Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
98 巻, 2 号
選択された号の論文の11件中1~11を表示しています
Critical Reviews
  • Stephen Commiskey, Lir-Wan Fan, Ing K. Ho, Rob W. Rockhold
    2005 年 98 巻 2 号 p. 109-116
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/08
    ジャーナル フリー
    The opioid analgesic, butorphanol (17-cyclobutylmethyl-3,14-dihydroxymorphinan) tartrate is a prototypical agonist-antagonist opioid analgesic agent whose potential for abuse has been the cause of litigation in the United States. With a published affinity for opioid receptors in vitro of 1:4:25 (μ:δ:κ), the relative contribution of actions at each of these receptors to the in vivo actions of the drug are an issue of active investigation. A body of evidence has been developed which indicates that a substantial selective action of butorphanol on the κ-opioid receptor mediates the development of tolerance to butorphanol and cross-tolerance to other opioid agonists; to the production of dependence upon butorphanol, particularly in the rodent; and to compensatory alterations in brain opioid receptor-effector systems. This perspective will identify the current state of understanding of the effects produced by butorphanol on brain opioid receptors, particularly on the κ-opioid receptor subtype, and on the expression of phosphotyrosyl proteins following chronic treatment with butorphanol.
  • Mohammad Hasan Zaki, Teruo Akuta, Takaaki Akaike
    2005 年 98 巻 2 号 p. 117-129
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/04
    ジャーナル フリー
    The pathogenic mechanism of infections is a complicated but important scientific theme that is now attracting great attention because of its association with host-derived as well as microbial factors. Recent advances in free radical research revealed that reactive oxygen and nitrogen oxide species such as superoxide (O2) and nitric oxide (NO) play a leading role in the pathogenesis of infections caused by viral pathogens including influenza virus and other RNA viruses. Although NO and O2 have antimicrobial activity against bacteria, fungi, and parasites, in some viral infections they have an opposite effect. This exacerbation caused by NO and O2 is mediated by reactive nitrogen oxides, for example, peroxynitrite (ONOO), generated by reaction of NO with O2. These nitrogen oxides have strong oxidation and nitration potential and can modify biological molecules, thereby creating oxidative and nitrative stress that contributes to pathogenic processes during viral infection. Nitrative stress-mediated 8-nitroguanosine formation during influenza or Sendai virus infection has been the focus of enormous interest because it involves unique biochemical and pharmacological properties such as redox activity and mutagenic potential. In this review, we discuss the nature and impact of nitrative stress in viral infection, with emphasis on nitrative stress-mediated viral pathogenesis, which we have recently been investigating.
Full Papers
  • Nermin Ali, Masanori Yoshizumi, Yoshiko Fujita, Yuki Izawa, Yasuhisa K ...
    2005 年 98 巻 2 号 p. 130-141
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/04
    ジャーナル フリー
    Vascular endothelial growth factor (VEGF) was reported to be a potent proangiogenic factor that plays a pivotal role in both physiological and pathological angiogenesis. M475271, 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl) methoxy]-(9Cl), is a new anilinoquinazoline derivative that showed selective inhibition of Src kinase activity and tumor growth in vivo. Here, we examined the effect of M475271 on VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation and migration and their intracellular mechanisms. Our findings showed that M475271 pretreatment resulted in a significant inhibition of VEGF-induced HUVEC proliferation, [3H]thymidine incorporation, and migration. M475271 inhibited VEGF-induced Flk-1 and Src phosphorylation and their association. Confocal laser microscopic examination confirmed the inhibitory effect of M475271 on VEGF-induced Flk-1/Src association. M475271 inhibited VEGF-induced extracellular signal-regulated kinase1/2 (ERK1/2) and p38 but not Akt activation in a concentration-dependent manner. M475271, PI3-K inhibitor, and p38 inhibitor inhibited VEGF-induced HUVEC proliferation and migration. However, a MEK1/2 inhibitor inhibited VEGF-induced proliferation but not migration. These findings suggest that M475271 attenuates VEGF-induced HUVEC proliferation and migration through the inhibition of signaling pathways involving Src, ERK1/2, and/or p38. Taken together, these data indicate that M475271 may be a useful candidate for inhibition of endothelial cell proliferation and migration relevant to angiogenesis.
  • Masami Hashimoto, Yoko Takada, Yusuke Takeuchi, Jiro Kasahara, Hiroaki ...
    2005 年 98 巻 2 号 p. 142-150
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/04
    ジャーナル フリー
    We here assessed the effects of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel calmodulin antagonist, on infarct size in the rat heart subjected to ischemia/reperfusion. Rats were subjected to a 30-min coronary occlusion followed by a 24-h reperfusion. DY-9760e was intravenously infused for 20 min, starting at 20 min after coronary occlusion. Treatment with DY-9760e (10 mg/kg) significantly reduced the infarct size in the risk area assessed by Evans Blue/TTC (triphenyltetrazolium chloride) staining. DY-9760e treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. DY-9760e significantly inhibited fodrin breakdown and caspase-3 activation. The inhibitory effect of DY-9760e on the fodrin breakdown was prominent in the rim rather than in the center of the risk area. DY-9760e also blocked protein tyrosine nitration associated with infarction. These results suggest that the cardioprotective effect of DY-9760e involved inhibition of calpain/caspase activation and protein tyrosine nitration.
  • Ali Bouallegue, Nobuharu Yamaguchi
    2005 年 98 巻 2 号 p. 151-160
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/08
    ジャーナル フリー
    The role of nitric oxide (NO) in bradykinin (BK)-induced adrenal catecholamine secretion still remains obscure. The present study was to investigate whether an inhibition of NO synthase with Nω-nitro-L-arginine methyl ester (L-NAME) would modulate BK-induced adrenal catecholamine secretion (ACS) and adrenal vasodilating response (AVR) in anesthetized dogs. Plasma catecholamine concentrations were determined with an HPLC coupled with an electrochemical detector. All drugs were locally administered to the left adrenal gland via intra-arterial infusion. BK dose-dependently increased both ACS and AVR. Hoe-140, a selective B2 antagonist, significantly blocked the BK-induced increases in both ACS and AVR. In the presence of L-NAME, the BK-induced ACS was significantly enhanced, while the simultaneous AVR remained unaffected. These results suggest that the both BK-induced ACS and AVR are primarily mediated by B2 receptors in the canine adrenal gland. Our results also suggest that the enhanced ACS in response to BK in the presence of L-NAME may have resulted from a specific inhibition of NO formation in the adrenal gland. It is concluded that the BK-induced NO may play an inhibitory role in the B2-receptor-mediated mechanisms regulating ACS, while it may not be implicated in the B2-receptor-mediated AVR under in vivo conditions.
  • Toshitaka Kido, Yoichiro Nakai, Yoshio Kase, Iwao Sakakibara, Masaaki ...
    2005 年 98 巻 2 号 p. 161-167
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/04
    ジャーナル フリー
    We evaluated the effects of Rikkunshi-to and several of its ingredients on the delay of gastric emptying induced by a nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NNA). After oral administration of L-NNA to rats, the gastric emptying rate at 24 h was decreased from 82.8 ± 2.4% to 53.3 ± 5.7%. The decrease of the gastric emptying rate induced by L-NNA treatment was markedly ameliorated by administration of Rikkunshi-to (250 and 500 mg/kg, p.o.) in a dose-dependent manner. To identify the active ingredient of Rikkunshi-to, the components were separated according to polarity, and the effects of the respective fractions on gastric emptying were evaluated. Significant efficacy was found in the water and methanol fractions, but not in the 50% aqueous-methanol fraction. Furthermore, hesperidin (1 - 4.29 mg/kg, p.o.) contained in the methanol fraction and L-arginine (4.5 mg/kg, p.o.) contained in the water fraction ameliorated the decrease in the gastric emptying rate induced by L-NNA treatment. These results suggest that Rikkunshi-to ameliorated abnormalities of NO-mediated gastric functions such as delayed gastric emptying, and hesperidin and L-arginine were identified as two of the active ingredients contributing to the ability of Rikkunshi-to to facilitate gastric emptying.
  • Masashi Fukutomi, Motohiro Nishida, Yoshiko Maruyama, Hiroyuki Kobayas ...
    2005 年 98 巻 2 号 p. 168-174
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/08
    ジャーナル フリー
    Cardiomyocytes express both β1- and β2-adrenergic receptors, and these receptors play a differential role in chronotropic and inotropic effects of the heart. Caveolae are known as an important regulator of G-protein-coupled receptor signaling. In the present report, we examined whether caveolae have a role in β-adrenergic receptor-stimulated cAMP production and protein kinase A activation in neonatal myocytes. Isoproterenol-stimulated cAMP production was mediated by β1- and β2-subtypes, which depends on the receptor number of each subtype. However, protein kinase A activation was exclusively mediated by the β1-subtype. Disruption of caveolae by methyl-β-cyclodextrin treatment did not affect the relative contribution of subtypes to isoproterenol-stimulated cAMP production. β1-Subtype-mediated protein kinase A activation was also not affected by the disruption of caveolae. These results suggest that β1-adrenergic receptor-mediated protein kinase A activation is compartmentalized and independent of caveolae.
  • Shu-ichi Kojima, Masashi Ikeda, Yuichiro Kamikawa
    2005 年 98 巻 2 号 p. 175-180
    発行日: 2005年
    公開日: 2005/06/18
    [早期公開] 公開日: 2005/06/08
    ジャーナル フリー
    The effect of loperamide on tachykinin NK2- and NK3-receptor-mediated 5-HT outflow from guinea pig colonic mucosa was investigated in vitro. The selective tachykinin NK2-receptor agonist [β-Ala8]-neurokinin A4-10 (βAla-NKA) or the selective NK3-receptor agonist senktide elicited an increase in 5-HT outflow from whole colonic strips, but not from mucosa-free muscle layer preparations. The enhancing effect of βAla-NKA and senktide was prevented by the selective NK2-receptor antagonist GR94800 or the selective NK3-receptor antagonist SB222200. Loperamide concentration-dependently suppressed the senktide-evoked 5-HT outflow, but failed to affect the βAla-NKA-evoked 5-HT outflow. The κ-opioid receptor antagonist nor-binaltorphimine or the δ-opioid receptor antagonist naltrindole displaced the concentration-response curve for the suppressant action of loperamide to the right without significant depression of the maximum. However, the μ-opioid receptor antagonist CTOP did not affect the suppressant effect of loperamide. We concluded that the NK3 receptor-triggered 5-HT release from colonic mucosa is suppressed by loperamide-sensitive mechanisms, whereas the NK2-receptor-triggered 5-HT release is loperamide-insensitive. Our data also suggest that the suppressant effect of loperamide is probably mediated by the activation of κ- and δ-opioid receptors located on intrinsic neurons.
Short Communications
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