.3 and 3 μM elevated [Ca2+]i in huvecs, and its potency was about 30 times lower than that of S1P. When human umbilical vein endothelial cells (huvecs) were treated with 100 ng/ml pertussis toxin (PTX) for 15 h, they failed to respond to palcar or S1P, but did respond to 3 μM histamine (His), suggesting that the response induced by palcar as well as S1P is mediated by a PTX-sensitive GTP binding protein, Gi. Although the sensitivity to palcar and S1P varied widely among huvecs from individuals, response to 3 μM palcar in each huvec clearly paralleled that to 0.3 μM S1P (r = 0.79, P<0.001). On the other hand, pre-treatment of huvecs with palcar abolished subsequent S1P-induced elevation of [Ca2+]i, but not the His-induced elevation. Our data indicate that palcar has a novel action on huvecs as a potential agonist of receptors for S1P. Effective inhibition of the response to S1P by palcar suggests that palcar affects functions regulated by S1P.
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  • Yun Zhu, Yoshihiro Miwa, Akihiro Yamanaka, Toshihiko Yada, Megumi Shib ...
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 259-266
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    Signal transduction pathways of orexin receptors were examined using a nerve-like cell line transfected with orexin receptor type-1 (OX1R) and orexin receptor type-2 (OX2R). Forskolin-stimulated cyclic adenosine 3,5-monophosphate (cAMP) accumulation in OX2R-expressing cells was inhibited by orexin in a dose-dependent manner, and the effect was abolished by pretreatment with pertussis toxin (PTX). The inhibitory effect of orexin on forskolin-stimulated cAMP accumulation was not observed in OX1R-expressing cells. Administration of orexin to these cells resulted in a transient increase of intracellular calcium concentration ([Ca2+]i). Orexin-stimulated increases in [Ca2+]i in OX1R- or OX2R-expressing cells were not affected by the PTX pretreatment. These observations suggest that OX1R couples exclusively to PTX-insensitive G-proteins, while OX2R couples to both PTX-sensitive and -insensitive G-proteins. To examine the relative contributions of these G-proteins in OX2R-mediated activation of neurons, we used histaminergic tuberomammillary nucleus neurons, in which OX2R is abundantly expressed. We found that a phospholipase C (PLC)-inhibitor, U73122, inhibits orexin-mediated neuronal activation, but PTX showed no effect on it. This suggests that although OX2R couples to multiple G-proteins, activation of neurons by orexins through OX2R is mediated via a PTX-insensitive, PLC dependent pathway.
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  • Koji Nobe, Hikaru Suzuki, Hiromi Nobe, Yasushi Sakai, Kazutaka Momose
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 267-282
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    The effect of the thromboxane A2 analogue U46619 (9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α) on sustained contraction in the mouse aorta was investigated. U46619 induced concentration-dependent (1 – 100 nM) increases in contraction. These contractile responses were enhanced significantly under high-glucose-physiological salt solution (HG-PSS) (2-fold greater than normal-PSS) conditions. This hyperactivation may be associated with aortic dysfunction in diabetes. However, the mechanisms remain unclear. HG-PSS enhanced U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibitor (U73122) suppressed DG accumulation under normal conditions; however, suppression was not observed under high-glucose conditions. The HG-PSS-induced enhancement of contraction was inhibited by protein kinase C (PKC) inhibitor (calphostin C). This result indicated that accumulated DG might increase PKC activity, which then stimulates DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed HG-PSS-induced enhancement of contraction. Increased myo-inositol incorporation was detected under high-glucose conditions, indicating an acceleration of phosphatidylinositol (PI)-turnover. Moreover, rho kinase inhibitor (Y27632) suppressed U46619-induced contraction exclusively in normal-PSS. These findings indicated that HG-PSS treatment increases DG synthesis derived from incorporated glucose, PKC and DG kinase activation, and enhances the U46619-induced contraction via acceleration of PI-turnover. This series of responses may be involved in the dysfunction of aorta under high-glucose conditions occurring in association with diabetes.
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  • Yoshiyuki Mizushina, Xianai Xu, Chikako Murakami, Toshio Okano, Masaha ...
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 283-290
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    As described previously (H. Togashi et al. Biochem Pharmacol. 1998;56:583–590), the irradiated products of provitamin D2 (ergosterol) inhibit the activities of eukaryotic DNA polymerases. In this report, therefore, we investigated whether vitamin D and its related compounds inhibited the activities of DNA polymerases. As expected, vitamin D2 and vitamin D3 were found to be selective inhibitors of mammalian DNA polymerase α (pol α) with IC50 values of 123 and 96 μM, respectively. On the other hand, provitamin D2, provitamin D3, and the active form of vitamin D3 such as 1α,25-dihydroxyvitamin D3 could not influence any of the DNA polymerase activities. Interestingly, vitamin D3-3β-sulfate was a much stronger pol α inhibitor with an IC50 value of 7.1 μM. Vitamin D2, vitamin D3, and vitamin D3-3β-sulfate could prevent the growth of NUGC-3 human gastric cancer cells with LD50 values of 133, 77, and 44 μM, respectively, but provitamin D2 and provitamin D3 could not. The cells were halted at the G1 phase in the cell cycle by these compounds.
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Short Communications
  • Yukiko Morimoto, Tadashi Yasuhara, Akiko Sugimoto, Atsuko Inoue, Izumi ...
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 291-295
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    Following prolonged exposure to some of the flavonoids with RBL-2H3 cells, secretion of hexosaminidase, a granule constituent, stimulated by an immunologic was enhanced. RBL-2H3 cells do not normally respond to polybasic secretagogues, but as reported here, they do so after prolonged exposure. Effect of flavonoids on secretion of hexosaminidase was also investigated. Of the thirteen flavonoids, quercetin and fisetin were the most potent inhibitors. A structure-activity study indicated that the position, number, and substitution of the hydroxy group of the B ring and saturation of the C2-C3 bond are important factors affecting flavonoid inhibition of secretary granules in RBL-2H3 cells.
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  • Yoshiaki Ohishi, Tomoya Matsutomi, Taixing Zheng, Jun-ichi Kakimura, H ...
    Subject area: Infomation Science
    2003 Volume 92 Issue 3 Pages 296-300
    Published: 2003
    Released on J-STAGE: July 23, 2003
    JOURNAL FREE ACCESS
    Effects of 4-aminopyridine (4-AP) on the transient K+ current (IA) was studied in rat sensory neurons using the whole cell patch-clamp technique. The amplitude of IA was reduced by 4-AP. The steady-state inactivation curve for IA was shifted in the positive direction by 4-AP, suggesting that the blocking action of 4-AP may be attenuated by membrane depolarization. When two IAs were evoked with variable intervals, the peak amplitude of the IA induced by the second pulse was augmented in the presence of 4-AP. These results indicate that the action of 4-AP can be modulated by concurrent neuronal activities.
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