The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
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Volume 88, Issue 4
Displaying 1-12 of 12 articles from this issue
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Reviews
  • Molecular Diversity of Structure and Function of the Voltage-Gated Na+ Channels
    Nobukuni Ogata, Yoshiaki Ohishi
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 365-377
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.365
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    A variety of different isoforms of voltage-sensitive Na+ channels have now been identified. The recent three-dimensional analysis of Na+ channels has unveiled a unique and unexpected structure of the Na+ channel protein. Na+ channels can be classified into two categories on the basis of their amino acid sequence, NaV1 isoforms currently comprising nine highly homologous clones and NaX that possesses structure diverging from NaV1, especially in several critical functional motifs. Although the functional role of NaV1 isoforms is primarily to form an action potential upstroke in excitable cells, recent biophysical studies indicate that some of the NaV1 isoforms can also influence subthreshold electrical activity through persistent or resurgent Na+ currents. NaV1.8 and NaV1.9 contain an amino acid sequence common to tetrodotoxin resistant Na+ channels and are localized in peripheral nociceptors. Recent patch-clamp experiments on dorsal root ganglion neurons from NaV1.8-knock-out mice unveiled an additional tetrodotoxin-resistant Na+ current. The demonstration of its dependence on NaV1.9 provides evidence for a specialized role of NaV1.9, together with NaV1.8, in pain sensation. Although NaX has not been successfully expressed in an exogenous system, recent investigations using relevant native tissues combined with gene-targeting have disclosed their unique “concentration”-sensitive but not voltage-sensitive roles. In this context, these emerging views of novel functions mediated by different types of Na+ channels are reviewed, to give a perspective for future research on the expanding family of Na+ channel clones.
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  • Pharmacological, Pharmacokinetic and Clinical Properties of Olopatadine Hydrochloride, a New Antiallergic Drug
    Kenji Ohmori, Ken-ichi Hayashi, Toshihiko Kaise, Etsuo Ohshima, Satosh ...
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 379-397
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.379
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    Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritis cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).
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Full Papers
  • Involvement of Glutamate Receptors Within the Central Nucleus of the Amygdala in Naloxone-Precipitated Morphine Withdrawal-Induced Conditioned Place Aversion in Rats
    Takeshi Watanabe, Takayuki Nakagawa, Rie Yamamoto, Akifumi Maeda, Masa ...
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 399-406
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.399
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    Chronic use of morphine leads to physical and psychological dependence. The amygdala is known to be involved in the expression of emotion such as anxiety and fear, and several studies have shown that the central nucleus of the amygdala (CeA) is involved in morphine dependence. In the present study, we investigated the role of glutamate receptors within the CeA in the negative affective component of morphine abstinence by evaluating naloxone-precipitated withdrawal-induced conditioned place aversion (CPA) in morphine-dependent rats. We found that microinjection of the AMPA/kainate-glutamate-receptor antagonist CNQX (30 nmol/side) into the bilateral CeA significantly attenuated the naloxone-precipitated withdrawal-induced CPA, as well as several somatic signs, in morphine-dependent rats, without preference or aversive effects by itself in non-dependent rats. Furthermore, microinjection of the non-competitive NMDA-receptor antagonist MK-801 (30 nmol/side) or competitive NMDA-receptor antagonist D-CPPene (0.01 and 0.1 nmol/side) into the CeA significantly attenuated the naloxone-precipitated morphine withdrawal-induced CPA, but not somatic withdrawal signs. These results suggest that the activation of AMPA/kainate and NMDA receptors within the CeA play a crucial role in the negative affective component of morphine abstinence.
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  • Involvement of Adenosine A2 Receptors in the Changes of Tissue Factor-Dependent Coagulant Activity Induced by Polymorphonuclear Leukocytes in Endothelial Cells
    Tohru Watanabe, Shogo Tokuyama, Masako Yasuda, Tadanori Sasaki, Toshin ...
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 407-413
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.407
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    We have already reported that polymorphonuclear leukocytes (PMNs) could increase tissue factor-dependent coagulant activity (TF activity) in endothelial cells mediated by adhesion of PMNs to endothelial cells. In the present study, the role of adenosine receptors in the changes of TF activity and of adhesion between PMNs and endothelial cells was examined. The increases of the TF activity and adhesion were significantly reduced in a concentration-dependent manner by pretreatment of adenosine (0.1 and 1.0 mM); an adenosine A1/A2-receptor agonist, CGS-21680 (5, 10 and 50 μM); and an adenosine A2-receptor agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 1.0, 10 and 100 nM). An adenosine A2-receptor antagonist, 3,7-dimethyl-1-(2-propynyl) xanthine (DMPX; 1.0 and 100 nM), antagonized significantly the reduction of the TF activity and the adhesion induced by adenosine (1.0 mM), while 8-cyclopentyl-1,3-dimethylxanthine (CPDMX; 1.0 and 100 nM), an adenosine A1-receptor antagonist, did not affect it. On the other hand, the TF activity and the adhesion were not changed by N6-cyclohexyladenosine (CHA; 10 and 100 nM) and 2-chloro-N-cyclopentyladenosine (CCPA; 10 and 100 nM), adenosine A1-receptor agonists in the same conditions. These results suggest that the reduction in the TF activity stimulated by PMNs is closely related to the adhesive inhibition between PMNs and endothelial cells through the adenosine A2-receptor-mediated system.
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  • Effects of a Typical IKr Channel Blocker Sematilide on the Relationship Between Ventricular Repolarization, Refractoriness and Onset of Torsades de Pointes
    Atsushi Sugiyama, Keitaro Hashimoto
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 414-421
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.414
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    The effects of a typical IKr channel blocker sematilide on the relationship between ventricular repolarization, refractoriness and onset of torsades de pointes (TdP) were studied using the canine isolated, blood-perfused ventricular septum preparation with monophasic action potential (MAP) recording. Intra-coronary infusion of sematilide (10 – 100 μg/min) prolonged the repolarization phase and effective refractory period, the extent of which was greater in the former than in the latter, resulting in prolongation of terminal repolarization process. Prolonging the basic pacing cycle length from 400 to 600 ms and/or increasing the drug doses enhanced each of these actions. Reverse use-dependence was obvious in the drug-induced prolongation of MAP duration, but it was less clear in the effective refractory period. More importantly, during sematilide infusion, in preparations paced at longer basic cycle length of 600 – 2000 ms, TdP-like polymorphic ventricular tachycardia was repeatedly induced by an extra-stimulus applied on the terminal repolarization phase, which indicates the appearance of electrically vulnerable period. Prolonging the basic pacing cycle length and/or increasing the drug doses prolonged this electrically vulnerable period in parallel with the terminal repolarization phase. These results suggest that prolongation of the terminal repolarization process by sematilide would enhance the chance of conduction slowing at less complete repolarization levels, which may be associated with a high incidence of TdP induction.
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  • Prostate Apoptosis Response-4 Involved in the Protective Effect of Salvianolic Acid B Against Amyloid β Peptide-Induced Damage in PC12 Cells
    Minke Tang, Juntian Zhang
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 422-427
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.422
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    To observe the effect of salvianolic acid-B (SalB) against the cytoxicity of amyloid β peptide (A-beta)(25 – 35) to PC12 cells, the cells were incubated with A-beta, and the cytoxicity was investigated by MTT, flow cytometry and a cell free apoptotic system. The expression of prostate apoptotic response-4 (Par-4) was detected by Western blot. Aged A-beta 10 μmol/L significantly inhibited the MTT reduction of PC12 cells, SalB 1 μmol/L inhibited the toxicity induced by A-beta. In flow cytometric analysis, PC12 cells treated with A-beta exhibited degraded DNA content characteristic of apoptosis cells (1.53% vs 19.9%). PC12 cells pretreated with SalB (10 nmol/L, 100 nmol/L, 1 μmol/L) manifested relatively low proportion of apoptosis (15.7%, 13.5%, 11.8%, respectively). SalB (10 nmol/L – 1 μmol/L) when added at the beginning of the cell free apoptotic reaction had no apparent effect on the nuclei apoptosis. Pretreatment of PC12 cells with SalB largely prevented the increase in Par-4 expression of the cells when they were exposed to A-beta. The results suggest that Par-4 is involved in the protective effect of SalB against A-beta-induced damage in PC12 cells.
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  • Characteristics of ATP-Induced Current Through P2X7 Receptor in NG108-15 Cells: Unique Antagonist Sensitivity and Lack of Pore Formation
    Tomokazu Watano, Isao Matsuoka, Junko Kimura
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 428-435
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.428
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    ATP activates the mouse P2X7 receptor and induces a nonselective-cation current in NG108-15 cells. We investigated the effects of five receptor antagonists on the ATP-induced nonselective-cation current through P2X7 receptor (INS · P2X7) in NG108-15 cells. Nonselective P2 receptor antagonists, RB-2, PPADS and suramin inhibited the INS · P2X7 with IC50 values of 4.3, 53 and 40 μM, respectively. However, KN-04, which is a potent antagonist of human P2X7 receptors but is not that of rat P2X7 receptors, had only a weak blocking effect. Furthermore, oxidized-ATP (300 μM), an antagonist of the P2X7 receptor-mediated pore-formation, did not affect the INS · P2X7. Prolonged ATP application did not increase the membrane permeability to large molecules, N-methyl-D-glucamine or Yo-Pro-1, indicating that pore-formation was not promoted by the P2X7 receptor activation in NG108-15 cells. These results suggest that antagonist sensitivities and pore-forming properties of the P2X7 receptors in NG108-15 cells are different from those of other cells types.
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  • Effects of Angiotensin II on the Renal Interstitial Concentrations of NO2/NO3 and Cyclic GMP in Anesthetized Rats
    Matlubur Rahman, Shoji Kimura, Hirohito Yoneyama, Hiroaki Kosaka, Tosh ...
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 436-441
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.436
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    The present study was conducted to determine whether exogenous angiotensin II (Ang II) may increase the renal interstitial fluid concentrations of NO2/NO3 (NOx) and cyclic guanosine monophosphate (cGMP) concomitantly and which Ang II receptor subtypes may induce these changes in anesthetized rats, using a microdialysis method. Ang II (50 ng/kg per min, i.v.) significantly increased mean blood pressure (MBP), extraction rates of renal interstitial NOx from 23.9 ± 1.0 to 31.2 ± 1.9 pmol/min, and cGMP from 4.1 ± 0.3 to 6.4 ± 0.5 fmol/min, and decreased renal blood flow (RBF). The AT1-receptor antagonist CV11974 alone significantly increased RBF, but did not alter MBP, renal interstitial concentrations of NOx and cGMP. A superimposition of Ang II on CV11974 did not affect MBP and RBF, but significantly increased renal interstitial concentrations of NOx and cGMP. The AT2-receptor antagonist PD123319 alone did not change any of the parameters. However, superimposition of Ang II on PD123319 increased MBP and decreased RBF without any effects on renal interstitial concentrations of NOx and cGMP. These results suggest that Ang II stimulates NO production via the AT2-receptor in the kidney.
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  • Dipeptidyl Peptidase IV Inhibition Improves Impaired Glucose Tolerance in High-Fat Diet-Fed Rats: Study Using a Fischer 344 Rat Substrain Deficient in Its Enzyme Activity
    Hironobu Mitani, Misato Takimoto, Thomas E. Hughes, Masaaki Kimura
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 442-450
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.442
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    This study was performed to determine the effects of a high-fat diet on glucose metabolism after an oral glucose challenge in high-fat diet-fed dipeptidyl peptidase IV (DPP-IV) positive (+) and deficient (−) Fischer 344 (F344) rats and the effects of novel DPP-IV inhibitor NVP-DPP728 (1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in high-fat diet-fed F344 rats. In DPP-IV(+) rats, a high-fat diet load caused impaired glucose tolerance, such as increases of plasma insulin and blood glucose concentrations after oral glucose challenge, compared with a standard chow-fed group. In contrast, no marked change in glucose tolerance was induced by the high-fat diet in DPP-IV(−) rats. Blood glucose concentrations in DPP-IV(−) rats after glucose challenge were significantly lower than in DPP-IV(+) rats under high-fat diet load conditions. In standard chow and high-fat diet-fed DPP-IV(+) rats, NVP-DPP728 significantly suppressed glucose excursions after glucose challenge by inhibiting the plasma DPP-IV activity, associated with the stimulation of early insulin secretion. NVP-DPP728 did not affect glucose tolerance in DPP-IV(−) rats under both conditions. These results indicate that the amelioration of glucose tolerance by NVP-DPP728 in DPP-IV(+) rats was directly due to the inhibition of plasma DPP-IV activity, which might be via the subsequent increase in endogenous incretin action.
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  • Dipeptidyl Peptidase IV Inhibitor NVP-DPP728 Ameliorates Early Insulin Response and Glucose Tolerance in Aged Rats but Not in Aged Fischer 344 Rats Lacking Its Enzyme Activity
    Hironobu Mitani, Misato Takimoto, Masaaki Kimura
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 451-458
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.451
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    The aim of this study was to investigate the effects of aging on glucose metabolism after oral glucose challenge in aged dipeptidyl peptidase IV (DPP-IV) positive (+) Fischer 344 (F344), DPP-IV deficient (−) F344 and DPP-IV(+) Wistar rats and to determine the effect of a DPP-IV inhibitor NVP-DPP728 (1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in aged rats. Aging caused a decrease in early insulin response after an oral glucose challenge in aged Wistar or DPP-IV(+) F344 rats, but not in aged DPP-IV(−) F344 rats, compared with young control groups. Glucose tolerance after an oral glucose challenge in aged DPP-IV(−) F344 rats was better than in aged DPP-IV(+) F344 and Wistar rats associated with the preservation of the early insulin response. NVP-DPP728 improved the glucose tolerance after an oral glucose challenge by potentiating the early insulin response throughout the inhibition of plasma DPP-IV activity in aged DPP-IV(+) Wistar and F344 rats. In contrast, NVP-DPP728 did not affect the glucose tolerance after an oral glucose challenge in aged DPP-IV(−) F344 rats. These results indicate that treatment with NVP-DPP728 ameliorated glucose tolerance in aged rats by the direct inhibition of plasma DPP-IV activity and presumably the subsequent increase in endogenous incretin action.
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Short Communications
  • Hyperpolarization-Activated Current Ih in Nucleus of Solitary Tract Neurons: Regional Difference in Serotonergic Modulation
    Yuki Iwahori, Yuji Ikegaya, Norio Matsuki
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 459-462
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.459
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    The nucleus of solitary tract (NTS) contains diverse neural circuits responsible for basic vital functions. We examined the effect of serotonin (5-HT) on hyperpolarization-activated current (Ih) in neurons acutely isolated from caudal, medial and rostral parts of the NTS. Caudal and medial NTS neurons showed a large amplitude of Ih compared with rostral neurons. In these neurons, perfusion with 5-HT potentiated Ih amplitude in a concentration-dependent manner. The effect of 5-HT was blocked by NAN-190, a 5-HT1A receptor antagonist. Thus, 5-HT1A receptors may regulate Ih channel activity in caudal and medial NTS neurons.
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  • Inhibitory Effect of Olopatadine on Antigen-Induced Eosinophil Infiltration and the LFA-1 and Mac-1 Expression in Eosinophils
    Nobuyuki Fukuishi, Motoko Matsuhisa, Takeshi Shimono, Nobutoshi Murata ...
    Subject area: Infomation Science
    2002 Volume 88 Issue 4 Pages 463-466
    Published: 2002
    Released on J-STAGE: May 10, 2002
    DOIhttps://doi.org/10.1254/jjp.88.463
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    The inhibitory effect of olopatadine, a new antiallergic drug, on antigen-induced eosinophil infiltration and its mechanisms were examined using the local sensitized rat allergic rhinitis model and isolated IL-5-stimulated rat peritoneal eosinophils. Olopatadine dose-dependently inhibited antigen-induced eosinophil infiltration in the nasal mucosa. Olopatadine dose-dependently repressed the IL-5-induced expressions of CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) on rat peritoneal eosinophils. However, olopatadine had no effect on IL-5-induced CD49d/CD29 (VLA-4) expression. These results suggest that olopatadine may inhibit antigen-induced eosinophil infiltration through repression of LFA-1 and Mac-1 expression.
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