日本薬理学雑誌
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
110 巻 , 6 号
選択された号の論文の7件中1~7を表示しています
  • 漆谷 徹郎, 長尾 拓
    1997 年 110 巻 6 号 p. 303-313
    発行日: 1997年
    公開日: 2007/01/30
    ジャーナル フリー
    The parietal cell has three types of activating receptors for acid secretion on its basolateral membrane, i.e., histamine H2, acetylcholine M3, and gastrin CCKB. Activation of acid secretion is achieved by two concomitant functional changes namely: (i) tubulovesicles fuse with the apical secretory membrane, thus recruiting functional pumps to the expanded microvillar surface, and (ii) the apical membrane acquires a permeability to KCl. The major path for parietal cell stimulation is via H2-receptor-mediated adenylate cyclase and elevation of cAMP to activate protein kinase A (PKA), which phosphorylates key effector proteins, e.g., ezrin, a membrane-cytoskeletal linker, apical Cl- or K+-channels. Ca2+ is liberated from intracellular stores by IP3, which in turn is the result of M3-, CCKB-, or possibly H2-coupled activation of phospholipase C. The resulting protein kinase C activation may have both inhibitory and excitatory roles. Elevated Ca2+ activates calmodulin-dependent kinases, e.g., calmodulin kinase II and myosin light chain kinase, that could promote vesicular motor activity. Ezrin is considered to play a main role in the vesicular transport system of the parietal cell. The regulation might be conducted through the phosphorylation of the molecule to modify its property to interact with the cytoskeletal components, membranes or membrane proteins.
  • 木皿 憲佐, 丹野 孝一, 櫻田 司
    1997 年 110 巻 6 号 p. 315-324
    発行日: 1997年
    公開日: 2007/01/30
    ジャーナル フリー
    Progress in the characterization of tachykinin receptors and the understanding of the physiological and pathological roles of tachykinins is highly dependent on the discovery of potent and selective antagonists with metabolic stability. We have recently described a peptidic antagonist of the tachykinin NK 1 receptor, sendide (Tyr-D-Phe-Phe-D-His-Leu-Met-NH2), that is a selective and extremely potent antagonist of NK-1 receptors, but displays no antagonistic activity on the response induced by NK-2 or NK-3-receptor agonists in the mouse spinal cord. When coadministered with substance P (SP) intrathecally (i.t.), sendide markedly inhibited the scratching, biting and licking behavior induced by SP in a dose-dependent manner. The antagonistic effect of sendide on the SP-induced behavioral response was approximately 7300 times more potent than that of CP-96, 345, a non-peptidic NK-1-receptor antagonist. The duration of the antagonistic effect of sendide was longer than that of CP-96, 345. The behavioral response elicited by other NK-1-receptor agonists, septide, physalaemin and [Sar9, Met (O2)11]-SP, was reduced significantly by a small dose of sendide. In the [3H]-SP binding assay using mouse spinal cord membranes, sendide potently displaced [3H]-SP binding, with a potency approximately 5.4×104 times greater than that of CP-96, 345. Moreover, Lt. administration of sendide was found to produce the antinociceptive effect through the blockage of NK-1 receptors in the mouse formalin and capsaicin tests. Sendide is therefore likely to become a powerful pharmacological tool for studying the functional roles of NK-1 receptors in the central nervous system.
  • 橋本 修二
    1997 年 110 巻 6 号 p. 325-332
    発行日: 1997年
    公開日: 2007/01/30
    ジャーナル フリー
    Problems of multiple comparison were discussed without assuming technical knowledge of statistics. For the first question concerning why to use multiple comparison procedures, theoretical bases of statistical inference and multiple comparison (including type I error rate and familywise error rate) were briefly outlined. For the second question concerning how to properly use multiple comparison procedures, multiple comparison procedures were introduced, and their characteristics were compared. Families of comparisons are different among Dunnett's, Tukey's and Scheffe's tests. Assumptions of dose-response relationship are different among Dunnett's, Williams' tests and linear regression analysis. Duncan's test does not control familywise error rate at a fixed level. For the last question concerning what is remarked for multiple comparison, approaches to several problems such as abnormality and heteroscedasticity were provided. Philosophy and strategy to multiple comparison problems were discussed.
  • 吉村 功, 大森 崇
    1997 年 110 巻 6 号 p. 333-340
    発行日: 1997年
    公開日: 2007/01/30
    ジャーナル フリー
    This paper considers the method of data analysis for a pharmacological experiment with multiple dose groups, in which a response variable is observed repeatedly at several time periods. The inappropriateness of conventionally used statistical methods such as the t-test, Dunnett's multiple comparison procedure and analysis of variance method is pointed out. We recommended that the dose-response relationship should be estimated as a response function of time incorporating the dose effect as parameters. We also propose to adopt a strategy that the researcher tests some hypotheses on the parameters in the response function appropriate to the objective of the experiment after estimating parameters of the response function based on the observed data. A numerical example applying the strategy to real data is presented.
  • 松本 一彦
    1997 年 110 巻 6 号 p. 341-346
    発行日: 1997年
    公開日: 2007/01/30
    ジャーナル フリー
    The cumulative chi-squared statistic has been proposed for testing against ordered alternatives in various statistical models. As usual statistical tests of ordered column categorical data, the χ2 test, Fisher's exact test and Wilcoxon test are used. Pharmacological studies often are performed by multiple dosing. Data obtained from these studies are called ordered categorical data. The cumulative chi-squared statistic, which has been proposed by Hirotsu and Shibuya for testing against ordered alternatives in various statistical models, is little used in spite of its good applicability in the field of pharmacology. This method was too difficult for the general pharmacologist and biological scientists because it requires the use of a complex matrix and a powerful computer to carry out the analysis. However since a more simple method was proposed by Matsumoto and Yoshimura this method has been used more frequently in the biological sciences. In this paper, the one way cumulative chi-squared statistic test and two way chi-squared statistic test are compared with the chi-squared statistic test and Wilcoxon test.
  • 吉岡 三四, 王 宝禮, 大浦 清
    1997 年 110 巻 6 号 p. 347-355
    発行日: 1997年
    公開日: 2007/01/30
    ジャーナル フリー
    歯周病原因菌と言われるPorphyromonas gingivalis (P.gingivalis)由来プロテアーゼ(Arg-gingipain)のヒト歯根膜線維芽細胞の接着分子への影響を検討した.本実験では,P. gingivalis上清から43kDaのトリプシン様活性をもつArg-gingipainを分離精製し,24時間歯根膜培養細胞を刺激した.形態学的観察から16時間目より細胞は足場を失い浮遊し球状化し始めた.MTTアッセイによる細胞増殖率の判定では12時間目に上昇しその後減少した.また,細胞中のフィブロネクチン量は12時間目に上昇しその後減少した.歯根膜線維芽細胞はフローサイトメーターによって接着分子であるICAM-1 (inter-cellular adhesion molecule-1; CD54),VCAM-1(vascular cell adhesion molecule-1; CD106), VLA-4 (very late antigen-4; CD49d/cd29)の発現が認められた.これらの接着分子の発現は12時間目から16時間目まで上昇しその後下降した.以上の結果よりプロテアーゼの刺激は経時的に細胞に影響を与えることが形態的観察で明らかになった.本実験の培養条件下では,16時間で歯周病原因菌由来プロテアーゼが歯根膜線維芽細胞のフィプロネクチン量を減少させたがICAM-1,VCAM-1,VLA-4の発現が元進するという興味深い知見を得た.実際の口腔内では歯周組織破壊には歯周病原因菌が深く関与し炎症の緩解と増悪を繰り返しながら進行していく.本実験系から,細菌性プロテアーゼであるArg-gingipainによる急速な細胞破壊に至る過程で,細胞外マトリックスの破壊による細胞の接着能の減少が示されたことから,細胞の防御機構としてこれら接着分子発現の増強は減少した細胞一細胞外マトリックス間の接着を補うことが考えられる.あるいは,発現が亢進されてこれら細胞接着分子が細菌の細胞への付着能の増強に介在していることが考えられる.
  • 楠 淳, 荒金 克己, 北峰 哲也, 山浦 哲明, 大西 治夫
    1997 年 110 巻 6 号 p. 357-365
    発行日: 1997年
    公開日: 2007/01/30
    ジャーナル フリー
    シャーレ上に培養したヒト腸上皮細胞株Caco-2を用いて,14C-オレイン酸のコレステロールエステル(CE)への取り込みを指標としたacyl-CoA:cholesterol acyltransferase(ACAT)活性を測定し,本活性に対するACAT阻害薬,F-1394並びに類似薬の阻害作用を比較検討した.F-1394は本細胞のACAT活性を濃度依存的に阻害し,その50%阻害濃度(IC50値)は71nMと算出された.他のACAT阻害薬であるYM-17E,CI-976,CL-277,082およびDL-melinamide並びにシンバスタチンの本活性に対するIC50値は,それぞれ,121nM,702nM,21.5μM,20.9μMおよび22.5μMと算出された.また,プラバスタチン,プロブコール及びクロフィブレートは本活性にほとんど影響を与えなかった.さらにCaco-2細胞をフィルター上に培養し,tightjunctionを形成させた小腸粘膜モデルを用いて,漿膜側へのCE分泌に対するF-1394の作用を検討したところ,F-1394は,漿膜側培養液へのCE分泌を濃度依存的に抑制した(F-1394 100nMでの抑制率;90%).以上の成績から,ACAT阻害薬F-1394は,細胞膜機能を有するACAT活性測定系においても,類似薬に比して強力に本活性を阻害することが明らかとなり,ヒト小腸粘膜においてコレステロール吸収を抑制することが示唆された.
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