巻号一覧
106 巻 (1995)
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前身誌
106 巻, supplement 号
選択された号の論文の48件中1～48を表示しています
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大塚 正徳1995 年 106 巻 supplement 号 p. 1-4
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーThe mammalian nervous system contains 3 main tachykinins, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), and 3 subtypes of tachykinin receptors, NK1, NK2 and NK3. There is persuasive evidence that SP and NKA act as neurotransmitters in mammalian central and peripheral nervous systems. The possibility of development of new drugs related to tachykininergic signalling will be discussed, comparing with the opioid peptide-mediated signalling. Concerning the opioid peptides, a large field of narcotic analgesics had been developed since long time ago, which was one of the hints leading to the recent discovery of opioid peptides and receptors. In contrast, tachykinins and their receptors were found recently, and attempts for the drug development are just starting. The amounts of tachykinins in mammalian CNS are comparable to those of opioid peptides, and 3 subtypes of receptors are known for both tachykinin and opioid systems, which suggests that the tachykininergic signalling in mammalian nervous system may be as important as the opiopid-mediated signalling. Therefore, we may expect that many useful drugs related to tachykinins may develop for therapeutics of pain, inflammation, central and visceral dysfunctions.抄録全体を表示PDF形式でダウンロード (3655K) -
友池 仁暢1995 年 106 巻 supplement 号 p. 5-7
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーStrategies of diagnosis and management in patients with cardiovascular diseases has been improved by experience and knowledge in various fields of science, including hematology, immunology, endocrinology, biochemistry, pharmacology, genetics, engineering, etc. Ischemic heart disease has been a number-one killer in the Western countries, which forced physicians and basic scientists to understand the pathophysiological events and to advance technologies related to remedies of this disease. The trend of prevalence of cardiovascular diseases in Japanese and the rational bases for deciding new remedies will be discussed.抄録全体を表示PDF形式でダウンロード (2768K) -
日高 弘義1995 年 106 巻 supplement 号 p. 8-13
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーSignal transduction is essential for life. In living cells, several signal transduction pathways interact with each other to form complicated signal network. Second messengers, such as Ca2+, cAMP and cGMP, play fundamental roles in the cellular responses via binding to their target proteins. Recent advances in signal transduction research enables us to design more specific and selective inhibitors of a certain signaling molecule or pathway. Specific inhibitors (molecular probes) of the signal transduction pathway, once identified, will be of vital importance to pharmacological intensive experiments, and also to clinical applications, that is “signal transduction therapy”. For example, Ca2+/ calmodulin-dependent protein kinases (CaM kinases) are involved in a variety of cell functions including regulation of gene expression and cell cycle via phosphorylation of CREB and cdc25 (a p34cdc2 phosphatase), respectively. Furthermore, a derivative of CaM kinases inhibitors has been proved to be clinically available. Pharmacological and molecular biological approaches on protein kinases will become more and more powerful strategy not only to investigate the signal transduction systems but to create novel remedies. The first aim of this presentation is to highlight recent findings in Ca2+ signaling. The other aim is to discuss the usefulness of specific protein kinase inhibitors (KN-62 and its derivatives), with introducing the first example of “Signal transduction therapy”.抄録全体を表示PDF形式でダウンロード (4398K) -
渡邉 建彦, 谷内 一彦, 大津 浩1995 年 106 巻 supplement 号 p. 14-19
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーHistamine is an important chemical mediator involved in type I allergic diseases (such as ulticaria, allergic rhinitis and bronchial asthma) and digestive ulcers (such as gastric and duodenal ulcers). These diseases are very popular, and thus researches aimed to elucidate a series of events from the stimulation to the response in taget organs are worthwhile to develop potential and safe drugs against diseases mentioned above. The possible tagets for drug development with astham as an example involves the six points: (1)suppression of IgE production, (2)blockade of IgE binding to IgE receptors on mast cells, (3)inhibition of histidine deacarboxylase, a histamine-forming enzyme, (4)inhibition of histamine release from histamine-storing cells like mast cells and basophils, (5)blockade of binding of histamine to histamine receptors, and (6) antagonism of the reaction evoked by histamine in taget organs. The currently used drugs are disodium cromoglycate or theophylline, HI blockers and adrenaline in points (4), (5) and (6), respectively, and steroid hormones. We reviewed and discussed our studies on histamine in relation to the series of events from stimulation to response. We also suggested possible newer tagets such as genetic control of expression of histidine decarboxylase in specific sites, H3 receptors and histamine N-methyltransferase.抄録全体を表示PDF形式でダウンロード (4623K) -
加藤 隆一1995 年 106 巻 supplement 号 p. 20-22
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーAlthough many new chemical entities have been put into therapeutic drug market in Japan, innovative drug discovery from Japanese pharmaceutical industries is poor.
Author divided innovative drug discovery sciences into two phases: The first phase consist of discovery of seed compound and development of lead compound from seed compound. The second phase consist of development of therapeutic drug from lead compound. Strategic drug metabolism studies and toxicological studies are indispensable for rescue of toxicologically and pharmacokinetically difficult compounds. The author emphasize the importance of development of sciences for the second phase for innovative drug discovery. The author also pointed out the necessity of colaborations among universities, industries and regulatory agent for the promotion of innovative drug discovery.抄録全体を表示PDF形式でダウンロード (2462K) -
芳賀 達也, 郭 政東, 中村 史雄, 加藤 真理子, 芳賀 和子, 亀山 仁彦, 津賀 浩史1995 年 106 巻 supplement 号 p. 23-28
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーPDF形式でダウンロード (5821K) -
市川 厚, 根岸 学, 杉本 幸彦1995 年 106 巻 supplement 号 p. 29-34
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe reviewed the recent advances in the molecular characterization of prostanoid receptors. Prostanoids exert versatile actions in diverse tissues and cells through specific cell surface receptors. Molecular biological studies revealed the primary structure of eight types and subtypes of prostanoid receptors from various species. In mouse, these include the thromboxane A2 receptor (TP), prostacyclin receptor (IP), prostaglandin(PG)F receptor (FP), PGD receptor and four subtypes of PGE receptors (EP1, EP2, EP3 and EP4). In addition, at least three isoforms of PGE receptor EP3 subtype have been identified. They are produced through alternative RNA splicing from a single gene and differ only in their carboxy-terminal tails. These isoforms differ in the efficiency of G protein activation, in the specificity of coupling to G proteins or in sensitivity to desensitization. The IP, EP2, EP4 and DP receptors are coupled to stimulation of adenylate cyclase, the TP, EP1, and FP receptors are coupled to Ca2 mobilization, and EP3 receptors are coupled to inhibition of adenylate cyclase. Sequence homology among these functionally related receptors is higher than that between the two groups, indicating that the functionally related receptors may be localized on the near branches of evolution tree. The conserved sequences of the receptors may involve counter binding sites for the groups of prostanoid structure such as an α-carboxylic acid, a hydroxy group at position 15, and two aliphatic side chains. Among these sequences, the arginine residue in the seventh transmembrane domain, was proposed to be the binding site of the α-carboxylic acid of the prostanoid molecules. The molecular characterization is useful for understanding not only the diverse physiological actions of prostanoids, but the interaction between receptor structure and specific analogue.抄録全体を表示PDF形式でダウンロード (4185K) -
長尾 拓1995 年 106 巻 supplement 号 p. 35-40
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーThe signal transduction system in cardiac myocytes has been studied extensively, such as cAMP-dependent protein kinase, Ca2+- and protein kinase C pathways. Classical second messengers are cAMP and Ca2+. Here we studied the positive inotropic action and cAMP system and the mechanism of down-regulation of β-adrenoceptors. we have developed the most potent β1-adrenoceptor full agonist T-0509. The positive inotropic effect of isoproterenol, T-0509 and procatelol are correlated closely with a particulate fraction of cAMP. This shows a compartmentalized increase in cAMP levels are important for positive inotropic effects of β-adrenoceptor agonists. Prolonged infusion of T-0509 decreased the number of β-adrenoceptors and the isoproterenol-stimulated adenylyl cyclase activity. However, blockade of β-adrenoceptor binding sites by an irreversible β-adrenoceptor antagonist could not mimic the desensitization state induced by chronic administration of T-0509. This result suggested that mechanism other than down-regulation can play a significant role in the loss of responsiveness. Fundamental studies on physiological responses of β1receptor mediated transduction system in cardiac myocytes will be important for undestanding disease state such as heart failure and also discovery of novel drugs.抄録全体を表示PDF形式でダウンロード (3909K) -
飯野 正光1995 年 106 巻 supplement 号 p. 41-44
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーThe Ca2+ release activity of inositol 1, 4, 5-trisphosphate receptor (InsP3R) is biphasically dependent on the cytoplasmic Ca2+ concentration: activation near 100 nM and inhibition around 1 μM. We have found that the cytoplasmic Ca2+ concentration is not simply a modulator of InsP3R but is an indispensable factor for channel activation. The Ca2+ requirement of InsP3R places the Ca2+ release channel within a Ca2+-mediated positive feedback loop, which has been demonstrated with caged InsP3 and Ca2+. The positive feedback mechanism seems to be the important basis for the generation of Ca2+ wave in various cell types including smooth muscle cells. To further clarify the role of Ca2+ stores in the smooth muscle function, we measured the Ca2+ concentration in individual smooth muscle cells in isolated vascular tissues stimulated with perivascular sympathetic nerves using a confocal microscope. We observed in these cells Ca2+ waves/oscillations due to Ca2+ release from the stores. These results show that the Ca2+ requirement of InsP3 receptor plays an important role in the regulation of vascular contraction. They also throw new light on both pharmacological and pathophysiological studies of vascular tone.抄録全体を表示PDF形式でダウンロード (2981K) -
堅田 利明, 紺谷 圏二, 柊元 巌, 井上 晋一, 星野 真一, 櫨木 修, 高橋 勝宣, 仁科 博史1995 年 106 巻 supplement 号 p. 45-49
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーThe human cell surface antigen CD38 is a 46-kDa type II transmembrane glycoprotein with a short N-terminal cytoplamic domain and a long Cys-rich C-terminal extracellular one. Although CD38 and Aplysia ADP-ribosyl cyclase exhibit amino acid-sequence homology and both catalyze the formation of nicotinamide from β-NAD+, the other reaction products of the two enzymes are different; ADP-ribose and cyclic ADP-ribose being predominantly generated by CD38 and Aplysia cyclase, respectively. To identify the structural determinant responsible for the different reaction products, we synthesized a series of chimeric proteins between the two enzymes in COS-7 cells. Our results indicated that a limited sequence near the carboxyl terminus of CD38 plays an important role not only in the enzyme activity but also in determination of the enzyme type categorized as a hydrolase. We also investigated the intracellular signaling mediated through CD38 in HL-60 cells which had been caused to differentiate by retinoic acid (RA). Addition of an anti-CD38 monoclonal antibody (mAb) to the cells induced a rapid tyrosine phosphorylation of the cellular proteins with the molecular weights of 120, 000, 87, 000 and 77, 000. Tyrosine kinase activity in the cell lysate immunoprecipitated with anti-phosphotyrosine mAb was also stimulated after the addition of the anti-CD38 mAb. Moreover, one of the prominent phosphorylated proteins stimulated by the anti-CD38 mAb was identified as the cbl proto-oncogene product, p120c-cbl. These results indicated that tyrosine phosphorylation of cellular proteins including pl20c-cbl is possibly involved in transmembrane signaling mediated through CD38.抄録全体を表示PDF形式でダウンロード (4489K) -
唐木 英明1995 年 106 巻 supplement 号 p. 50-55
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーVascular smooth muscle contraction is regulated by various factors including membrane potential, receptor-linked signal transduction pathways, cytoplasmic Ca concentration, and Ca sensitivity of contractile elements. Vasodilator drugs are acting on either of these mechanisms to inhibit contraction. In 1922, 338 vasodilator drugs were sold in Japan. Among them, there were 67 Ca antagonists and one K channel opener. Mechanisms of action of other 270 drugs are not clarified yet (although 84 drugs increase cyclic AMP and 36 drugs increase cyclic GMP, mechanisms of action of these cyclic nucleotides are still ambiguous). To elucidate the mechanisms of vasodilator drugs will help not only to clarify the regulation mechanisms of smooth muscle contraction but also to develop new vasodilator drugs with novel sites of action including Ca sensitivity.抄録全体を表示PDF形式でダウンロード (5273K) -
倉智 嘉久1995 年 106 巻 supplement 号 p. 56-60
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe have cloned five distinct types of inward-rectifying K+ channels with two putative transmembrane regions from mouse and rat brain cDNA libraries. We designated these novel clones as MB-IRK1, MB-IRK2, MB-IRK3, MB-GIRK1 and KAB-2. Xenopus oocytes injected with cRNAs for MB-IRKs and KAB-2 elicited background K+ currents, which showed the classical inward-rectifying K+ characteristics at the whole cell current level and were blocked by Ba2+ and Cs+ in a concentration- and voltage-dependent manner. The single channel recordings revealed that the unitary conductance of MB-IRKI was ?? 22 pS; MB-IRK2, ?? 35 pS; MB-IRK3, ?? 12 pS; MB-GIRK1 which was activated by Gβγ, ?? 35 pS; and KAB-2, either ?? 15 pS or ?? 30 pS with 150 mM [K+]o. Distribution of mRNAs for the clones was examined by Northern blot analysis and in situ hybridization technique. MB-IRKI mRNA was detected strongly in forebrain, heart and skeletal muscle, and less in cerebellum, but not in kidney. MB-IRK2 mRNA was detected strongly in cerebellum and less in other previously described organs. MB-IRK3 mRNA was detected specifically in forebrain. MB-GIRK 1 mRNA was detected strongly in forebrain, cerebellum and heart, and less in skeletal muscle, but not in kidney. KAB-2 mRNA was detected strongly in forebrain and cerebellum, less in kidney, but not in heart or skeletal muscle. In situ hybridization showed mRNAs for the clones to be expressed in a variety of regions throughout the brain. These results indicate that the clones of inward-rectifying K+ channels with two putative transmembrane regions may play heterogeneous functional roles in various organs and provide a tool for future development of novel therapeutic strategies of various diseases.抄録全体を表示PDF形式でダウンロード (3743K) -
大泉 康1995 年 106 巻 supplement 号 p. 61-66
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーIn the course of our study on bioactive substances from marine organisms we found that eudistomin D derivatives isolated from the Caribbean tunicate Eudistoma olivaceum exhibited Ca releasing activities in skeletal muscle sarcoplasmic reticulum(SR). Our structure-activity relationship studies on eudistomin D derivatives indicate that bromoeudistomin D and 9-methyl-7-bromoeudistomin D are approximately 500 and 1, 000 times more potent than caffeine with regard to Ca releasing activity. Furthermore, we have successfully found that 4, 6-dibromo-3hydroxycarbazole, one of these analogues is a novel type of Ca release channel inhibitors.
3H-MBED bound to the HSR in a replacable and saturable manner, indicating the existence of its specific binding site. Caffein competitively inhibited the 3H-MBED binding to SR, suggesting that MBED shares the same binding site as that of caffeine.
Myotoxin a (MYTX) has been found to induce Ca2+ release having novel properties. 125I-MYTX specifically bound to a single class of binding sites in SR. MYTX may binds to an important regulatory protein or channels of Ca release, which is not the ryanodine receptor, leading to Ca2+ release from HSR.
We have found that gingerol, xestoquinone and goniodomin A dramatically modified the functions of Ca2+ pump (Ca2+-ATPase), myosin and actin, respectively, isolated from skeletal muscle to increase muscle contractility and have proven to be a valuable pharmacological tools for studies on muscle contraction.抄録全体を表示PDF形式でダウンロード (3636K) -
木村 永一, 小山田 正人, 森 道夫, 大鹿 英世1995 年 106 巻 supplement 号 p. 67-71
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe studied the expression and localization of the major cardiac gap junction protein connexin 43 (Cx43) during the establishment of a synchronized contraction in confluently cultured neonatal rat cardiac myocytes, combined with a functional assay of gap junctional intercellular ccaniunication (GJIC) by using the microinjection-dye transfer method. We analyzed, by Fotonic Sensor, effects of heptanol on synchronized contraction of primary neonatal rat cardiac myocytes cultured at confluent density. We also examined the effect of heptanol on the changes in GJIC, on the expression and localization of Cx43, and on intracellular Ca2+ fluctuations by confocal laser scanning microscopy of myocytes loaded with the fluorescent Ca2+ indicator fluo 3.
Monitoring of the beating rate and synchronization by Fotonic Sensor showed that the contractile rate increased with culture time, and that a synchronized contraction was gradually formed. GJIC was also increased with culture time and correlated well with the total area of Cx43-positive spots and the amount of Cx43 protein. At day 6 of culture, numerous myocytes exhibited spontaneous, synchronous contractions, excellent dye coupling and synchronized intracellular Ca2+ fluctuations. At the concentrations of 2.0 and 2.5 mmol/L, heptanol reversely inhibited synchronized contraction, WIC and synchronization of intracellular Ca2+ fluctuations in the myocytes without preventing contraction and changes of intracellular Ca2+ in individual cells. Brief exposure (5-20 min) to heptanol (2.0 mmol/L) did not cause detectable changes in the expression and localization of Cx43, despite strong inhibition of WIC. These results suggest that GJIC plays an important role in synchronous intracellular Ca2+ fluctuations, which facilitate synchronized contraction of cardiac myocytes.抄録全体を表示PDF形式でダウンロード (4415K) -
渡邊 博之, 飯島 俊彦1995 年 106 巻 supplement 号 p. 72-76
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーBlock of L-type Ca channels by highly hydrophilic dihydropyridines, NKY-722 and KV-1360, was investigated in single ventricular cells of guinea-pig hearts using the whole-cell voltage clamp technique. At a holding potential of -30 mV, NKY-722 (1-100 nM) decreased the amplitude of the L-type Ca channel current (ICa) in a concentration-dependent manner. NKY-722 did not change time constants of the decay of ICa. In the presence of NKY-722 (1 μM), the steady-state inactivation curve was shifted toward a more negative potential (by minus;33.0 ± 2.0 mV) without changing its slope factor. The use-dependent block was elicited at pulse frequency of 3.3 Hz or more. Even after washing out the drug at -80 mV for 20 min, ICa inhibited by NKY-722 (100 nM) at -30 mV was scarcely recovered when the membrane potential was clamped back to -30 mV. A permanently charged compound KV-1360 (0.1-1 μM), a quaternary amine derivative of NKY-722, hardly affected ICa by intracellular and extracellular application. These results suggest that, in spite of the high degree of ionization (91 % in the charged form at pH 7.4), the mode of the L-type Ca channel block by NKY-722 is quite similar to that by lipophilic dihydropyridines.
Consequently, the neutral form of NKY-722 is the active compound and this reaches the dihydropyridine receptor by “membranous approach”.抄録全体を表示PDF形式でダウンロード (3739K) -
中谷 晴昭, 森 勝巳, 渡邊 泰秀, 原 幸男, 石川 稔生1995 年 106 巻 supplement 号 p. 77-79
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーAmiodarone is one of the most promising antiarrhythmic drugs to reduce likelihood of sudden cardiac death. In this study effects of amiodarone on the ligand-gated K+ channels, i.e., acetylcholine receptor-operated K+ (KACh) channels, ATP-sensitive K+ (KATP) channels and Na+-activated K+ (KNa) channels, were examined in isolated guinea-pig atrial and ventricular myocytes by patch clamp techniques. Amiodarone in therapeutic concentrations (1-10 μM) inhibited the muscarinic acetylcholine receptor-operated K+ current (IK.ACh) activated by extracellular application of carbachol or adenosine or by intracellular loading of GTPγS to a similar extent in atrial cells.
Amiodarone in similar concentrations inhibited the activity of the KATP channels in inside-out membrane patches of ventricular cells exposed to an ATP-free solution. In a similar concentration range amiodarone also inhibited the opening of the KNa channels in inside-out membrane patches exposed to a high Na+ (100 mM)-containing solution. Thus, these ligand-gated K+ channels are commonly inhibited by amiodarone in the therapeutic concentrations. The inhibitory effects of amiodarone on the ligand-gated K+ channels may play a role in the suppression of cardiac arrhythmias under pathological conditions.抄録全体を表示PDF形式でダウンロード (2596K) -
西 勝英, 頼 仲方, 劉 悉1995 年 106 巻 supplement 号 p. 80-81
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe examined effects of changes in intracellular pH and chloride ion on isolated papillary muscle of guinea-pig ventricle subjected to simulated ischemia which was induced by covering the papillary muscle preparation with mineral oil, by measuring intracellular pH using ion-selective microelectrodes and by a conventional microelectrode technique. SITS and DIDS partly prevented shortening of action potential duration(APD) and intracellular acidosis induced by simulated ischemia. DIDS significantly prevented the shortening process of APD induced by chlomakarium (10 μM). DIDS and SITS significantly depressed Na current recorded from dispersed myocytes using whole cell patch-clamp technique. Present results provided a new finding that stilben-derivatives (DIDS and SITS) possess not only blocking action on ion-transporters, but also Na current depressant action on myocardium.抄録全体を表示PDF形式でダウンロード (1303K) -
藤野 雅子, 藤野 澄子, 藤野 和宏1995 年 106 巻 supplement 号 p. 82-86
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーThe present study was done to learn the mechanism of ouabain (0.1 μM) potentiation and its relation to excitation-contraction (E-C) coupling in cardiac muscle. The fibers were prepared from frog ventricle by enzymatic and mechanical disruption. Developed tensions were measured isometrically. If fibers were immersed in Ringer (22°C) containing 5 mM phenylglyoxal (PGO) for 5 min and then washed out in normal Ringer for 30 min, E-C coupling was inhibited. Ouabain cancelled the decreased tension development. DHP (200-110) gave results quite similar to PGO. 60 min after PGO-removal, rapid cooling contracture (RCC) was weakened. Ouabain-induced acceleration of RCC occurred not only under the condition of Ca- and Na-deprived Ringer but also in PGO-treated fibers. To determine the real location of Ca-transients induced by high K, fibers were fixed by replacing the bathing fluid with a solution of 1 % OsO4 and 110 mM potassium pyroantimonate. Use of energy dispersive X-ray analyzers showed that many Ca-pyroantimonate grains existed in the region near the N-line.
In conclusion, both PGO and DHP inhibit E-C coupling due to binding to their respective, receptor proteins, PGO to electrometrin and DHP to DHP-protein. Also, ouabain accelerates the coupling due to binding to electrometrin (a new ouabain receptor protein).抄録全体を表示PDF形式でダウンロード (3929K) -
木村 郁子, 高田 美和子, 牧野 充弘, Islam, Md. A., 木村 正康1995 年 106 巻 supplement 号 p. 87-91
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe investigate the mechanisms of interaction between aconitine and higenamine (component compounds contained in processed aconite extract) for pulse rate and for chronotropy in isolated right atria of, mice. (1) Higenamine (peripherally β 1-adrenergic) enhanced aconitine-incuced tachyarrhythmia, and aconitine enhanced higenamineinduced positive inotropy in isolated right atria. (2) Aconitine (i.p. and i.c.v. injected) induced bradycardia in mice. (3) Aconitine (i.p.)-induced bradycardia was inhibited by scopolamine (s.c.), and atropine (i.c.v.), but not by hexamethonium (i.c.v.)and mecamylamine (i.c.v.). Aconitine (i.c.v.) induced bradycardia was inhibited by sooplamne and atropine (i.c.v.). (4) Aconitine (i.p.)-induced bradycardia was hardly generated in mice by the bilateral lesions of anterior hypothalamic area and by bilateral adrenalectomy. (5) In two groups of diabeticKK-CAm mice specifically bred for high and low sensitivity to acetylcholine (ACh), aconitine (i.p.) caused bradycardia, which was counteracted by higenamine (i.p.) in ACh-low sensitive but not in ACh-high sensitive mice. These results demonstrate that peripherally admnstered aconitine induces bradycardia by muscarinic mechanisms through hypothalamio-pituitary adrenal axis, which is counteracted by peripherally β1 -adrenergic higenamine.抄録全体を表示PDF形式でダウンロード (3938K) -
古川 賢一, 坂本 比呂志, 中村 英士, 大泉 康1995 年 106 巻 supplement 号 p. 92-96
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーXestoquinone isolated from an Okinawan sea sponge Xestospongia sapra inhibited both Ca2+- and K+ (EDTA)-ATPase but not Mg2+-ATPase of skeletal muscle myosin. The inhibition was abolished in the presence of dithiothreitol. However, xestoquinone unlike N-ethylmaleimide, a well-known sulfhydryl (SH)1 reagent markedly activated actomyosin ATPase. Modification of 2 moles of SH groups per myosin by xestoquinone caused a marked increase in the actomyosin ATPase activity. Kinetical analysis of stimulatory effects of xestoquinone indicates decrease in the actin concentrations which gives half of the maximum velocity (Vmax) of actomyosin ATPase reaction without affecting the Vmax, suggesting the increase in the affinity of myosin for actin. N-ethylmaleimide can modify both the SH1 and SH2 groups still after modification of 2 mole SH groups by xestoquinone. Xestoquinone modified myosin SH groups to cause a change in the fluorescence intensity of intrinsic tryptophan residues and circular dichroism. These results suggest that xestoquinone modifies the specific SH groups in myosin distinct from SH1 and SH2 resulting in activation of actomyosin ATPase. It is also suggested that xestoquinone strengthens the interaction between actin and myosin through conformational change in myosin molecule.抄録全体を表示PDF形式でダウンロード (3965K) -
守時 英喜, 久山 哲廣, 近藤 渉, 高石 喜久1995 年 106 巻 supplement 号 p. 97-101
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe examined the characteristics of Ca2+ (Ca) signaling pathway for activation of endothelial NOS, with reference to 1) Ca entry triggered by depletion of stored Ca in the endothelium, 2) Ca entry channels in response to depletion of the stores, and 3) possible involvement of tyrosine kinase in the signaling pathway. In vascular endothelium, Ca-ATPase inhibitors depletes Ca stores by inhibiting Ca pump of the stores, which in turn triggers influx of Ca and activates cNOS and NO production. The channels through which Ca enter into the endothelial cells following agonist-stimulation or Ca-ATPase inhibitors seem to be of the SK&F96365-sensitive Ca channels. However, in the case of ACh, intracellularly stored Ca in part participates in NOS activation. Tyrosine kinase may be involved in the signaling pathway for Ca entry or Ca channel mechanism, because tyrosine kinase inhibitors inhibited effects of Ca-ATPase inhibitors. Triptoquinone A which has been reported to inhibit NOS induction primed by LPS/IL-1β attenuated endothelium-dependent relaxation induced by Ca-ATPase inhibitors and agonists, possibly via tyrosine kinase inhibition.抄録全体を表示PDF形式でダウンロード (3965K) -
田中 利男, 湯淺 右人, 三野 照正, 中 充子1995 年 106 巻 supplement 号 p. 102-106
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーCalponin is a thin filament-associated smooth muscle protein that has been implicated to play a role in the regulation of smooth muscle. It inhibits actomyosin ATPase but the capacity for such inhibition is lost upon phosphorylation of calponin by protein kinase C. Thus, it seems possible that phosphorylation of calponin might modulate the contraction of smooth muscle. The objective of the present investigation was to determine whether calponin is phosphorylated by protein kinase C in intact smooth muscle in response to a vasoconstrictor and whether such phosphorylation is of functional significance with respect to the contraction of smooth muscle. Endothelin-1 and phorbol 12, 13-dibutyrate (PDBu) caused 2.3-fold and 2.6-fold increases, respectively, in tthe extent of phosphorylation of calponin during contraction of porcine coronary artery. However, high levels of KCl were ineffective despite development of an identical contractile force. These results suggest that the phosphorylation of calponin in vivo by protein kinase C might play an important role in the contraction of smooth muscle that occurs in response to endothelin-1 and PDBu.抄録全体を表示PDF形式でダウンロード (3467K) -
今泉 祐治, 邊見 智, 村木 克彦, 渡辺 稔1995 年 106 巻 supplement 号 p. 107-111
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWhen a single smooth muscle cell isolated from guinea-pig trachea was depolarized or treated with caffeine under whole cell voltage-clamp, Ca-dependent K and Cl currents (IK-Ca and ICI-Ca) were elicited. Spontaneous transient outward and inward currents (STOC and STIC) were simultaneously recorded at holding potential of -40 mV. These were IK-Ca and ICI-Ca, respectively, which were activated by spontaneous Ca release from local store sites. The time-course of activation and deactivation of these ICI-Cas was several times slower than that of corresponding IK-Cas. The slower time-course of ICI-Ca activation may be due to the involvement of signal transduction and phosphorylation of channel protein, whereas Ca-dependent K channel activity is directly regulated by [Ca2+]i. Alternatively, the Cl channel may also be directly regulated by [Ca2+]i but has much slower kinetics than the K channel. Pharmacological analyses suggest that calmodulin and related signal transduction may not be involved in the activation of ICI-Ca. It was also unlikely that activation of protein kinase A, G or C or tyrosine-kinase is primarily responsible for the channel activation. Single CI channel activity was recorded using cell-attached patch clamp from cells which were skinned by β-escin. The Cl channel had low density and large conductance (370 pS) and its activity strongly depended upon [Ca2+]i. Cytosolic large molecules may be essential for the channel activation since the activity did not run down significantly in skinned cells, whereas it did in excised patches.抄録全体を表示PDF形式でダウンロード (4047K) -
礒濱 洋一郎, 九万田 由貴江, 金丸 美由紀, 甲斐 広文, 高浜 和夫, 宮田 健1995 年 106 巻 supplement 号 p. 112-116
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーAlveolar type II cells synthesize and secrete pulmonary surfactant. Type II cells maintained on tissue culture plastic lose their diffrentiated functions and become flattened like alveolar type I cells. This phenotypic change observed in these cells in vitro has been suggested to represent differentiation of type II cells to type I cells. However, the analysis of this phenotypic progression demands specific functional markers to both cells. We have previously reported that both β1 and β2-adrenoceptors coexist in type II cells and both receptors are involved in pulmonary surfactant secretion. In some cell types the expression levels of β-adrenoceptor mRNAs change with a process of cell differentiation. In this study, therefore, we determined the levels of mRNA for β1- and β2-adrenoceptor in cultured type II cells by a quantitative RNase protection assay, developed by us.
The mRNA levels for β1 and β2-adrenoceptors in the freshly isolated cells were 0.51 ± 0.07 and 1.92 ± 0.19 amol/μg total cellular RNA, respectively. These values did not change after 24 h-culture. However, in the over 48 h-cultured cells, which failed to synthesize and secrete pulmonary surfactant, only β1 mRNA level was remarkably reduced. Dexamethasone treatment of 24 h-cultured cells caused increase in the level of β2-adrenoceptor mRNA, without changing that of β1 mRNA. These results suggest that each mRNA expression may be separately regulated in cultured alveolar type II cells. The expression levels of these adrenoceptor mRNAs may be useful as a new marker in the investigation of alveolar epithelial cell differentiation.抄録全体を表示PDF形式でダウンロード (4515K) -
小池 勝夫, 高柳 一成1995 年 106 巻 supplement 号 p. 117-121
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーβ-Adrenoceptors in the guinea pig taenia caecum were investigated. In control preparations, catecholamines caused relaxation with the following rank order of potency: isoprenaline>adrenaline>noradrenaline. However, in the presence of 10-6M phentolamine, 3×10-4M atenolol and 10-4M butoxamine, the rank order of potency of the agonist was: isoprenaline>noradrenaline>adrenaline. CGP12177 caused graded relaxation of the guinea pig taenia caecum. This response was antagonized by bupranolol and SchiId plots of the data revealed a pA2 value of 5.61. The isoprenaline-induced increase in cyclic AMP levels was inhibited by propranolol. However, propranolol did riot significantly affect the CGP12177-induced increase in cyclic AMP levels. These results suggest that β-adrenoceptor-mediated relaxations of the guinea pig taenia caecum predominantly involve β2 and β3-adrenoceptors, whereas CGP12177-induced relaxation is mediated solely through β3-adrenoceptors, and suggest that the production of cyclic AMP contributes to the β3-adrenoceptor-mediated relaxation of the guinea pig taenia caecum. The concentration-response curves for noradrenaline and adrenaline were unaffected by propranolol or phentolamine. However, the responses to noradrenaline and adrenaline were antagonized by hupranolol, and Schild plots of the data revealed pA2 values of 5.53 and 6.10, respectively. These results suggest that the relaxant responses to noradrenaline and adrenaline in the guinea pig taenia caecum are mainly mediated by β3-adrenoceptors, and that in the guinea pig taenia caecum noradrenaline arid adrenaline behave as a β3-selective adrenoceptor agonist.抄録全体を表示PDF形式でダウンロード (4450K) -
野部 浩司, 相澤 裕美, 大幡 久之, 百瀬 和享1995 年 106 巻 supplement 号 p. 122-126
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーChanges in diacylglycerol kinase (DG kinase) activity in carbachol (CCh)-stimulated guinea pig taenia coli were investigated. In phosphorus-32 ([32P]Pi)- and exogenous substrate of DG (dioctanoylglycerol; diC8)-prelabeled guinea pig taenia coli, diC8 was phosphorylated by DG kinase to [32P]dioctanoyl-phosphatidic acid ([32P]diC8-PA). CCh increased the accumulation of both [32P]diC8-PA and endogenous [32P]PA in a time- and dose-dependent manner. CCh-induced increase in [32P]diC8-PA was inhibited by atropine. These findings indicated the activation of DG kinase by muscarinic receptor stimulation. CCh-induced [32P]diC8-PA accumulation was dependent on intracellular calcium concentration. However, a KCl-induced increase in intracellular calcium, without receptor stimulation, was ineffective. Moreover, treatment with phorbolester also increased the accumulation of [32P]diC8-PA in KCl-treated tissues. These findings suggest that activation of DG kinase may require both an increase in intracellular calcium and protein kinase C (PKC) activation. In an mixed micellar assay system, DG kinase activities were distributed in both membrane and cytosolic fractions. Treatment of the tissue with CCh increased the activity in membrane fraction and decreased the cytosolic fraction without affecting total DG kinase activity. These findings suggested that DG kinase might be translocated from the cytosol to the membrane by CCh-stimulation. Treatment with PKC inhibitor blocked CCh-induced DG kinase translocation, and phorbolester induced the translocation only in intracellular calcium accumulated tissue. Considering these results, CCh-induced DG kinase activation appears to involve DG kinase translocation from the cytosol to the membrane in association with both PKC and intracellular calcium concentration.抄録全体を表示PDF形式でダウンロード (4429K) -
松岡 功, 石本 裕美, 大久保 聡子, 熊坂 忠則, 木村 純子, 中西 弘則1995 年 106 巻 supplement 号 p. 127-131
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーExtracellular ATP interacts with membrane-bound receptors to induced several physiological functions. The signal transaction pathways associated with the various ATP receptor subtypes have not been fully elucidated. In the present study, we demonstrate the second messenger signaling responses mediated by different ATP receptor subtypes in NG108-15 cells. In fura 2-loaded cells, we observed two different Ca2+ signaling pathways in response to ATP; one was a intracellular Ca2+ mobilization mediated by phospholipase C activation, and the other was Ca2+ influx via nonselective cation channel. The former effect was induced by lower concentration of ATP (1-100μM) and functionally related with the initial transient increase in intracellularCa2+ level ([Ca2+]i), whereas the later effect required higher concentration of ATP above 500 μM and produced a sustained increase in [Ca2+]i. The effects of several ATP analogues on [Ca2+]i indicated that two distinct receptor subtypes, P2u and P2z, were involved in ATP-induced the Ca2+ mobilization and Ca2+ influx, respectively. The stimulation of NG108-15 cells with ATP also increased cyclic AMP level. This effect of ATP was mediated by a unique receptor population different from P2u or P2z subtypes, since UTP and BzATP had little effect on cyclic AMP level. Similar effects on cyclic AMP response were observed with βγMeATP, ATPγS, AppNHp, ADPβS and FSBA, but P2x agonist αβMeATP and P2y agonist 2MeSATP were without effect, indicating that ATP induced cyclic AMP accumulation was mediated by a novel purinergic receptor subtype. These results indicate that NG108-15 cells possess at least three different ATP receptors which are coupled to different signal transduction mechanisms.抄録全体を表示PDF形式でダウンロード (4247K) -
櫨木 薫, Mosleh U. Ahmed, 櫨木 修, 堅田 利明, 宇井 理生1995 年 106 巻 supplement 号 p. 132-137
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーSuperoxide anion and arachidonic acid were produced in guinea pig neutrophils in response to a chemotactic peptide (fMLP). Both responses were markedly, but the former response to a phorbol ester was not at all, inhibited when the cellular cAMP level was raised by prostaglandin E1 combined with a cAMP-phosphodiesterase inhibitor. Increasing cAMP was also inhibitory to fMLP-induced activation of phosphatidylinositol (PI) 3-kinase and Ca2+ influx without any effect on the cation mobilization from intracellular stores. The fMLP-induced respiratory burst was abolished when PI 3-kinase was inhibited by wortmannin or LY294002, but was not affected when Ca2+ influx was inhibited. On the contrary, fMLP released arachidonic acid from the cells treated with the PI 3-kinase inhibitors as well as from non-treated cells, but it did not so when cellular Ca2+ uptake was prevented. The chemotactic peptide activated PI 3-kinase even in cells in which the receptormediated intracellular Ca2+ mobilization and respiratory burst were both abolished by exposure of the cells to a permeable Ca2+ chelating agent. Thus, stimulation of fMLP receptors gave rise to dual effects, activation of PI 3-kinase and intracellular Ca2+ mobilization; both effects were necessary for the fMLP-induced respiratory burst. Increasing cellular cAMP inhibited the respiratory burst and arachidonic acid release as a result of the inhibitions of PI 3-kinase and Ca2+ influx, respectively, in fMLP-treated neutrophils.抄録全体を表示PDF形式でダウンロード (4628K) -
石本 裕美, 木村 純子, 松岡 功, 熊坂 忠則, 中西 弘則1995 年 106 巻 supplement 号 p. 138-142
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーATP at 100 μM induced a trasient [Ca2+]i increase, while at 1 mM it induced the transient increase followed by a sustained [Ca2+]i increase in NG108-15 cells. We examined the mechanism of this sustained [Ca2+] increase using the fura-2 fluorescent method and the whole-cell patch clamp technique. Pretreatment of the cells with U73122 (PLC inhibtor) completely inhibited the trasient [Ca2+]i increase but not the sustained [Ca2+]i increase by ATP. The sustained [Ca2+]i increase was not observed in the absence of extracellular Ca2+, suggesting that this component was due to Ca2+ influx. Under the whol-cell patch clamp, 1 mM ATP induced a membrane current with the reversal potential at 12.5±0.8 mV in Tyrode solution with the Cs+ aspartate pipete solution. The ATP-induced current increased in a concentration dependent manner with EC50 value of approximately 0.75 mM ATP. When external Na+ was replaced by Li+, K+, Rb+, Cs+ or NMG+, ATP induced the current with a slight shift in the reversal potentials, suggesting that ATP activated a nonselective cation current. From the reversal potentials, the permeability ratio was calculated to be Na+ (1) > Li+ (0.93) > K+ (0.89) > Rb+ (0.56) > Cs+ (0.47) > NMG+ (0.12). Upon total replacement of external cation with Ca2+, ATP could induce the current, inicating that Ca2+ was permeable through the current. The permeability ratio of Ca2+ : Na+ was 1 : 0.6. ATP analogues which induced the current were 2MeSATP, BzATP, ATPγs and ADPβs. UTP had only a small effect and adenosine did not induce any current. α, β MetATP, β, γMetATP and ADP induced a different type of current. In fura-2 fluorescent method, ATPγs increased [Ca2+]i sustaindly but α, β MetATP and β, γ MetATP did not do so. These results indicated that ATP induced a nonselective cation current via P2Z receptor subtype. ATP-induced current was larger at lower [Mg2+]o, indicating that ATP4- was an effective agonist form of ATP. Calculated EC50 value was 21.5 μM ATP4-. We conclude that a high concentration of ATP stimulates P2Z receptor which is coupled to a class of Ca2+-permeable nonselective cation channels through which Ca2+ influx occurs in NG 10815 cells.抄録全体を表示PDF形式でダウンロード (4440K) -
平岡 未明, 林 正彦, 金 容必, 高松 智, 小宮山 寛機, 大村 智1995 年 106 巻 supplement 号 p. 143-146
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーPotent anti-adherent activity was detected in fermentation extracts of microbial strain FO-5050. Active compounds designated macrosphelide A, B was isolated and determined to be 16-membered macrolide antibiotics possessing three ester bonds in the ring structure. Macrosphelide A dose-dependently inhibited the adhesion of HL-60 cells to LPS-activated HUVEC monolayer (IC50, 2.5 μM); macrosphelide B also inhibited HL-60 adhesion but to a lesser extent (IC50, 36 μM). Macrosphelide A showed no any antimicrobial and cytocidal activities at the concentration of 1000 μg/ml and 100 μg/ml, respectively.
Macrosphelide is the newly discovered anti-cell adhesion substance, which is, but not peptide or antibody, a low molecular weight and unique 16-membered macrolide antibiotics possessing three ester bonds. Therefore, it is of interest to examine the mode of action of macrosphelide inhibiting cell-cell adhesion molecule and the availability for the therapy against refractory disease such as tumor invasion and metastasis or chronic inflammatory disease.抄録全体を表示PDF形式でダウンロード (2242K) -
金子 周司, 矢田 宜道, 足立 圭, 赤池 昭紀, 佐藤 公道1995 年 106 巻 supplement 号 p. 147-151
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーRNA-injected Xenopus oocytes were used for studying homologous desensitization of opioid receptors to G-protein-coupled intracellular signaling pathways. In the oocytes expressing K opioid receptor, voltage-dependent Ca2+ channel α2+ and β subunits, the κ agonist U50488H (1 μM) inhibited Ca2+ channel current in a reversible manner, and the inhibition was diminished by sustained agonist exposure (homologous desensitization). More than 10 min was required to halve the inhibition of BI- or Q-type Ca2+ channels by the κ agonist, however, the t½ for U50488H-induced inhibition of BIII- or N-type channels was only 6±1 min. Moreover, in the oocytes expressing κ opioid receptor, EP4 prostaglandin receptor and CFTR channel, no apparent desensitization was observed in the κ receptor-mediated potentiation of the cyclic AMP production by prostaglandin E2 even when the oocytes were treated with U50488H for 2 hours or more. The time-course of desensitization of μ opioid receptor was also different in the effector molecules. These observations suggest that rate of homologous desensitization of opioid receptor is not only dependent on the receptor molecule itself but also on its intracellular signaling systems.抄録全体を表示PDF形式でダウンロード (3551K) -
村山 俊彦, 佐藤 壮一, 野村 靖幸1995 年 106 巻 supplement 号 p. 152-156
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーNitrogen monoxide (NO) is supposed to be an important neuronal messenger molecule. We investigated the effects of NO-donors such as sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on noradrenaline (NA) release from rat hippocampus. 1) SNP stimulated [3-H]NA release in the presence of dithiothreitol (DTT) from the prelabeled slices. 2) SNAP stimulated NA release in the presence of L-cysteine or DTT. 3) SNP, SNAP and reducting agents had no stimulatory effect on NA release by themselves. 4) Coaddition of SNAP and L-cysteine stimulated endogenous NA from hippocampus in microdialysis assay. 5) Pretreatment with W-7, calmodulin antagonist, inhibited the effect of NO-donors in a dose-dependent manner. 6) SNP and SNAP stimulated cyclic GMP content in the slices by themselves. 7) The effects of NO-donors on NA release were not modified by the addition of methylene blue or oxyhemoglobin, although the effects on cyclic GMP content were abolished by these agents. These findings suggest that NOdonor stimulated NA release from the hippocampus in cyclic GMP-independent manner.抄録全体を表示PDF形式でダウンロード (3296K) -
吉岡 充弘, 松本 真知子, 富樫 広子, 齋藤 秀哉1995 年 106 巻 supplement 号 p. 157-161
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーIn vivo microdialysis was used to measure the effects of long-term treatment of rats with desipramine upon the regulation by α2-adrenoceptors of serotonin (5-HT) release from the serotonergic neurons in the hippocampus. Extracellular levels of 5-HT were estimated by assaying its concentrations in the perfusate using HPLC-ECD. When the α2-adrenoceptor agonist brimonidine was added to the perfusion solution, the K+-evoked 5-HT release was significantly inhibited in a concentration-dependent manner. Treatment with pertussis toxin did not alter the K+-evoked release of 5-HT but abolished the inhibitory effect of brimonidine. Long-term desipramine treatment significantly reduced the inhibitory effect of brimonidine upon the K+-evoked 5-HT release, and both the 5-HT content of the hippocampus and the basal 5-HT concentration in the dialysate were significantly increased. The present study suggests that long-term administration of desipramine causes a functional subsensitivity of the presynaptic α2-adrenoceptors that regulate serotonergic neuronal function in the rat hippocampus. It also supports the concept that changes in the sensitivity of α2-adrenoceptors that regulate neurotransmitter release play an important role in the mechanism of antidepressant drug action.抄録全体を表示PDF形式でダウンロード (3561K) -
南 雅文, 佐藤 公道1995 年 106 巻 supplement 号 p. 162-166
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーThe structural basis of opioid receptors (OPRs) for the subtype-selective binding of DAMGO, a μ-opioid receptor selective agonist, was investigated using chimeric μ/δ and μ/κ-OPRs. Replacement of the region around the first extracellular loop of the δ-OPR with the corresponding region of the μ-OPR gave the resultant chimeric receptor the similar affinity for DAMGO compared with the wild-type μ-OPR, while reciprocal replacement deprived the high affinity for DAMGO from the μ-OPR. On the other hand, replacement of the region around the third extracellular loop of the μ-OPR with the corresponding region of the κ-OPR remarkably decreased the binding affinity for DAMGO, while the reciprocal chimera revealed the high affinity for DAMGO. These results indicate that DAMGO distinguishes between μ- and δ-OPRs at the region around the first extracellular loop, while the third extracellular loop is important for the distinction between μ- and κ-OPRs by DAMGO. Furthermore, displacement studies revealed that the region around the first extracellular loop is, at least in part, involved in the discrimination between μ- and δ-OPRs by peptidic μ-selective ligands, such as dermorphin, morphiceptin and CTOP, but not by non-peptidic ligands, such as morphine and naloxone. On the contrary, the region around the third extracellular loop is involved in the discrimination between μ- and κ-OPRs not only by the peptidic μ-selective ligands but also by the non-peptidic ligands.抄録全体を表示PDF形式でダウンロード (3648K) -
小山 豊, 馬場 明道1995 年 106 巻 supplement 号 p. 167-171
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーEndothelins, potent vasoconstricting peptides, have multiple actions on nonmuscle tissues. ETs present in brain and the ET contents increase on brain injuries, suggesting an involvement in path hysiological responses of the injured rain. Astrocytes have receptors for ET. However, significance of astrocytic ET receptors are unknown. On brain damages such as ischemia and head trauma, astroc rtes changes their phenotype to “reactive astrocytes”. Reactive astrocytes produce neurotro is factors and support synaptic regeneration after brain damages. In this study, effect of ET on induction of reactive astrocytes were examined by immunohistochemical staining for GFAP, a marker of reactive astrocytes. Injection of ET-3 (40pmole) into rat caudiate utamen increased GFAP positive cells. An ETB receptor agonist, Ala1, .3, 11, 15-ET-1 (40pmole), also increased GFAP positive astrocytes, while marked cell dams a was not induced. Applications of vasodilators, hydrarazine (20mg/Kg/day, i.p.) and ifenprodil (4mg/Kg/day, i.p.), did not prevent ET-induced increase in GFAP positive cells. These results suggest that ETs are involved in the generation of reactive astrocyte after brain injuries.抄録全体を表示PDF形式でダウンロード (4740K) -
伊藤 芳久, 石毛 久美子, 愛澤 昌宏, 福田 英臣1995 年 106 巻 supplement 号 p. 172-176
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーPharmacological profiles of generalized absence-like seizures in animal models were studied. Selective GABAB antagonists, CGP 35348 and CGP 46381, suppressed absence seizure behavior and spike and wave discharges (SWDs) in lethargic (1h/1h) and γ-butyrolactone (GBL)-treated mice but not in stargazer (stg/stg) mice. Administration of GBL increased nuclear CRE- and AP-1 DNA-binding activities in mouse whole brain. CGP 35348 suppressed the increases in DNA-binding activities. It has been shown that the cortical and thalamic circuitry plays an important role in the genesis and spreading of absence seizures. Gel-shift assays in various brain regions revealed that administration of GBL increased nuclear CRE- and AP-1 DNA-binding activities significantly in the thalamus + midbrain and cerebral cortex but not in the hippocampus, cerebellum or pons-medulla. The region-specific increases in nuclear DNA-binding activities were also suppressed by CGP 35348. These results suggest that GABAB receptors play a significant role in generalized absence seizures in lethargic and GBL-treated mice and that the increases in nuclear CRE- and AP-1 DNA-binding activities are correlated with the GBL-induced absence seizures. It is also suggested that different mechanisms are involved in absence seizures in stargazer mice.抄録全体を表示PDF形式でダウンロード (4093K) -
細機 好章, 佐々木 佳子, 丸山 恵子, 服部 薫, 長友 孝文1995 年 106 巻 supplement 号 p. 177-181
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe investigated the effects of chronic administration of bopindolol in the heart of spontaneously hypertensive rats (SHR) The values of Kd and Bmax of α1 and β-adrenoceptors in the heart of SHR were calculated by Scatchard analysis used 3H-prazosin and 3H-CGP 12177 binding. In addition, their blood pressure was also determined and these effects of bopindolol were compared with those of other β-blockers. SHR were given bopindolol (1 mg/kg and 3 mg/kg), atenolol (50 mg/kg), propranolol (60 mg/kg) in drinking water during 12 weeks. The systolic blood pressure of SHR was lowered by chronic administration of bopindolol, dose-dependently observed. The chronic administration of bopindolol (3 mg/kg) to SHRs increased the Kd and Bmax values of the a lx-adrenoceptors (high affinity binding sites for 3H-prazosin). On the other hand, the administration of bopindolol (1 mg/kg and 3 mg/kg) decreased the Bmax values of the β-adrenoceptor. These findings suggest that chronic administration of bopindolol had a beneficial effect on the blood pressure and had a dose-dependent effect on the α1- and β-adrenoceptors in the heart. These effects of bopindolol maybe involved in the inhibition of the development of hypertension.抄録全体を表示PDF形式でダウンロード (3859K) -
宮本 謙一, 大前 真司, 早苗 富士子, 澤西 啓之, 高木 健三1995 年 106 巻 supplement 号 p. 182-186
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーThe inotropic actions of xanthine derivatives, having long alkyl chains, were investigated in guinea-pig ventricular papillary muscle. A potent and nonselective phosphodiesterase (PDE) inhibitor, 3-isobutyl-l-methylxanthine, elicited a positive inotropy and inhibited the negative inotropic effects of calcium channel inhibitors, as well as a selective PDE III inhibitor, amrinone, these effects which were canceled by a protein kinase inhibitor, N-[2-(ρ-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89). However, 1, 3-di-n-butyl-7-(2'-oxopropyl)xanthine (denbufylline) and 1-n-butyl-3-n-propylxanthine (XT-044), which possess potent and selective PDE IV inhibitory activities, showed negative inotropic actions which became more potent in the presence of H-89. Denbufylline allowed to disappear late restoration phase induced by ryanodine. This xanthine derivative attenuated the both effects of calcium channel acting agents, Bay K 8644 and verapamil, without interaction with caffeine and dihydropyridine calcium channel inhibitors. A nonxanthine PDE IV inhibitor, Ro 20-1724, did not affect the inotropic actions of calcium channel inhibitors. The attenuation by denbufylline or XT-044 of the negative inotropic action of verapamil was not influenced by pretreatment with H-89. These results suggest that these xanthine derivatives elicit negative inotropy through acting on a verapamil-sensitive site of calcium channel without involving of their PDE inhibitory activitiy, in the ventricular papillary muscle.抄録全体を表示PDF形式でダウンロード (4001K) -
渡辺 章, 遠藤 政夫1995 年 106 巻 supplement 号 p. 187-191
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーEffects of a novel Ca2+ sensitizer Org 30029 [N-hydroxy-5, 6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride] (ORG) on the myocardial contractile depression induced by acidosis and 2, 3-butanedione monoxime (BDM) were investigated in aequorin-loaded dog right ventricular trabeculae. The maximal positive inotropic effect (PIE) of ORG was about 150% of the isoproterenol-induced maximum (ISOmax), while the maximal response of the Ca2+ transient (CaT) to ORG was only 30% of ISOmax. Elevation of [Ca2+]o elicited PIE equivalent to ISOmax in association with an increase in CaT to 55% of ISOmax. Acidosis (pH 6.6) depressed the contraction markedly to 30% of the basal force with a small increase in the amplitude of CaT. Acidosis abbreviated the twitch but prolonged CaT. BDM (3 mM) depressed the contraction markedly to 40% of the basal force with only a slight change in the amplitude of CaT. BDM abbreviated the twitch without changing the duration of CaT. Elevation of [Ca2+]o increased CaT to the same extent as control but reversed the force only to 50% of ISOmax. In contrast, ORG completely reversed the contractile depression induced by acidosis or BDM, and elicited PIE to the same extent as control with only a small change in the amplitude of CaT. In addition, ORG prolonged the twitch that had been shortened previously by acidosis or BDM, to a level equivalent to the control in association with prolongation of CaT. This action of ORG may be mainly due to an increase in Ca2+ sensitivity of myofibrils. Furthermore, it is evident that the Ca2+ sensitizing effect of ORG is exerted also in pathophysiological situation where the Ca2+ sensitivity of myofibrils has been decreased by acidosis or BDM. Thus, ORG may be an effective cardiotonic agent capable of reversing the myocardial depression induced by decrease in Ca2+ sensitivity of myofibrils occurring in pathophysiological situation, such as acidosis in cardiac ischemia.抄録全体を表示PDF形式でダウンロード (4324K) -
杉山 篤, 齋藤 雅樹, 萩原 淳, 橋本 敬太郎, 中澤 知男1995 年 106 巻 supplement 号 p. 192-196
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーA novel azulene-1-carboxamidine delivative (HNS-32) was synthesized and its cardiovascular effects were assessed using well-established isolated, blood-perfused, canine sinoatrial node, papillary muscle and atrioventricular node preparations. The yields of HNS-32 was about 44 % of the amount expected from the chemical equation. The found, chemical structure, molecular weight and color of HNS-32 were C24H30N3, N1-dimethyl-N2-(2-picolino) azulene-l-carboxamidine, 360.242 and dark blue, respectively. HNS-32 suppressed the sinus nodal automaticity and contractile force, while increased the coronary blood flow and AH and HV intervals (n=5). The drug shortened the repolarization phase of monophasic action potentials of right ventricle (n=4). The vasodilator effect was 3-10 times more potent than each cardiac effect. The pharmacological properties resemble those of calcium channel blocking drugs with modest sodium channel inhibition and potassium channel opening. HNS-32 may become a new drug with unique chemical structure that affects cardiovascular system.抄録全体を表示PDF形式でダウンロード (3378K) -
高野 静子, 中西 弘則1995 年 106 巻 supplement 号 p. 197-201
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーWe investigated the role of 5-HT in thrombus formation and the effects of 5-HT2A antagonists in rabbit platelets and isolated aortic vessels. 1) Supernatant of collagen-aggregated platelets induced further aggregation volume-dependently. The supernatant-induced aggregation was inhibited by either 5-HT2A antagonists or ADP scaverger. 2) The supernatant induced contraction of the aortic vessels volume-dependently. The supernatant-induced contraction was inhibited by 5-HT2A antagonists but not by ADP scaverger. 3) The sensitivity of aortic vessels to the supernatant and to the inhibitory effects of 5-HT2A antagonists was 20 to 175 times higher than that of platelets.
These findings suggest that 5-HT released from the platelets by stimulation of collagen fibrils induces furter aggregation and contraction of vascular vessels via 5-HT2A receptors, accelerating arterial thrombus formation. These 5-HT2A antagonists may improve effectively the thrombus formation by inhibiting the platelet aggregation and the vascular contraction.抄録全体を表示PDF形式でダウンロード (3470K) -
平藤 雅彦, 根津 顕弘, 金井 幸辰, 南 勝1995 年 106 巻 supplement 号 p. 202-206
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーIn cardiovascular system, serotonin (5-hydroxytryptanune; 5-HT) induces very strong vasoconstriction, which is considered to be associated with hypertension or vasospasm. Intracellular calcium ions play a key role as second messenger in the regulation of vasoconstriction. In the present study, we investigated the effect of Ni2+, a cation chenel inhibitor, on 5-HT-induced increase in intracellular calcium concentration ([Ca2+]i) using cultured rat aortic smooth muscle cells (VSMCs). VSMCs were obtained by collagenase digestion and seeded on coverglass. Cells were cultured in 95% air and 5% C02 for 8-10 days in Dulbecco's MEM containing 10% fetal calf serum. [Ca2+]i was measured by a fluorescence spectrophotometer using fura-2. 5-HT (10 μM) caused a biphasic increase in [Ca2+]i of VSMCs, i.e., transient and tonic increase. Ni2+ (1 mM) significantly inhibited the tonic increase, but had no effect on the transient increase. Ni2+ also suppressed 5-HT-induced increase in IP3 content, suggesting that extracellular calcium influx is involved in the transient increase, in addition to the release from intracellular stores. However, Ni2+ completely inhibited calcium influx through voltagedependent calcium channel induced by high KCl (80 mM). Also, Ni2+ significantly inhibited calcium influx induced by thapsigargin (1 μM). These results suggest that 5-HT induces transient calcium influx through Ni2+ -sensitive calcium channel, which is distinct from voltage-dependent, capacitative or second messengeroperated calcium channels.抄録全体を表示PDF形式でダウンロード (3664K) -
加納 礼子, 福石 信之, 交久瀬 善隆, 吉田 隆志, 波多野 力, 伊東 秀之, 赤木 正明1995 年 106 巻 supplement 号 p. 207-211
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーPreviously, we demonstrated that potassium superoxide (KO2) elicited degranulation and histamine release from rat peritoneal mast cells by biological reactions. In the present study, we investigated the effects of 20 tannins and 10 antiallergic drugs on KO2 and compound 48/80 (48/80)-induced histamine release from rat peritoneal mast cells. Rat peritoneal mast cells were preincubated with various concentrations of tannins or antiallergic drugs at 37°C for 15 min, and K02 (10 mM) or 48/80 (0.5 μ g/ml) were added. The reactions were continued for 20 min and terminated by chilling the test tubes in an ice bath. The amount of histamine in the supernatant and the residual histamine content were determined fluorometrically. The pretreatment with tannins (1-100 μ M), which have many hexahydroxydiphenoyl (HHDP) groups and galloyl groups, prevented K02-induced histamine release, significantly. Higher molecular weight tannins prevented 48/80-induced histamine release, significantly. The pretreatment with azelastine, astemizole, ketotifen and epinastine prevented K02-induced histamine release, dosedependently. On the other hand, DSCG, repirinast, ibudilast and tazanolast had no effect. These findings indicate that the radical-scavenging activities may participate in the inhibitory effects of tannins, and antiallergic drugs may inhibit histamine release due to membrane-stabilizing action. The inhalation of tannins in the airway may prevent airway hypersensitivity.抄録全体を表示PDF形式でダウンロード (3784K) -
佐藤 博, 加藤 仁, 丹野 慶紀, 市田 隆文, 佐藤 祐一, 佐藤 万成1995 年 106 巻 supplement 号 p. 212-216
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーEffect of liposome preparation including immunomodulator OK-432(OK-Lipo) on hepatocellular carcinoma(HCC) was investigated. The liposome composed of L-α-dipalmitoylphospha-tidylcholine, cholesterol and stearylamine in a molar ratio of 52:40:8 was preparated by extrusion and/or ultrasonication with OK-432. Experiments as concerning with liver associated lymphocyte in mice were exerted prior to clinical use. In the cases of transportalvenous injection of OK-Lipo, CD3+/IL-2Rβ+ cells as liver associated lymphocyte were increased in the liver. It was shown that CD8+ cells were predominant. CD3-/IL-2Rβ+ cells as natural killer cell were increased in the liver for intravenous injection.
Patients with HCC were received transarterial injection of OK-lipo + cisplatin-epiru-bicin-lipiodol emulsion(CELE). Prominent lymphocyte infiltrations in the tumor and the extra-tumor were observed in case 1 patient, who was operable. Compared with patients received by CELE only, the proportion of CD3+ cells was elevated in the liver and tumor.
CD4+ cells were predominant in OK-Lipo. In all cases(OK-Lipo), fever was not detected and rise in white cell counts and rapid fall in lymphocyte counts were obserbed after therapy. A combination with OK-Lipo and CELE for HCC appears to be more effective.抄録全体を表示PDF形式でダウンロード (4040K) -
高橋 秀明, 北村 佳久, 谷口 隆之1995 年 106 巻 supplement 号 p. 217-221
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーTo clarify the expression pathway of inducible nitric oxide synthase (iNOS) in the brain, we examined the effects of interferon-γ(IFN-γ) and lipopolysaccharide (LPS) on expression of iNOS in glial cells cultured from neonatal rats, compared to those in macrophage cell line RAW264.7. NOS activities (NO2- accumulation) and l 30-kDa iNOS protein were induced 24 hr after treatment with IFN-γ or LPS in both glial cells and RAW264.7 macrophages. These expression activities was inhibited by a tyrosine kinase inhibitor, herbimycin A. From immunoprecipitation assay using antibodies against Janus kinase, IFN-γ induced tyrosinephosphorylation of Jak2 but did not induce phosphorylation of Jak 1 and Tyk2. The IFN-γ-induced-phosphorylation of Jak2 was inhibited by herbimycin A. While, LPS did not phosphorylate Janus kinase at all. These results suggest that IFN-γ-induced iNOS expression involves in the activation of Jak2 in both glial cells and macrophages. However, LPS-induced iNOS expression may involve in other kinases.抄録全体を表示PDF形式でダウンロード (3573K) -
鴨島 渉, 北村 佳久, 野村 靖幸, 谷口 隆之1995 年 106 巻 supplement 号 p. 222-226
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーRecently, it is known that NO is a cellular mediator with multiple biological functions including neurotoxicity and Bcl-2 inhibit a variety of a apoptotic deaths. We studied i) effects of several NO-related reagents on ADP-ribosylation, ii) effects of several kinase modulators on Bcl-2 expression, and iii) effects of several NO-donors on cell death of SH-SY5Y. NO-donors (SNP and SNAP) enhanced ADP-ribosylation of purified glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 37 kDa and 110 kDa proteins in SH-SY5Y, and 110 kDa proteins in rat fetal brain. SNP-enhanced ADP-ribosylation of GAPDH was inhibited by ADP-ribose. While, ADP-ribosylation of 110 kDa proteins in fetal brain was inhibited by benzamide. These results suggested that 37 kDa protein is GAPDH and 110 kDa protein is poly(ADP-ribose) synthetase. Although Bcl-2 is expressed in nontreated SH-SY5Y, Bcl-2 was more increased by PMA (a PKC activator), and was decreased by staurosporine (a PKC inhibitor) and dibutyryl cAMP (a PKA activator), suggesting that the expression of Bcl-2 is modulated by PKC and PKA. In addition, NO-donors induced cell death of SH-SY5Y in a concentrationdependent manner. From these results, we will discuss relationship between NO-donor, ADPribosylation and Bcl-2 in SH-SY5Y.抄録全体を表示PDF形式でダウンロード (3288K) -
田北 学, 村松 郁延1995 年 106 巻 supplement 号 p. 227-230
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーEffects of chronic treatment with propranolol or atenolol on stress-induced changes in blood pressure and cerebral β-adrenoceptors were examined in rats. Immobilization stress (2 h daily for 2 weeks) induced a moderate elevation of blood pressure and downregulation of cerebral β-adrenoceptors. Chronic administration of propranolol (5 mg•kg-1) or atenolol (5 mg•kg-1) inhibited stress-induced hypertension. Propranolol and atenolol increased the density of cerebral β-adrenoceptors and inhibited the downregulation induced by stress. These results suggest that the antihypertensive action of propranolol and atenolol may be partly associated with the inhibition of stress-activated central β-adrenoceptor transmission.抄録全体を表示PDF形式でダウンロード (2735K) -
茶珍 元彦, 下濱 俊, 藤本 貞毅, 谷口 隆之1995 年 106 巻 supplement 号 p. 231-235
発行日: 1995年
公開日: 2007/02/06
ジャーナル フリーRecent studies in Alzheimer brains have shown aberrant protein phosphorylation, suggesting an alteration in protein kinases and/or phosphoprotein phosphatases. The separation profile on Sephadex G-100 gel filtration chromatography revealed that two major forms of high-molecular-weight (HMW) and low-molecular-weight (LMW) acid phosphatase were present in the crude extracts of human brains. In Alzheimer brains, the LMW acid phosphatase activity was significantly decreased compared to that in control brains. A specific antibody was prepared to analyze the protein level of this enzyme. Western blot analysis indicated that the level of LMW acid phosphatase protein was significantly reduced, whereas the activity of LMW acid phosphatase per enzyme molecule was not changed in Alzheimer brains. These results suggest that the reduction of LMW acid phosphatase activity in Alzheimer brains is due to its decreased protein level in Alzheimer's disease. The endogenous substrate of LMW acid phosphatase in the brain was also investigated. LMW acid phosphatase was purified from bovine brain with a molecular mass of 17 kDa. The LMW acid phosphatase from bovine brain dephosphorylated a Mr. 170 kDa phosphotyrosine protein in rat brain extracts. This Mr. 170 kDa protein was considered to be the epidermal growth factor (EGF) receptor using a specific antibody. These results suggest that LMW acid phosphatase in the brain may regulate EGF receptor-dependent transmembrane signalling by dephosphorylating the phosphorylated receptor.抄録全体を表示PDF形式でダウンロード (4249K)
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