甲基莲心碱对高脂血症患者及健康成人血小板聚焦的影响

目的 观察甲基莲心碱（ｎｅｆｅｒｉｎｅ，Ｎｅｆ）体外给药对高脂血症患者及健康成人血小板聚集功能的影响。方法 用比浊法测定血小板聚集率。结果 Ｎｅｆ在体外呈剂量依赖性明显抑制ＡＤＰ，胶原，盐酸肾上腺素注射液（Ａｄｒ）诱导的人血小板聚集，高脂血症患者组，Ｎｅｆ对ＡＤＰ，Ａｄｒ诱聚的１ｍｉｎ时的ＩＣ５０分别为４５．３８μｍｏｌ．Ｌ＾－１对ＡＤＰ，Ａｄｒ胶原诱聚的５ｍｉｎ时的ＩＣ５０分别为３６，２７和１６     

甲基莲心碱对高脂血症患者及健康成人血小板聚集的影响

目的观察甲基莲心碱（ｎｅｆｅｒｉｎｅ，Ｎｅｆ）体外给药对高脂血症患者及健康成人血小板聚集功能的影响。方法用比浊法测定血小板聚集率。结果Ｎｅｆ在体外呈剂量依赖性明显抑制ＡＤＰ、胶原、盐酸肾上腺素注射液（Ａｄｒ）诱导的人血小板聚集。高脂血症患者组，Ｎｅｆ对ＡＤＰ、Ａｄｒ诱聚的１ｍｉｎ时的ＩＣ５０分别为４５、３８μｍｏｌ·Ｌ－１；对ＡＤＰ、Ａｄｒ、胶原诱聚的５ｍｉｎ时的ＩＣ５０分别为３６、２７和１６μｍｏｌ·Ｌ－１。健康成人组，对ＡＤＰ、Ａｄｒ诱聚的１ｍｉｎ时的ＩＣ５０分别为５９和３６μｍｏｌ·Ｌ－１；对ＡＤＰ、Ａｄｒ、胶原诱聚的５ｍｉｎ时的ＩＣ５０分别为４２，８９和１１０μｍｏｌ·Ｌ－１。结论体外给药，Ｎｅｆ可明显抑制多种诱聚剂诱导的高脂血症患者和健康成人血小板聚集，且作用强于阿斯匹林。提示Ｎｅｆ对高脂血症患者并发血栓性疾病有一定的防治作用     

API_（0134）对四种诱聚剂致血小板聚集的影响

采用比浊法观察到ＡＰＩ０１３４显著抑制二磷酸腺苷（ＡＤＰ）、肾上腺素（Ａｄｒ）、花生四烯酸（ＡＡ）和胶原（Ｃｏｌｌ）诱导的人和大鼠血小板聚集。ＡＰＩ０１３４体外给药（２８．８～９１０ｍｇ·Ｌ－１）呈剂量依赖性的明显抑制ＡＤＰ、Ａｄｒ和ＡＡ诱导的人血小板聚集，其中对ＡＤＰ诱导的血小板聚集抑制作用最强，１ｍｉｎ和５ｍｉｎ时的半抑制浓度（ＩＣ５０）分别为１３４ｍｇ·Ｌ－１和７６．６ｍｇ·Ｌ－１，对Ａｄｒ诱导的血小板聚集之ＩＣ５０分别为１９４和１３７．６ｍｇ·Ｌ－１，对ＡＡ诱导的血小板聚集抑制作用较弱，５ｍｉｎ时的ＩＣ５０为２０３ｍｇ·Ｌ－１，ｉｖＡＰＩ０１３４７０和１００ｍｇ·ｋｇ－１，对ＡＤＰ和Ｃｏｌｌ诱导的大鼠血小板聚集也呈显著抑制作用，抑制率分别为２７．８％～３９．５％和２４．３％～３５．０％。     

人血小板密度亚群在聚集反应,ATP释放及细胞内游离钙浓度的异质性

研究人血小板密度亚群在聚集和释放反应及细胞内钙浓度的异质性。Ｐｒｅｃｏｌ间断梯度离心法。正常人血小板分为高，中和低密度三个亚群。血小板的大小随密度的降低而减小。ＨＤ对凝血酶，ＡＤＰ和血清素诱导的聚集反应明显强于ＬＤ，ＡＴＰ释放反应，除５－ＨＴ无ＡＴＰ释放外，与聚集反应的结果一致。     

盐酸非洛普对人和兔血小板聚集的影响

用比浊法和放射免疫法分别测定盐酸非洛普对兔和人血小板聚集及兔血栓素Ａ２（ＴＸＡ２）和动脉壁前列环素（ＰＧＩ２）含量的影响。盐酸非洛普呈剂量依赖性抑制ＡＤＰ（ＩＣ５０＝５．８×１０－４ｍｏｌ·Ｌ－１）和ＡＡ诱导的兔血小板聚集。对ＡＤＰ和Ａｄｒ诱导的人血小板聚集亦有明显抑制作用且呈剂量依赖性，ＩＣ５０值分别为１．２和１．３×１０－４ｍｏｌ·Ｌ－１。盐酸非洛普短期应用（８ｍｇ·ｋｇ－１ｉｖｔｉｄ×２ｄ）明显抑制ＡＤＰ和ＡＡ诱导的兔血小板聚集及ＴＸＢ２的产生和释放，对兔动脉壁和血浆６－ｋｅｔｏ－ＰＧＦ１α含量无显著影响。研究结果表明，盐酸非洛普抗血小板聚集作用与其抑制血小板ＴＸＡ２合成和释放有关，亦可能与其α２受体阻断作用有关。     

MK—447对家兔凝血酶诱导的血小板聚集,ATP释放及细胞内游离钙动…

研究ＭＫ－４４７对家兔凝血酶诱导的血小板聚集释放反应及单细胞内钙水平的影响，方法利用浊度法及测定ＰＲＰ中ＡＴＰ的含量评价聚集和释放反应，以荧光图像法分析细胞内钙浓度。结果：ＭＫ－４４７仅使兔多血小板血浆透光度降低，即血小板变形，单血小板轻度增加     

吡啶-2,6(1H,3H)二酮生物碱对ADP、AA、Collagen诱导的兔血小板聚集的影响

目的观察吡啶－２，６（１Ｈ，３Ｈ）二酮生物碱（ＳＨ１）对ＡＤＰ、ＡＡ、Ｃｏｌｌａｇｅｎ诱导的兔血小板聚集的影响。方法用比浊法测定了ＳＨ１体外对兔血小板聚集的影响。结果ＳＨ１对３种诱导剂的最大抑制率分别为６２．１６％、４５．２５％、５３．６７％。大剂量组明显加快ＡＤＰ诱导的兔血小板聚集后的解聚速度。ＳＨ１显著延长Ｃｏｌａｇｅｎ的诱导起聚时间。结论ＳＨ１０．８～４．０ｍｍｏｌＬ－１范围内明显抑制ＡＡ、ＡＤＰ、Ｃｏｌａ－ｇｅｎ诱导的兔血小板聚集。其抑制作用有明显的量效关系。其机制待进一步研究。     

吡啶—2,6（1H,3H）二酮生物碱对ADP,AA,Collagen诱导的兔血小板 …

目的 观察吡啶－２，６（１Ｈ，３Ｈ）二酮生物碱（ＳＨ１）对ＡＤＰ，ＡＡ，Ｃｏｌｌａｇｅｎ诱导的兔血小板聚集的影响，方法 用比浊法测定了ＳＨ１体外对兔血小板聚集的影响。结果 ＳＨ１对３种诱导剂的最大抑制率分别为６２．１６％，４５．２５％，５３．６７％，大剂量组明显加快ＡＤＰ诱导的兔血小板聚集后的解聚速度，ＳＨ１显著延长Ｃｏｌｌａｇｅｎ的诱导起聚时间，结论ＳＨ１０．８～４．０ｍｍｏｌ．Ｌ＾－１范围内明     

骨髓增生性疾病血小板聚集功能的变化

骨髓增生性疾病（ＭＰＤ）是一组克隆性疾病，许多病人存在血小板功能异常。本文共测定１２例ＭＰＤ病人血小板对五种不同诱聚剂诱导聚集的变化，同时选择１５例健康正常人作为对照。结果表明，每种诱聚剂与正常对照二组间的均数比较，仅胶原诱导的血小板聚集有统计学意义（ｘ±ｓ４５．１０±１９．６４；正常对照５７．９２±８．６２），Ｐ＝０．０５；而ＡＤＰ、ＰＡＦ、ＳＪＡＭＰ和Ａｄｒ诱导血小板聚集无统计学意义，Ｐ＞０．０５。但我们发现，ＭＰＤ组５／１２血小板ＰＡＦ聚集异常，３／１２胶原聚集异常，３／１２ＳＪＡＭＰ聚集异常。血浆纤维蛋白原浓度的变化二组间比较无明显统计学意义，Ｐ＞０．０５。总之，ＭＰＤ血小板聚集功能异常常见，可是并不是所有病人都会出现，其可能的原因与血小板膜糖蛋白异常及血小板代谢异常有关，或是巨核细胞的异常克隆所致。     

人血小板上的ADP受体

５＇一二磷酸腺苷（ＡＤＰ）引起人的血小板聚集，但血小板与ＡＤＰ的反应方式尚不明确。在激活血小板过程中，细胞内ＣＡ＾２＋浓度的增加起重要作用。ＡＤＰ是怎样引起Ｃａ＾２＋浓度增加，以及它用什么样的信号传导机制，尚不清楚。也不清楚ＡＤＰ发挥作用是与血小板上ＡＤＰ的一个受体还是多个受体的相互作用结果。本文叙述了一些有关资料，得出了一些人的血小板上ＡＤＰ受体的数量与性质的试验性结论。     

Inhibition of aggregation of rabbit and human platelets induced by adrenaline and 5-hydroxytryptamine by KB-R7943, a Na(+)/Ca(2+) exchange inhibitor

1. We investigated the effect of KB-R7943, a Na(+)/Ca(2+) exchange inhibitor, on the aggregation response induced by adrenaline and 5-hydroxytryptamine (5-HT), alone or in combination in human and rabbit platelets in the presence or absence of ouabain. 2. KB-R7943 inhibited aggregation induced by the combination of adrenaline and 5-HT in a concentration-dependent manner. The IC(50) values of KB-R7943 were 4.2+/-2.0 or 3.0+/-0.7 microM with washed rabbit platelets with or without ouabain pretreatment, respectively. 3. In platelet-rich human plasma, the aggregation was biphasic. The IC(50) value of KB-R7943 was 17.2+/-4.4 microM for the first phase aggregation. 4. KB-R7943 did not inhibit the first phase of aggregation induced by adrenaline alone, or the monophasic aggregation induced by 5-HT alone. 5. The aggregation of rabbit platelets depended on the presence of K(+) in the medium, and K(+)-dependent and K(+)-independent Ca(2+) influx were observed in resting platelets. Ouabain treatment increased only the K(+)-dependent but not the K(+)-independent Ca(2+) influx. 6. KB-R7943 inhibited K(+)-dependent Ca(2+) influx with or without ouabain pretreatment, but not K(+)-independent Ca(2+) influx. 7. From these results, we conclude that KB-R7943 inhibits the adrenaline plus 5-HT induced aggregation of rabbit and human platelets by inhibiting K(+)-dependent Na(+)/Ca(2+) exchange (NCKX). Our results suggest that NCKX plays an important role in platelet aggregation.     

Cloricromene inhibits the activation of human platelets by ADP alone or in combination with adrenaline

Cloricromene may inhibit platelet activation induced by several agonists. In this study we report that ADP and adrenaline synergistically promote platelet aggregation and cytoplasmic Ca2+ movements in aequorin-loaded platelets. Cloricromene caused dose-dependent reduction in platelet aggregation and cytoplasmic Ca2+ movements after exposure of the cells to a low concentration of ADP (2 microM) or to a combination of ADP (2 microM) and adrenaline (10 microM). Cloricromene's inhibitory action may be of considerable pharmacological interest since platelet activation by a combination of agonists may mimic the conditions under which thrombosis occurs in vivo.     

Synthesis and Antithrombotic Effect of Xanthone Derivatives

A series of xanthone derivatives was synthesized and tested in-vitro for their ability to inhibit aggregation of rabbit washed platelets and human platelet-rich plasma (PRP) induced by various inducers. 2-Prenyloxyxanthone showed the most potent inhibition of rabbit washed platelet aggregation induced by arachidonic acid (IC50 = 10.2 μM). Of the compounds tested in human PRP, 2-[3 (propylamino)-2-hydroxypropoxy]xanthone (4) hydrochloride salt exhibited the most potent inhibition of platelet aggregation induced by adrenaline (IC50 = 4.4 μM), whereas in evaluation of mouse antithrombotic activity, compound 4 exhibited the most potent protection of mice from thrombotic challenge. Compound 4, 2-[3-(isopropylamino)-2-hydroxypropoxylxanthone hydrochloride salt and 2,5 dihydroxyxanthone suppressed the secondary aggregation induced by adrenaline in human PRP. We conclude that the antiplatelet effects of these compounds are mainly due to an inhibitory effect on thromboxane formation.     

Urapidil inhibits 5-hydroxytryptamine induced platelet aggregation and 14C-5-hydroxytryptamine uptake in platelets

The effect of urapidil, an a1-antagonist with additional antihypertensive action via central 5HT1A agonism, was determined on platelet aggregation induced by 5HT and adrenaline. The 5HT uptake in human platelets was determined as well. Urapidil inhibited both the 5HT and adrenaline-induced human platelet aggregation and the 5HT uptake by platelets in vitro. The 5HT-induced aggregation was inhibited with a K1 value of 8.8 microM, the adrenaline-induced aggregation with a K1 value of 21.6 microM, and the 5HT uptake non-competitively with a K11 = 11.5 microM and a K12 = 13 microM.     

EFFECT OF LABETALOL ON HUMAN PLATELET FUNCTION

1. The effects of the alpha-beta-adrenergic antagonist labetalol on the activation of human platelets by adrenaline and other aggregating stimuli have been investigated. 2. Labetalol inhibited platelet aggregation and secretion induced by collagen and the second phase of aggregation caused by ADP, platelet activating factor, adrenaline and ionophore A23187. Adrenaline-induced platelet activation was inhibited by the lowest labetalol concentration. The response to Na arachidonate was minimally affected and the arachidonate-induced thromboxane B2 generation was only partially prevented. 3. The pre-incubation with low concentration of ionophore A23187 overcame labetalol's inhibition of collagen-induced platelet aggregation. 4. Labetalol did not influence intraplatelet cyclic AMP levels. 5. The present investigation provided evidences that the modulation of human platelet function by labetalol could be related also to a decreased Ca2+ availability.     

The inhibitory effects of cannabinoids, the active constituents of Cannabis sativa L. on human and rabbit platelet aggregation

Olivetol, cannabigerol (CBG), cannabidiol (CBD), cannabinol (CBN) and tetrahydrocannabinol (delta 1-THC) were assessed for their ability to inhibit agonist-induced platelet aggregation and [14C]5-HT release. With the exception of olivetol, (40% maximal effectiveness), none of the compounds inhibited tetradecanoylphorbolacetate (TPA)-induced aggregation of human or rabbit platelets. All of these cannabinoids partially inhibited primary aggregation and totally inhibited secondary aggregation of human platelets when adrenaline was used as the agonist. Inhibition was dose-dependent over the range 10(-3)-10(-5) M. Both rabbit and human platelet aggregation induced by adenosine diphosphate was inhibited in a dose-dependent manner and the order of potency was CBG greater than CBD greater than olivetol greater than THC greater than CBN, the IC50 of CBG being 2.7 x 10(-4) M. PAF-induced aggregation of rabbit platelets was also inhibited by these compounds in a dose-dependent manner over the concentration range 10(-3) to 10(-4) M, however [14C]5-HT release was only partially prevented by the cannabinoids in a manner which did not correlate with inhibition of aggregation.     

Inhibitory effect of a toxin okadaic acid, isolated from the black sponge on smooth muscle and platelets.

1. Effects of okadaic acid, a toxin isolated from marine sponges, on smooth muscle contraction and platelet activation were examined. 2. Contractions in rabbit aorta induced by high concentrations of K+ and noradrenaline were inhibited by 0.1-1 microM okadaic acid in a concentration-dependent manner. Spontaneous rhythmic contractions as well as high K+-induced contraction in guinea-pig taenia caeci were also inhibited by 1 microM okadaic acid. 3. High K+-induced contraction in rabbit aorta was accompanied by increased Ca2+ influx measured with 45Ca2+ and increased cytosolic Ca2+ [( Ca2+]cyt) measured with fura-2-Ca2+ fluorescence. Okadaic acid inhibited the contraction without inhibiting Ca2+ influx and produced only a small decrease in [Ca2+]cyt. 4. In a saponin-skinned taenia, Ca2+-induced contraction was not inhibited but rather potentiated by okadaic acid. 5. Okadaic acid, 1 microM, inhibited aggregation, ATP release and increased in [Ca2+]cyt induced by thrombin in washed rabbit platelets. Okadaic acid itself did not change the platelet activities. 6. Okadaic acid did not change the cyclic AMP content of rabbit aorta although the inhibitory effects of okadaic acid were similar to those of cyclic AMP. 7. Although the mechanism of the inhibitory effect of okadaic acid was not clarified in the present experiments, it is suggested that okadaic acid acts by inhibiting protein phosphatases resulting in an indirect activation of cyclic AMP-dependent protein phosphorylation.     

Structure-activity relationship studies on chalcone derivatives: potent inhibition of platelet aggregation

In an effort to develop potent antiplatelet agents with anti-inflammatory action, a novel series of anti-inflammatory chalcones was screened to evaluate their antiplatelet effects. Structure-activity relationships and mode of action were investigated and characterized. The antiplatelet effects of the chalcones on washed rabbit platelets and human platelet-rich plasma were evaluated. Arachidonic acid-induced platelet aggregation was potently inhibited by almost all the chalcone derivatives. Collagen-induced platelet aggregation was potently inhibited by all the chalcone derivatives at 300 microM, except for compound 4 at 100 microM. Compounds 6, 7 and 9 significantly inhibited the aggregation of washed rabbit platelets induced by platelet-activating factor at 300 microM. Of the compounds tested in human platelet-rich plasma, compounds 2, 8 and 9 showed significant inhibition of secondary aggregation induced by adrenaline. It is concluded that the antiplatelet effect of 2, 8 and 9 is mainly owing to an inhibitory effect on thromboxane formation. The inhibitory effect of 6, 7 and 9 on platelet aggregation induced by platelet-activating factor could be owing to a calcium antagonizing effect or inhibition of intracellular calcium mobilization.     

2′,5′-Dihydroxychalcone as a Potent Chemical Mediator and Cyclooxygenase Inhibitor

Eleven chalcone derivatives have been tested for their inhibitory effects on platelet aggregation in rabbit platelet suspension and the activation of mast cells and neutrophils. Arachidonic acid-induced platelet aggregation was potently inhibited by almost all the compounds and some also had a potent inhibitory effect on collagen-induced platelet aggregation and cyclooxygenase. Some hydroxychalcone derivatives showed strong inhibitory effects on the release of β-glucuronidase and lysozyme, and on superoxide formation by rat neutrophils stimulated with the peptide fMet-Leu-Phe (fMLP). We found that the anti-inflammatory effect of 2′,5′-dihydroxychalcone was greater than that of trifluoperazine. 2′,5′-Dihydroxy and 2′,3,4,4′-tetrahydroxyl chalcones, even at low concentration (50 μm), tested in platelet-rich plasma from man almost completely inhibited secondary aggregation induced by adrenaline. These results suggest that the anti-platelet effects of the chalcones are mainly a result of inhibition of thromboxane formation.