日本薬理学雑誌
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
105 巻 , 5 号
選択された号の論文の12件中1~12を表示しています
  • 松本 章
    1995 年 105 巻 5 号 p. 273-283
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    The effect of cell environment on obsteoblastic function was described in this review article. Hypocalcemia, hypocalcified dentin and inhibition of bone formation were demonstrated in rats fed a low calcium diet. These phenomena led us to hypothesize that a low-calcium environment must be one of the important factors to induce the inhibition of bone formation. This proposed mechanism was verified in an in vitro experiment. In the rat neonatal femur cultured in a lowcalcium medium, the head size of the femur, full longitudinal length of the femur and total hexosamine content increased. Alkaline phosphatase activity, chondroitin sulfate synthesis and DNA synthesis activity increased, but proline synthesis activity decreased. In the calvarial bone cells, the total calcium, IP3 contents and PKC activity decreased, but the sensitivity of the cell membrane to a stimulation was enhanced. In mouse osteoblastic MC3T3-E1 cells, c-fos mRNA expression increased after the treatment with fetal bovine serum (FBS) or epidermal growth factor (EGF), and the degree of increase was highest with the 30-min treatment period in both FBS and EGF-treated cells. The expression was significantly higher in the low Ca group as compared to the control group (P<0.01). From these results, it was suggested that tha femur and osteoblasts react to restore the normal cell function against a low-calcium environment, the mediating and intracellular signal transduction system, and a transcriptional activity at the gene level.
  • 篠田 壽
    1995 年 105 巻 5 号 p. 285-294
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Bisphosphonates have a P-C-P bond instead of the P-O-P bond of inorganic pyrophosphate that makes them resistant to enzymatic degradation and gives them a high affinity for hydroxyapatite. They are potent blockers of osteoclastic bone resorption and have been successfully used to treat metabolic bone diseases that involve increased bone resorption. It is possible to synthesize a variety of bisphosphonates by substituting the hydrogen on the carbon atom. The pharmacological characteristics and activity varies greatly from compound to compound, ranging from 1 to 10, 000. Some structure-activity relationships have been found, but no clear-cut one has been established yet. There is a general consensus that the inhibition of bone resorption by bisphosphonates is not caused by the inhibition of dissolution of the hydroxyapatite crystal, but is actually caused through a cellular mechanism that is not completely understood. In the present review article, the possible mode of bisphosphonate action was discussed with special reference to: (1) whether bisphosphonates inhibit the function of mature osteoclasts directly or through osteoblasts and (2) whether bisphosphonates inhibit the proliferation or differentiation of osteoclast progenitors to osteoclasts.
  • 川口 充, 山岸 久子
    1995 年 105 巻 5 号 p. 295-303
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Investigators have demonstrated many types of receptors or acceptors for endogenous substances in salivary glands. These suggest that salivary glands contain receptive systems for many drugs. These receptors can be classified into three types based on the property of saliva secretion: (1) receptors involved in fluid secretion, (2) receptors involved in exocytosis for the protein secretion, (3) receptors involved in both types of secretion. The receptors involved in fluid secretion include the group of α1B, M3, NK-1 receptors coupled with IP3; the group of β2 and VIP receptors coupled with cAMP; and the group of P2Z and P2U receptors coupled with the ATP-gated calcium channel. Whereas α1A, β1, VIP, M3, insulin and H2 receptors mediate exocytosis via the cAMP-proteinkinase A pathway. Moreover, the another pathway of diacylglycerol-proteinkinase C has also been demonstrated to be involved in the exocytosis occurring via NK-1 and M3 receptors. Thus, salivary gland cells have many kinds of drug-receptor system. These receptors are all positive to fluid and/or protein exocytosis. Recently our study on the inhibitory regulation of saliva secretion have suggested the existences of GABA and the GABA-synthetic/metabolic pathway, GABA(A) receptors and benzodiazepine (BDZ) receptors of both central and peripheral types, and furthermore, the coupling of GABA(A) and the central type of BDZ receptors. These receptors are involved in decreasing fluid secretion and amylase release elicited by secretagogues. In the future, mechanisms of the intracellular transduction elicited by BDZ or GABA must be clarified.
  • 小椋 秀亮, 大谷 啓一
    1995 年 105 巻 5 号 p. 305-318
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    This review described the effects of several drugs on the formation and the resorption mechanism of tooth and bone. The enamel formed during high fluoride exposure showed marked hypocalcification, and the organic substances appeared on the incisors in these regions. Such changes following fluoride administration appear to indicate an inhibition of the mineral deposition and/or an inhibition of organic matrix withdrawal. The successive bisphosphonate (HEBP) injections reduced both the progress of the mineral deposition and the formation of the enamel matrix. Colchicine showed a remarkable inhibitory effect on the matrix-forming cells of the dentin and enamel in teeth through its striking inhibitory action on the cytoskeletal system and secretary function. The dentin formation in rabbit and rat incisor dentin was reduced markedly. Colchicine induced reparative dentinogenesis in dental pulp and ectopic calcification in the bone marrow. Both sodium salicylate and aspirin reduced dentin formation through a mechanism that reduces the incorporation of collagen precursors into odontoblasts. Sodium salicylate also inhibited the growth of the upper jaw and tibia in rats. The recruitment of osteoclast-like multinucleated cells was inhibited by sodium salicylate in vitro. A pharmacological approach for studying the formation and resorption mechanism of hard tissue is useful tool for developing hard tissue research.
  • 大浦 清, 篠原 光子
    1995 年 105 巻 5 号 p. 319-329
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    ODU Plaque-susceptible rats (ODUS/Odu) exhibit markedly heavy plaque formation in the lower incisors and develop both periodontal pockets and gingivitis after being fed a commercially available powder diet. These rats have been established as an inbred strain. We have demonstrated that the ODUS/Odu are a very suitable experimental model for studying periodontitis. We already reported about the allelic distribution, changes of plaque formation and body weight, biochemical nature, toxic activity, vascular permeability factor and bradykinin inactivating factor of the plaque, histological and immunological studies, the pH in the periodontal pocket, amount of saliva, IgA in the saliva, salivary kallikrein, the relationship between sialic acid in the saliva and the serum, leukocyte functions (chemotaxis and superoxide anion) in ODUS/Odu, histamine, mast cell, free radicals, superoxide dismutase activities in gingiva and gingival nerve fibers with substance P or calcitonin gene-related peptide, and effect of diabetes. Streptozotocin-induced diabetic ODUS/Odu may be a useful tool for studying the pathological mechanisms in the development of periodontal tissue breakdown in diabetes. ODUS/Odu should help to further establish the utility of this strain as a model for experimental periodontal disease.
  • 松本 昌世, 戸苅 彰史
    1995 年 105 巻 5 号 p. 331-343
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    In this study, we introduce a cultivation method for mandibular first molars from mouse embryos. We also investigate the in vitro effects of several drugs on tooth formation. Histological observations demonstrated that the tooth germ dissected from 17-day-old embryonic mice and cultivated for 7 days under the conditions described here showed clear mineralization in the dentin and enamel. Alkaline phosphatase (ALP) activity and calcium content in the tooth germ increased developmentally during 7-day cultivation. The increase of calcium was preceded by that of ALP in the germ. The removal of ALP attached covalently to the external surface of plasma membranes by phosphatidylinositol specific phospholipase C disturbed in vitro mineralization in the tooth germ, suggesting that ALP functioning as an ectoenzyme is involved in the physiological process of tooth formation. To elucidate the effects of calcium regulating hormones and several drugs on tooth mineralization, ALP and calcium content were measured and also the tooth germ was observed histologically. The results obtained from the present study suggest that this in vitro system provides a useful tool for investigating both the direct action of drugs on tooth formation and the mechanisms of drug action.
  • 山本 健二
    1995 年 105 巻 5 号 p. 345-355
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Progressive periodontal disease is characterized by acute progressive lesions of gingival connective tissues, excessive leukocyte infiltration, and occurrence of a characteristic microflora. A variety of proteolytic enzymes derived from oral bacteria and host cells are found in gingival crevices and thought to play an important role in the onset and development of progressive periodontal disease. The anaerobic bacterium Porphyromonas gingivalis has been implicated in the etiology of the disease. Recently, we have purified a novel arginine-specific cysteine proteinase, termed “argingipain”, from the culture supernatant of the organism. The enzyme was shown to have two important abilities related to the virulence of the organism. One is direct association with periodontal tissue breakdown through its abilities to degrade physiologically important proteins such as human collagens (type I and IV) and to evade inactivation by internal protease inhibitors. The other is associated with disruption of the normal host defense mechanisms through its abilities to degrade immunoglobulins and to inhibit the bactericidal activity of polymorphonuclear leukocytes. The virulence of argingipain was further substantiated by disruption of argingipainencoding genes on the chromosome by use of suicide plasmid systems. On the other hand, we have studied roles of host cell-derived proteinases in the periodontal tissue breakdown. Levels of lysosomal proteinases such as cathepsins B, H, L, G and medullasin were determined in gingival crevicular fluid from periodontitis patients and experimental gingivitis subjects by activity measurement and sensitive immunoassay. The results suggested that all of these enzymes would be involved in the development of both gingivitis and periodontitis.
  • 古林 伸二郎, 木村 郁子, 木村 正康
    1995 年 105 巻 5 号 p. 357-363
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    To study the sites of action of cytokines and anti-angiogenic agents, bioassays have been developed to systematically investigate not only the entire process of angiogenesis in vivo but also its individual steps including capillary tube formation and proliferation of vascular endothelial cells (EC). Angiogenesis in vivo is quantitatively assayed by measuring the carmine dye content in Freund's complete adjuvant-induced mouse pouch granuloma after the intravenous administration of dye solution. Angiogenesis in vitro is quantified by counting the number of microvessels developed from blood vessels cultured in fibrin gel. Tube formation is quantitatively estimated by measuring the total length of capillary tubes from EC cultured in type I collagen gel. EC proliferation is assayed by measuring both the increase in cell number and 3H-thymidine incorporation into the cells. The competence and progression activities in the EC proliferation are analyzed by our convenient method. By these bioassays, the mechanism of an anti-differentiation agent can be easily clarified to develop new types of therapies for rheumatoid arthritis and diabetic retinopathy.
  • 山原 條二, 松田 久司, 下田 博司, 割石 紀子, 矢木 信博, 村上 啓寿, 吉川 雅之
    1995 年 105 巻 5 号 p. 365-379
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    ツンベルギノールAのI~IV型アレルギ―に対する作用を検討した.ツンベルギノールAは,I型アレルギーモデルのラットおよびマウスの受身皮膚アナフィラキシー反応(PCA反応)に対し,反応惹起2時間前の300mg/kg以上および50mg/kg以上の経ロ投与で,それぞれ有意に抑制した.また,IgE受動感作ラットの気道狭窄反応に対しても,300mg/kg以上の経ロ投与で有意(P<0.05)な抑制効果を示した.一方,in vitroにおいて,IgE受動感作ラット気管標本およびIgG受動感作モルモット肺切片の,抗原刺激による収縮反応をそれぞれ濃度依存的(10-7~10-4および10-5~10-4M)に抑制し,さらに感作ラット腹腔滲出細胞からのヒスタミン遊離に対しても,濃度依存的(10-5~10-4M)な抑制効果を示した.また,ケミカルメディエーターに対する拮抗作用として,マグヌス法およびマウス耳介血管透過性充進モデルを用いた検討で,シプロヘプタジンの1000分の1程度のごく弱い抗セロトニン様作用が認められた.ツンベルギノールAは,II型アレルギーの逆皮膚アナフィラキシー反応(RCA反応),III型アレルギーのアルサス反応を抑制しなかったが,IV型アレルギーモデルのマウス接触性皮膚炎の一次反応を,免疫翌日から反応惹起までの1日1回(100mg/kg)の経口投与で有意(P<0.01)に抑制した.また,マウス遅延型足浮腫反応に対しては,反応惹起直前と8時間後の2回経口投与(300,500mg/kg)で有意(P<0.01)な抑制効果が認められた.以上の結果より,ツンベルギノールAは,I型アレルギーに対して経口投与で有効で,その作用は肥満細胞からの脱穎粒の抑制と弱い抗セロトニン様作用に基づく可能性が考えられた.また,IV型アレルギーに対しても有効性が示唆された.
  • 福田 行男, 神谷 哲朗, 刀禰 寛, 安藤 正知, 北山 隆, 西澤 義則, 萬 秀憲, 土屋 秀一, 芋川 玄爾
    1995 年 105 巻 5 号 p. 381-388
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    3-octhylphthalide(NY-008)の血管平滑筋弛緩作用について,ラット摘出大動脈リング標本を用いて検討を行った.3×10-5MのNY-008は,10~70mMの塩化カリウム(KC1)収縮を抑制した.またNY-008は60mMのKCI収縮を濃度依存的に抑制し,そのIC50値は(6.17±1.75)×10-6Mであった.さらにNY-008は,10-6Mのノルエピネフリン(NE)による持続性収縮を10-6~10-4Mの範囲で濃度依存的に最大90.0±2.86%抑制し,そのIC50値は(2.06±0.38)×10-5Mであった.ベラバミルは10-6MのNEによる持続性収縮を10-8~3×10-6Mの範囲で濃度依存的に最大55.9±5.56%抑制した.また3×10-5Mおよび10-4MのNY-008は,Ca2+除去栄養液中での10-6MのNEによる相動性収縮を,それぞれ22.4±3.69%,35.4±5.74%抑制したが,3×10-7Mのベラバミルはこの収縮を抑制しなかった.あらかじめ60mMのKClで脱分極させた血管での塩化カルシウム(CaCl2)による収縮において,NY-008は濃度依存的にCaCl2に対する最大反応を抑制すると同時にCaCl2のED50値を増加させたが,ベラバミルはCaCl2に対する最大反応を抑制せずにCaCl2のED50値を濃度依存的に増加させた.10-5~3×10-4MのNY-008は,Ca2+除去栄養液中における10-5MのプロスタグランジンF(PGF)による収縮を濃度依存的に抑制したが,10-7~10-5Mのベラバミルはこの収縮を抑制しなかった.以上,NY-008の血管弛緩作用は,Ca2+に対する拮抗作用によることが明らかになった.さらに,Ca2+除去栄養液中でのPGFによる収縮に対する抑制作用から血管平滑筋の細胞内Ca2+に対する感受性の低下作用あるいは収縮タンパクの抑制作用の関与が示唆された.
  • 渡辺 正義, 尾崎 孝幸, 平田 佳久, 吉国 義明, 木村 喜代史, 鈴木 一幸, 佐藤 俊一
    1995 年 105 巻 5 号 p. 389-402
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    実験的高アンモニア血症モデルとして,Eck痕犬[門脈・大静脈吻合(PCS)犬]を作成し,血中および髄液中のアンモニアおよびアミノ酸濃度に対するラクチトールの作用をラクツロースと比較検討した.Eck痩作成3週目より被験薬物を4週間反復胃内投与し,投与開始後2週および4週目に採血と髄液採取を行った.対照群では,薬物投与開始前において静脈血,動脈血および髄液のアンモニア濃度が,術前に比べ明らかな高値(静脈血,2.84倍;動脈血,2.95倍および髄液,5.26倍)を示し,以後も漸増した.血漿アミノ酸分析では,肝硬変患者やPCS動物に特徴的な分枝鎖アミノ酸濃度[バリン(Val),ロイシン(Leu),イソロイシンおよびこれらの和(BCAA)]の低下と,芳香族アミノ酸(フェニールアラニン,チロシン),これらの和(AAA)およびトリプトファン(Trp)濃度の増加が認められた.また,髄液においては芳香族アミノ酸,AAA,グルタミン(Gln),Trpおよびグルタミン酸の増加が顕著であった.一方,ラクチトールは静脈血,動脈血および髄液のアンモニア濃度上昇を用量依存的に抑制し,1および3g/kg/dayでの作用は有意なものであった.また,ラクチトールは3g/kg/day4週間投与で,対照群に比べ,血漿中Trp濃度ならびに髄液中Va1,Leu,BCAA,芳香族アミノ酸,AAAおよびGln濃度を有意に低下させた.ラクチトールのこれらの作用はラクツロースの同用量においてほぼ同程度認められた.以上,ラクチトールはラクツロースと同様に肝性脳症発症に関与している血中および髄液中アンモニアならびに髄液中芳香族アミノ酸の濃度を低下させたことから,高アンモニア血症および肝性脳症の治療剤として期待される.
  • 渡辺 正義, 尾崎 孝幸, 莚井 武, 鵜飼 洋司郎, 上田 房雄, 木村 喜代史, 加藤 正巳, 松本 敦也, 古谷 恵美, 伊藤 小枝, ...
    1995 年 105 巻 5 号 p. 403-413
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    実験的慢性肝性脳症モデルとしてEck痩(門脈・大静脈吻合)犬を作成し,ラクチトールの肝性脳症改善効果を行動,脳波および視覚誘発電位を指標に検討した.Eck痩作成3週目よりラクチト―ルを1日1回,12週間反復胃内投与し,2週毎に行動,脳波および視覚誘発電位を観察,記録した.対照群ではEck痩作成後,時間経過とともにぽんやり状態,動作緩慢状態および昏迷状態を示した後,昏睡状態にまで進行し,死亡する例もみられた.脳波も,時間経過に伴って低振幅徐波化し,ほぽ完全に平坦化する例もみられた.また,視覚誘発電位では各コンポーネントの潜時の延長および振幅の増加傾向が認められた.これに対して,ラクチトール1および3g/kg/dayは対照群でみられた行動異常や脳波および視覚誘発電位の変化をいずれも著明に改善した.以上の結果より,ラクチトールは実験的慢性肝性脳症による多彩な精神神経症状を改善する作用を有することが示唆された.
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