4,5—二氢—6—[（苯乙酰基—哌嗪基）苯基]—5—甲基—3（2H）—哒…

４，５－二氢－６－［（苯乙酰基－哌嗪基）苯基］－５－甲基－３（２Ｈ）－达嗪酮（ＳＭⅡ４）０．１－２．５μｍｏｌ．Ｌ＾－＾１能使血小板激活因子（ＰＡＦ）及血栓素Ａ２类似物Ｕ４６６１９诱导的兔血小板聚集剂量一效应曲线左移且最大反应降低。其ｐＤ２分别为６．０±ｓ０．４及６．１±ｓ０．３．ＳＭⅡ４还能抑制ＡＤＰ，花生四烯酸（ＡＡ）及Ｕ４６６１９诱导的人血小板聚集，其ＩＣ５０分别是１．２，１．３及１．６．．     

四氢吡喃类药物对血小板激活因子诱导的脑微血管平滑肌细胞DNA合成及增殖的拮抗作用

研究了血小板激活因子（ＰＡＦ）对兔血小板聚集，牛脑微血管平滑肌细胞ＤＮＡ合成及增殖的影响及四氢吡喃类药物ｔｒａｎｓ－２，６－ｂｉｓ－（３，４－ｄｉｍｅｔｈｏｘｙ－ｐｈｅｎｙｌ）－ｔｅｔｒａｈｙｄｒｏ－（４Ｈ）ｐｙｒａｎ（ＳＺ－１）和ｔｒａｎｓ－２－（３，４，５－ｔｒｉｍｅｔｈｏｘｙｐｈｅｎｙｌ）－６－（２，４－ｄｉｆｌｕｏ－ｒｏｐｈｅｎｙｌ）－ｔｅｔｒａｈｙｄｒｏ－（４Ｈ）ｐｙｒａｎ（ＤＦＴＭ）的拮抗作用．结果表明：ＰＡＦ强烈刺激兔血小板聚集，在１．９１μｍｏｌ·Ｌ－１时，刺激的百分率为７１．７％．ＳＺ－１和ＤＦＴＭ剂量依赖性地抑制ＰＡＦ刺激的兔血小板聚集，ＩＣ５０分别为０．３９和０．８４ｎｍｏｌ·Ｌ－１．ＰＡＦ还刺激牛脑微血管平滑肌细胞增殖，在０．１ｎｍｏｌ·Ｌ－１时作用４８ｈ达最大效应．ＳＺ－１和ＤＦＴＭ显著抑制血小板激活因子的上述作用，在１ｎｍｏｌ·Ｌ－１时抑制率分别为２５．９％和３０．７％．ＳＺ－１和ＤＦＴＭ还抑制ＰＡＦ刺激的牛脑微血管平滑肌细胞ＤＮＡ合成，在１ｎｍｏｌ·Ｌ－１时抑制率分别为２９．１％和２４．４％．实验结果表明：ＰＡＦ可能通过促进血小板聚集，刺激脑血管平滑肌细胞增殖及ＤＮＡ合成而参与?     

粉防己碱，Fura 2－AM和Bay k 8644对脂多糖刺激大鼠腹腔巨噬细胞释放血小板活化因子的影响

目的：研究钙与脂多糖（ＬＰＳ）刺激大鼠腹腔巨噬细胞（ＰＭ）释放血小板活化因子（ＰＡＦ）的关系．方法：通过ＰＡＦ的生物测定法，观察了粉防己碱（Ｔｅｔ）、Ｆｕｒａ２ＡＭ和Ｂａｙｋ８６４４对ＬＰＳ刺激ＰＭ释放ＰＡＦ的影响．结果：ＬＰＳ刺激ＰＭ释放ＰＡＦ，但并不使其细胞内钙增高，Ｔｅｔ在０１，１０，１０，１００μｍｏｌ·Ｌ－１和Ｆｕｒａ２ＡＭ在００１，０１，１０，１０μｍｏｌ·Ｌ－１时降低ＬＰＳ刺激的ＰＭ释放ＰＡＦ（分别为９８±１１，６５±１６，４７±０８，３４±０４，９２±１７，５２±１３，３７±０４，３．２±０３μｇ·Ｌ－１，无药物时１１８±１２μｇ·Ｌ－１），Ｂａｙｋ８６４４在１０，５０，１０μｍｏｌ·Ｌ－１时能增加ＬＰＳ刺激的ＰＡＦ释放能增加ＬＰＳ刺激的ＰＡＦ释放（分别为１３２±１７，１６２±１４，１７６±１５μｇ·Ｌ－１），并且Ｂａｙｋ８６４４在５０μｍｏｌ·Ｌ－１时能全部或部分逆转Ｔｅｔ和Ｆｕｒａ２ＡＭ对ＰＡＦ释放的抑制作用．结论：尽管ＬＰＳ并不明显增加巨噬细胞内钙，但细胞内钙对ＬＰＳ刺激的ＰＡＦ释放是必要的．     

一氧化氮在青霉素致痫中的作用及与NMDA和非NMDA受体的关系

目的阐明一氧化氮（ｎｉｔｒｉｏｘｉｄｅ，ＮＯ）在青霉素致痫中的作用及与ＮＭＤＡ及非ＮＭＤＡ受体的关系。方法用自制的一氧化氮敏感电极——Ｎａｆｉｏｎ－壳聚糖合镍修饰铂电极（Ｎａｆｉｏｎ－ＣＴＳ（Ｎｉ）－Ｐｔ）连续测定了青霉素致痫海马脑片ＣＡ１区锥体层神经元ＮＯ的释放，并同时观察了Ｎ－ｍｅｔｈｙｌ－Ｄ－ａｓｐａｒａｔｅ（ＮＭＤＡ）受体阻断剂ＤＬ－２－ａｍｉｎｏ－ｐｈｏｓｐｈｏ－ｎｏ－ｖａｌｅｒｉｃａｃｉｄ（ＡＰ５）及非ＮＭＤＡ／ＡＭＰＡ受体阻断剂６，７－ｄｉｎｉ－ｔｒｏｑｕｉｎｏｘａｌｉｎｅ－２，３（１ｈ，４ｈ）－ｄｉｏｎｅ（ＤＮＱＸ）对诱发痫波及ＮＯ含量的影响。结果①自制ＮＯ敏感电极检测ＮＯ浓度线性范围为４．５×１０－４～１．０×１０－８ｍｏｌ·Ｌ－１，检测下限为５．０×１０－８ｍｏｌ·Ｌ－１；②青霉素致痫时ＮＯ释放增加，与诱发脑片痫波有剂量反应关系；③ＮＭＤＡ受体阻断剂ＡＰ５（５０μｍｏｌ·Ｌ－１）明显抑制电刺激Ｓｃｈａｆｅｒ＇ｓ纤维引起的ＣＡ１区诱发痫波，表现为痫波数减少，同时伴有ＮＯ释放下降；④非ＮＭＤＡ受体阻断剂ＤＮＱＸ（３μｍｏｌ·Ｌ－１）对诱发痫波作用不明显，ＮＯ释放亦无显著变化；⑤ＡＰ５与一氧化?     

谷胱甘肽对病毒性肝炎病人超氧化物歧化酶、过氧化脂质水平的影响及疗效

目的：探讨谷胱甘肽对病毒性肝炎病人ＳＯＤ和ＬＰＯ的影响及疗效。方法：治疗组２６例，男性２０例，女性６例；年龄３６±ｓ１０ａ。用肌苷０．４ｇ，甘草酸单铵６０ｍＬ或甘草酸二铵３０ｍＬ和门冬氨酸钾镁２０ｍＬ均加入１０％葡萄糖注射液２５０ｍＬ中静脉滴注（静滴），ｑｄ作基础治疗，同时用谷胱甘肽１．２ｇ，静滴，ｑｄ；对照组２５例，男性１８例，女性７例；年龄３２±９ａ，仅给予基础治疗。结果：治疗组ＴＢ，ＤＢ，ＡＬＴ分别下降３９±４６μｍｏｌ／Ｌ，１８±３２μｍｏｌ／Ｌ，７６±１１３ＩＵ／Ｌ，均优于对照组（分别为２９±４２μｍｏｌ／Ｌ，１４±３０μｍｏｌ／Ｌ，３９±１００ＩＵ／Ｌ），Ｐ值分别＜０．０１，０．０５和０．０１，但治疗前后ＳＯＤ（分别为４０±１０Ｕ／ｍＬ，４２±１５Ｕ／ｍＬ），ＬＰＯ（分别为０．５±０．５μｍｏｌ／Ｌ，０．４±０．３μｍｏｌ／Ｌ）无明显变化（Ｐ＞０．０５）。结论：谷胱甘肽对肝功能恢复有良好疗效，但不影响ＳＯＤ和ＬＰＯ水平     

糖尿病大鼠血中内源性一氧化氮合酶抑制物增高

目的：测定糖尿病大鼠血中内源性ＮＯ合酶抑制物二甲基精氨酸（ＤＭＡ）的含量，方法：在链佐星诱发的糖尿病大鼠测定血清ＤＭＡ的含量和乙酰胆碱（ＡＣｈ）诱导血管内皮依赖性舒张，结果：与对照组相比，糖尿病大鼠ＤＭＡ血清浓度显增加（５．４±１．０ｖｓ０．７±０．３μｍｏｌ．Ｌ＾－１，Ｐ〈０．０１）；丙二醛含量也高于对照组（２．５±０．３ｖｓ２１．５±０．１μｍｏｌ．Ｌ＾－１，Ｐ〈０．０１）；糖尿病大鼠ＡＣｈ     

用兔血小板膜受体筛选血小板激活因子（TAF）拮抗剂

在兔血小板膜中，血小板激活因子（ＰＡＦ）结合部位显示高度亲合性（Ｋｄ＝０．１±０．００７ｎｍｏｌ／Ｌ）、饱和性、显著的药理学特异性，其最大结合容量为２．８９±０．３２ｐｍｏｌ／ｍｇ蛋白。３Ｈ－ＰＡＦ饱和结合浓度为０．２ｎｍｏｌ／Ｌ。等温线表明为单一结合位点。红曲霉（Ｍｏｎａｓｃｕｓｓｐ．Ｆ４００）代谢产物中的小成份Ｄ（２Ａ）和Ｃ（４Ａ）与ＰＡＦ竞争受体结合部位，它们是ＰＡＦ的拮抗剂。Ｄ２Ａ的ＩＣ５０为３．１６×１０－５ｍｏｌ／Ｌ，Ｃ４Ａ的ＩＣ５０为３．０３×１０－５ｍｏｌ／Ｌ。     

Effects of platelet activating factor and ginkgolid B on the cAMP levels in washed rabbit platelets

研究了血小板激活因子（ＰＡＦ）和ＰＡＦ拮抗剂银杏内酯Ｂ对洗涤兔血小板中ｃＡＭＰ含量的作用．结果表明ＰＡＦ（０．１－１．０μｍｏｌ·Ｌ－１）对血小板的基础ｃＡＭＰ水平无影响，但对前列腺素Ｅ１（ＰＧＥ１）２μｍｏｌ·Ｌ－１及４，５－二氢－６－［４－（１Ｈ－咪唑－１－）苯基］－５－甲基－３－（２Ｈ）－哒嗪酮（ＣＩ－９３０）２０μｍｏｌ·Ｌ－１引起的ｃＡＭＰ升高有显著的抑制作用．银杏内酯Ｂ能完全拮抗ＰＡＦ抑制ＰＧＥ１和ＣＩ－９３０升高ｃＡＭＰ的作用，ＩＣ５０分别为４．７和１２．５μｍｏｌ·Ｌ－１．合用磷酸肌酸／磷酸肌酸激酶和阿司匹林对ＰＡＦ和银杏内酯Ｂ的作用均无影响．提示ＰＡＦ对磷酸二酯酶的激活作用及腺苷酸环化酶的抑制作用是ＰＡＦ的直接作用，与其同ＰＡＦ受体结合有关．     

茶色素对冠心病病人血中超氧化物歧化酶及过氧化脂质的影响

目的：用随机双盲安慰剂对照法观察茶色素对冠心病病人血清超氧化物歧化酶（ＳＯＤ）及过氧化脂质（ＬＰＯ）的影响。方法：将病人分成２组，治疗组２２例服茶色素１粒（每粒１２５ｍｇ）ｔｉｄ×４ｗｋ，对照组１８例服安慰剂１粒，ｔｉｄ×４ｗｋ，并设健康人组作比较。结果：服茶色素后血清ＳＯＤ活力明显增高，由用药前的８７±ｓ１７μＵ／Ｌ上升至１０３±２５μＵ／Ｌ（Ｐ＜０．０１）；ＬＰＯ含量由用药前５．１±０．７μｍｏｌ／Ｌ降至４．０±１．１μｍｏｌ／Ｌ（Ｐ＜０．０１）与健康人的水平相当。对照组ＳＯＤ活力及ＬＰＯ含量用药前后无明显改变。结论：茶色素能改善冠心病病人血中ＳＯＤ活力及降低血清ＬＰＯ。     

延髓腹外侧头端注射莫索尼定对大鼠血压,心率和肾交感神经放电…

目的：观察延髓腹外侧头端（ＲＶＬＭ）注射莫索尼定（Ｍｏｘ）对麻醉大鼠血压（ＢＰ）、心率（ＨＲ）及肾交感神经放电（ＲＳＮＡ）的影响。方法：麻醉大鼠ＲＶＬＭ注射１μＬ Ｍｏｘ１，１０，１００μｍｏｌ·Ｌ＾－１，同步记录ＢＰ，ＨＲ及ＲＳＮＡ。结果：Ｍｏｘ１，１０，１００μｍｏｌ·Ｌ＾－１分别使ＢＰ从１３．９±１．０ｋＰａ降至１３．０±１．７ｋＰａ（Ｐ〈０．０５），１３．８±１．８ｋＰａ至１１．４±１．５     

甲基黄酮醇胺对血小板花生四烯酸代谢通路的影响

甲基黄酮醇胺(MPA)40mg·Kg~(-1)iv,能使花生四烯酸(AA)诱发的小鼠死亡率降低61％.MFA12.5～200μmol·L~(-1)呈剂量依赖性地抑制AA诱导的免血小板聚集.聚集率为49％±10％～4％±4%,对照组为69％±3％.MFA0.1～0.4mmol·L~(-1)呈剂量依赖性抑制AA诱导兔的血小板丙二醛(MDA)的生成,为(nmol·10~(-9)血小板)0.075±0.011～0.111±0.023,对照组为0.170±0.017.MFA0.4 mmol·L~(-1)有效地抑制凝血酶和A A诱导的兔血小板内MDA生成.分别为0.016±0.006.0.080±0.017,对照组分别为0.048±0006,0.160±0.025;普萘洛尔仅抑制凝血酶诱导的MDA生成.对AA诱导的MDA无影响.MFA0.4mmol·L~(-1)不影响血小板内cAMP含量.结果提示MFA抑制血小板AA代谢通路可能是其抑制血小板聚集功能的机理之一.     

PLC对ADP诱导的兔血小板cAMP的影响

目的　测定磷酯酶C(phospholipaseC,简称PLC,下同)对ADP诱导的兔血小板cAMP的影响,从而进一步阐明PLC抗血小板聚集作用的机制。方法　取家兔的PRP,除去红细胞,分别用生理盐水、ASA和不同剂量的PLC处理,以ADP诱导激活,采用三氯醋酸法制备血小板cAMP,再用放射免疫分析法分别测定cAMP含量。结果　家兔血小板经生理盐水处理后的cAMP含量为 ( 20 16±0 91 ) pmol/109platelets,而经生理盐水、ASA668μmol·L-1、5、10、15、20和25UPLC·ml-1各组处理,并以ADP激活的血小板,测得的cAMP含量分别为 13 85±1 14, 16 27±0 36, 18 74±0 55,19 80±0 52, 20 49±0 43, 22 55±0 61和 24 24±0 85(pmol/109 platelets)。以生理盐水作为对照,ASA668μmol·L-1、5、10、15、20和 25UPLC·ml-1剂量组对激活状态下血小板cAMP的含量有增加的作用,增加率 (% )分别为17 47, 35 31, 42 96, 47 94, 62 82, 75 02。结论　PLC使得ADP激活后的兔血小板cAMP水平提高(P<0 01),且呈剂量依赖性,表明PLC具有提高血小板中cAMP水平的作用。这可能是PLC抗血小板聚集作用的重要原因之一。     

A new insight of anti-platelet effects of sirtinol in platelets aggregation via cyclic AMP phosphodiesterase

Sirtinol, a cell permeable six-membered lactone ring, is derived from naphthol and potent inhibitor of SIR2 and its naphtholic may have the inhibitory effects on platelets aggregation. In this study, platelet function was examined by collagen/epinephrine (CEPI) and collagen/ADP-induced closure times using the PFA-100 system reveal that CEPI-CT and CADP-CT were prolonged by sirtinol. The platelets aggregation regulated by physiological agonists such as: thrombin, collagen and AA and U46619 were significantly inhibited by sirtinol. Increases cAMP level was observed when sirtinol treated with Prostaglandin E1 in washed platelets. Moreover, sirtinol attenuated intracellular Ca²⁺ release and thromboxane B2 formation stimulated by thrombin, collagen, AA and U46619 in human washed platelets. This study indicated that sirtinol could inhibit the platelet aggregation induced by physiological agonists, AA and U46619. The mechanism of action may include an increase of cAMP level with enhanced VASP-Ser157 phosphorylation via inhibition of cAMP phosphodiesterase activity and subsequent inhibition of intracellular Ca²⁺ mobilization, thromboxane A2 formation, and ATP release during the platelet aggregation.     

EFFECTS OF CHROMAN DERIVATIVES ON PLATELET AGGREGATION INDUCED BY SOME AGGREGATING AGENTS IN RABBITS

1. We synthesized 10 chroman derivatives (CD-1 to CD-10) derived from khellactone, including praeruptorin A and praeruptorin B and examined the effects of these compounds on rabbit platelet aggregation. 2. These compounds exhibited an inhibitory effect on platelet-activating factor (PAF)-induced platelet aggregation and their effects were more potent on PAF-induced platelet aggregation than on adenosine triphosphate (ADP)-, arachidonate (AA)- or collagen-induced platelet aggregation. In particular, (±)-cis-5-methoxy-6-methoxycarbonyl-2,2-dimethyl-3,4-ditiglyloxychro-man (CD-6), (±)-cis-5-methoxy-6-(2-methoxycarbonylethenyi)-2,2-dimethyl-3,4-ditiglyloxychroman (CD-8), (±)-cis-3,4-diacetoxy-5-methoxy-2,2-dimethyl-6-propylchroman (CD-9) and (±)-cis-5-methoxy-2,2-dimethyl-6-propyl-3,4-ditiglyloxy-chroman (CD-10) showed a moderate inhibition of PAF-induced platelet aggregation. 3. From these findings, it is suggested that compounds with potent PAF antagonist activities have the following features: (i) a tiglyloxy moiety is required at the 3 and 4 positions; and (ii) the methoxy moiety is also required at the 5 position of chroman skeleton in khellactone.     

Modulation by cyclic AMP of arachidonic acid-induced platelet desensitization

We have previously demonstrated that arachidonic acid (AA) and the stable cyclic endoperoxide analogue (U46619) desensitize human platelets at a common site, which is sensitive to endoperoxides/thromboxane receptor antagonists. We now report on the influence of agents which evaluate intracellular levels of platelet adenosine 3',5'-cyclic monophosphate (cAMP) on AA- and U46619-induced platelet desensitization. Prostaglandin E1, prostacyclin, carbacyclin, forskolin or dibutyryl cAMP prevented platelet activation by and desensitization to AA and to U46619 under conditions where the formation of thromboxane B2 was not significantly modified. Inhibition of platelet activation (aggregation and secretion) required a lower increase of the cAMP content than was needed to inhibit desensitization, confirming previous findings that desensitization to and by AA or U46619 are independent from the platelet release reaction. Together, these results indicate that AA-induced desensitization can be modulated by the adenylate cyclase/cAMP system acting at a site distinct from the known mechanisms of Ca2+ sequestration. This site is shared by the AA metabolite responsible for desensitization and by U46619 and is related to their common platelet membrane receptor.     

Dicentrine, a novel antiplatelet agent inhibiting thromboxane formation and increasing the cyclic AMP level of rabbit platelets.

Dicentrine is an antiplatelet agent isolated from the Chinese herb Lindera megaphylla. We examined the in vitro effects of dicentrine on various aspects of platelet reactivity. Dicentrine inhibited the aggregation and ATP release of washed rabbit platelets induced by arachidonic acid (AA), collagen, ADP, platelet-activating factor (PAF), thrombin and U46619. Dicentrine also inhibited the thromboxane B2 formation caused by AA, collagen and thrombin in washed intact platelets or that induced by AA in lysed platelet homogenate, while prostaglandin D2 formation caused by AA was not increased. The generation of inositol monophosphates (in the presence of indomethacin) caused by thrombin, collagen and PAF was not suppressed significantly, nor did dicentrine suppress fibrinogen-induced aggregation of elastase-treated platelets. Dicentrine inhibited the intracellular Ca2+ increase in quin-2/AM-loaded platelets caused by thrombin, PAF, collagen and AA. The cyclic AMP level was elevated by dicentrine in a concentration-dependent manner. These data indicate that the inhibitory effect of dicentrine on platelet aggregation and ATP release was due to the inhibition of thromboxane formation and the elevation of the level of cyclic AMP.     

血小板激活因子和银杏内酯B对洗涤兔血小板中cAMP含量的影响

研究了血小板激活因子(PAF)和PAF拮抗剂银杏内酯B对洗涤兔血小板中cAMP含量的作用. 结果表明PAF(0.1-1.0 μmol·L^-1)对血小板的基础cAMP水平无影响, 但对前列腺素E₁(PGE₁) 2 μmol·L^-1及4,5-二氢-6-［4-(1H-咪唑-1)苯基］-5-甲基-3-(2H)-哒嗪酮(CI-930) 20 μmol·L^-1引起的cAMP升高有显著的抑制作用. 银杏内酯B能完全拮抗PAF抑制PGE₁和CI-930升高cAMP的作用, IC₅₀分别为4.7和12.5 μmol·L^-1. 合用磷酸肌酸/磷酸肌酸激酶和阿司匹林对PAF和银杏内酯B的作用均无影响. 提示PAF对磷酸二酯酶的激活作用及腺苷酸环化酶的抑制作用是PAF的直接作用，与其同PAF受体结合有关.     

Effects of CI-930, a novel phosphodiesterase III inhibitor, on platelet aggregation and arachidonic acid metabolism

In the platelet-rich plasma of rabbits, 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone (CI-930) inhibited platelet aggregation triggered by AA, U-46619, ADP, collagen and PAF, with the IC50 values of 0.91, 0.73, 2.12, 2.35 and 7.15 mumols/L, respectively. The inhibitory effect of CI-930 on AA-induced aggregation was potentiated by PGE1, an adenylate cyclase activator, and antagonized by SQ-22536, an adenylate cyclase inhibitor. The contents of cAMP in washed rabbit platelets were increased by CI-930 5-50 mumols/L. In the concentration range of 0.5-500 mumols/L, CI-930 reduced the synthesis of TXB2 by either washed rat or rabbit platelets or rat pleural neutrophils. At the same time, CI-930 induced a dose-dependent increase of PGE2, PGF2a, and PGD2 biosynthesis by rat platelets and had no significant influence on the formation of 6-keto-PGF1a by the neutrophils. It is showed that CI-930 is an anti-platelet agent with a wide-spectrum activity and its anti-aggregating action may be exerted by dual mechanisms, both increasing cAMP contents and selectively inhibiting TXA2 synthesis in platelets.