甲基莲心碱及与牛磺酸合用对大鼠血小板聚集和血栓形成的影响

甲基莲心碱（Ｎｅｆ）ｉｇ抑制大鼠血栓形成，单用Ｎｅｆ及与牛磺酸（Ｔａｕ）合用抑制率分别为５３．３１％和７４．３０％；对ＡＤＰ、胶原、凝血酶诱导的血小板聚集抑制率，Ｎｅｆ及Ｎｅｆ＋Ｔａｕ分别为５５．８％和７３．４％，４３．４５％和５９．３％，６５．３３％和７８．５％。两药对血浆纤维蛋白原、优球蛋白溶解时间均无明显影响。Ｎｅｆ能有效抑制ＡＤＰ诱导的血小板ＴＸＡ２释放，与Ｔａｕ合用抑制作用增强，而对血浆ＰＧＩ２含量无作用，Ｎｅｆ在ｉｖ后３０ｍｉｎ内对大鼠血清总胆固醇含量亦无影响，但与Ｔａｕ合用后能降低血清总胆固醇水平。     

短毛五加总甙对血小板聚集和PGI_2/TXA_2平衡的影响(英文)

短毛五加总甙(AGVPS)是中药短毛五加(Acanthopanax gracilistylus var. pubescens)的有效成份。本文发现短毛五加总甙能抑制正常家兔由多种诱导因素所致的血小板聚集。同时,它还抑制花生四稀酸所致血小板聚集时TXA_2的产生,增加离体家兔胸主动脉PGI_2产生。在高脂喂养的动脉粥样硬化的家兔模型上,能提高血浆PGI_2水平。     

甲基莲心碱对兔血小板聚集功能的影响

用比浊法和放射免疫分析技术研究甲基莲心碱(Nef)抗血小板聚集作用及其对TXA₂/PGI₂与cAMP/cGMP浓度的影响。结果显示,Nef在体外明显抑制ADP,胶原,AA及PAF诱导的家兔血小板聚集,IC₅₀分别为16,22,193及103μmol·L^-1;Nef明显抑制AA诱导的血小板TXA₂的生成和释放,对动脉环PGI₂的生成有促进作用;Nef剂量依赖性地升高血小板cAMP浓度,对cGMP无明显影响。结果提示Nef抗血小板聚集作用的机理与抑制TXA₂生成,增加血管PGI₂及血小板cAMP含量有关。     

卡托普利对肾血管性高血压大鼠血小板胞浆[Ca^2＋]i及血浆TXA2／PGI2…

AIM: To study the effect of captopril (Cap) on platelet cytosolic free calcium concentration ([Ca2+]i), platelet aggregation (PAg), and plasma TXA2/PGI2 ratio in the renovascular hypertensive rats. METHODS: Blood pressure was measured once a week by tail-cuff microphonic manometer. Platelet [Ca2+]i was measured by Fura 2-AM. Plasma angiotensin II (Ang), thromboxane A2 (TXA2), and prostacycline (PGI2) were measured by radioimmunoassay. RESULTS: Platelet [Ca2+]i and PAg increased (P < 0.01), while plasma Ang and TXA2/PGI2 ratio elevated (P < 0.05) in the renovascular hypertensive rats; platelet [Ca2+]i and plasma TXA2/PGI2 ratio reduced markedly after i.g. Cap 100 mg.kg-1.d-1 compared with saline for 2 wk. CONCLUSION: The altered TXA2/PGI2 after Cap treatment contributed to the improvement of the platelet [Ca2+]i and PAg.     

Different sensitivity of basilar and saphenous arteries to thromboxane A2-induced contractions. Effect of imidazole 2-hydroxybenzoate (ITF 182)

Superfused rings of rabbit basilar arteries are more sensitive than those of saphenous arteries to the contractions induced by a prostaglandin endoperoxide analogue (U-46 619) and by a thromboxane A2 (TXA2) generating system. 5-Hydroxytryptamine aggravates the latter. Prostaglandin I2 (PGI2) on the other hand, relaxes only the basilar rings without affecting the saphenous. Imidazole 2-hydroxybenzoate (ITF 182), at doses that do not interfere with platelet cyclooxygenase, reduces the contractions induced by the TXA2 generating system on both arteries because it reduces the platelet TXA2 synthetase enzyme. TXA2 is involved in the aetiology of strokes and cerebral vasospasms while PGI2 plays a physiological role in the maintenance of cerebral arterial tone. The high sensitivity of cerebral arteries to contractures caused by TXA2 together with the ability of ITF 182 to reduce them by inhibiting TXA2 production and to spare physiological PG production suggest a beneficial effect of the drug in cerebral vasospasms.     

Thromboxane A2 analogue (U-46619) stimulates vascular PGI2 synthesis

Since platelet release reaction products (e.g. serotonin, ADP) stimulate prostacyclin (PGI2) release in vitro, we have investigated whether thromboxane A2 (TXA2) also has a similar effect. An analogue, U-46619, was used for the experiments, since TXA2 is extremely unstable. U-46619 stimulated rat aortic PGI2 release; this stimulation was abolished by (a) EDTA and (b) verapamil. We conclude that TXA2 is a calcium-dependent stimulator of PGI2 release; this property may be relevant to the limitation of platelet aggregates in vivo and to vascular injury.     

Cigarette smoke exposure alters [14C]arachidonic acid metabolism in aortas and platelets of rats fed various levels of selenium and vitamin E

Rats were placed on a basal diet supplemented with 0, 0.03, or 3 ppm selenium and 0 or 20 ppm vitamin E for 41-43 wk. Selenium deficiency decreased hepatic glutathione peroxidase activity and lowered both aortic prostacyclin (PGI2) and platelet thromboxane (TXA2) production compared to selenium- and vitamin E-supplemented animals. Vitamin E deficiency increased hepatic lipid peroxidation and decreased aortic PGI2 synthesis. Rats exposed daily for 31-32 wk to fresh smoke from a UK 2R1 reference cigarette had carboxyhemoglobin levels of 0.75 +/- 0.12 and 4.73 +/- 0.12% in sham- and smoke-exposed groups, respectively. Animals chronically exposed to cigarette smoke displayed a nearly twofold increase in pulmonary arylhydrocarbon hydroxylase activity. Smoke exposure produced a 26-33% decrease in aortic PGI2 synthesis compared to shams in the Se3E20, Se0.03E20, and Se3E0 groups. Smoking also increased platelet thromboxane 91% and 98% in the Se3E20 and Se3E0 groups compared to shams. It is concluded that cigarette-smoke exposure and selenium or vitamin E deficiency alter aortic PGI2 and platelet TXA2 production.     

钩藤碱对血小板聚集和血栓形成的影响

钩藤碱(Rhy)明显抑制AA,胶原及ADP诱导的大鼠血小板聚集。Rhy不影响血小利用外源性AA合成TXA₂,但抑制胶原诱导的TXA₂生成;在抗血小板聚集有效剂量时,对PGI₂的生成无影响。Rhy有显著降低血栓形成诱导剂ADP及胶原加肾上腺素静脉注射所致小鼠死亡率。     

Selective inhibition by fenflumizole tissue cyclooxygenase in rabbits ex vivo

A new non-steroidal anti-inflammatory drug fenflumizole when administered orally to rabbits at therapeutic doses of 10 and 30 mg/kg affects neither PGI2 generation by arterial slices nor PGE2 generation by gastric mucosa, respectively. Fenflumizole at doses of 10 and 30 mg/kg per os inhibits platelet aggregability and generation of TXA2 by platelets. It is suggested that this selective action of fenflumizole on tissue cyclooxygenase ex vivo may justify with fenflumizole in anti-thrombotic therapy.     

乌苏里藜芦碱抗血栓作用机制的研究

目的研究乌苏里藜芦碱(VnA)抗血栓作用的机制。方法建立血瘀大鼠模型,检测VnA治疗前后血小板聚集率及血浆TXA2和PGI2水平的变化。结果静脉注射VnA可显著降低血小板聚集率,使血浆TXA2水平降低,PGI2水平升高。结论 VnA可显著抑制血小板聚集,其机制可能与升高血浆PGI2与TXA2比值有关。     

Advance in understanding the biosynthesis of prostacyclin and thromboxane A2 in the endoplasmic reticulum membrane via the cyclooxygenase pathway

Recent advances in topological and structural characterization of the prostacyclin (PGI(2)) and thromboxane A(2) (TXA(2)) synthases have led to the understanding of the biosynthesis of PGI(2) and TXA(2) at a structural level. This mini-review focuses on the molecular mechanism of the isomerization of the prostaglandin H(2) to PGI(2)and TXA(2) by their synthases in the endoplasmic reticulum (ER) membrane coordinated with cyclooxygenase-1 or -2. This review summarizes the evidences in which the biosynthesis of PGI(2)and TXA(2) are influenced/modulated by the membrane anchor residues of the synthases and the ER membrane itself, and provides the structural basis for engineering the synthases for the next generation of gene therapy and drug designs targeting the specific synthases.     

Routine measurement of thromboxane B2 and the prostacyclin metabolite 6-keto-prostaglandin F1 alpha in plasma

Thromboxane A2 (TXA2) is mainly formed in thrombocytes. It promotes thrombocyte aggregation and contracts the blood vessels. TXA2 appears to be a specific physiological thrombotic agent. Synthesis of TXA2 is elevated in patients with diabetes mellitus of types I and II and in hypertensive patients. TXA2 has a half-life of about 30 s under physiological conditions. Prostacyclin (PGI2) is formed in the vessel walls. Its action is antagonistic to TXA2, that is, it inhibits platelet aggregation and dilates the blood vessels. Synthesis of PGI2 is depressed in the presence of the classical 4 main risk factors for atherosclerosis: arterial hypertension, hyperlipoproteinaemia, smoking and diabetes mellitus. PGI2 has a half-life of about 3 min under physiological conditions. Since TXA2 and PGI2 are very labile and thus extremely difficult to measure, it is at present usual to measure their stable metabolites thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Radioimmunological measurement (RIA) of TXB2 in plasma requires no preliminary work, but radioimmunological measurement of 6-keto-PGF1 alpha in plasma requires prior extraction and concentrating, since the concentration of 6-keto-PGF1 alpha in the plasma is usually below the detection limit of commercial RIA kits. This paper describes standardized conditions for drawing the blood sample, a simple method of extraction from plasma, and the reliability of two commercial RIA kits with 125I tracer in measuring TXB2 and 6-keto-PGF1 alpha in plasma.     

乙酰丹酚酸A对血小板花生四烯酸代谢的影响

乙酰丹酚酸Ａ对血小板花生四烯酸代谢的影响吁文贵徐理纳（中国医学科学院、中国协和医科大学药物研究所，北京１０００５０）乙酰丹酚酸Ａ（ａｃｅｔｙｌｓａｌｖｉａｎｏｌｉｃａｃｉｄＡ，ＡＳＡＡ）在体内外能明显抑制花生四烯酸（ａｒａｃｈｉｄｏｎｉｃａｃｉｄ，Ａ...     

Pharmacological studies on the TXA2 synthetase inhibitor (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046)

The effects of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046) on thromboxane A2 (TXA2) synthetase in vitro and on experimental animal models of sudden death and cerebral infarction were studied. IC50 values of OKY-046 for the TXA2 synthetase of human, rabbit, dog and guinea pig washed platelets were 0.004, 0.004, 0.26 and 2.4 microM, respectively. OKY-046 at concentrations up to 1 mM, however, did not inhibit prostacyclin (PGI2) synthetase from bovine aorta microsomes or cyclooxygenase and PGE2 isomerase from sheep seminal vesicle microsomes. Similarly, platelet 12-lipoxygenase was not affected by OKY-046. Evidence for a re-direction of arachidonate metabolism from thromboxane synthesis toward PGI2 synthesis was obtained using rat peritoneal cells. Namely, OKY-046 increased PGI2 production accompanied by an inhibition of TXA2 production at a concentration of more than 1 microM. OKY-046 at a dose of 0.1 mg/kg (i.v.) in dogs inhibited the aortic and mesenteric arterial contraction of rabbit induced by the addition of arachidonate to extracorporated blood of the dogs. OKY-046 at a dose of 0.3 mg/kg (i.v.) prevented the arachidonate-induced sudden death and also decreased the incidence of cerebral infarction induced by injection of arachidonate into the internal carotid artery in rabbits. Aspirin also decreased the incidence of cerebral infarction at a dose of 30 mg/kg (i.v.). These results suggest that OKY-046 may be valuable for the treatment of cerebrovascular and cardiovascular diseases associated with vasoconstriction and thrombosis due to TXA2.     

Dipyridamole and aspirin in relation to platelet aggregation and vessel wall prostaglandin generation

Modification of platelet function and vessel wall prostaglandin synthesis by pharmacologic intervention has attracted considerable attention. We report our observations on the effects of aspirin and dipyridamole alone and their combination on platelet aggregation and vessel wall prostacyclin (PGI2) generation. Although dipyridamole alone had no effects on platelet aggregation, it potentiated the platelet aggregation inhibitory effects of aspirin in vitro in a dose-related fashion. Dipyridamole also enhanced the platelet aggregation inhibitory effect of synthetic PGI2 in vitro. Potentiation of aspirin- and PGI2-induced platelet aggregation inhibition was observed in therapeutic range (5-10 micrograms/ml). In an isolated umbilical vein model dipyridamole stimulated release of PGI2 at much higher concentration (50-100 microgram/ml). Treatment of umbilical vein with aspirin (180 micrograms/ml) for 10 min blocked the spontaneous release of PGI2. In aspirin-treated umbilical vein segments dipyridamole treatment did not cause PGI2 release as in the untreated segments. These experiments suggest that although dipyridamole enhances both aspirin- and PGI2-induced platelet aggregation inhibition in clinically achieved concentrations, much higher levels are necessary for PGI2 release from intact human vessels. Furthermore, aspirin treatment of human vessels may prevent release of PGI2 in response to dipyridamole by blocking cyclooxygenase enzyme.     

New trends in thromboxane and prostacyclin modulators

Thromboxane A2 (TXA2) and prostacyclin (PGI2) are two labile products formed from arachidonic acid by the way of cyclooxygenase. An overproduction of thromboxane A2 has been detected in a series of diseases whereby this prostanoid is assumed to contribute to the underlying pathomechanisms by its potent stimulation of platelet aggregation and smooth muscle contraction. This increased TXA2 biosynthesis is frequently accompanied by a stimulation of prostacyclin formation which is one of the most potent inhibitors of platelet aggregation and smooth muscle contraction. Therefore, TXA2 / prostaglandin endoperoxide H2 receptor antagonists, thromboxane synthase inhibitors and drugs which combine both activities have been developed with the aim to suppress the formation and/or the action of thromboxane A2. Since prostacyclin has been demonstrated to counterbalance the pathological effects of TXA2, several PGI2 agonists have also been developed. This review will highlight the evolution and some of the latest findings in the field of prostacyclin and thromboxane A2 modulators mainly those which are under clinical evaluation or marketed.     

Antiplatelet effects of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in relation to its disposition in rats, rabbits and dogs.

KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) was evaluated for the inhibition of platelet aggregation and prostanoid production in rats, rabbits and dogs, comparing with acetylsalicylic acid (ASA). Correlations between the inhibitory action and plasma concentration of KC-764 were examined in rabbits. KC-764 was 200 times more potent than ASA in inhibiting collagen-induced rabbit platelet aggregation and TXA2 production in vitro. KC-764 exhibited more selective inhibition of TXA2 production over PGI2 production than ASA. The ratio of IC50's of PGI2 production to TXA2 production of KC-764 was 175 in rats, 72 in rabbits and 65 in dogs, respectively. Such a selectivity was also confirmed ex vivo. The depression of plasma TXB2 levels was well correlated with the ex vivo antiaggregatory activity in rabbits at oral doses of KC-764 ranging from 0.02-1.5 mg/kg. The concentrations/in vitro inhibitory activity relationship was expressed by a sigmoid Imax model equation. The ex vivo antiplatelet activity and prostanoid production were reconstructed with Imax model equation using the simulated plasma drug concentrations and in vitro Imax model parameters in all animals. The relationship could be applied for the prediction of the inhibitory activity of KC-764 in humans. These results indicate that KC-764 is a potent, selective and reversible antiplatelet drug, being different from ASA.     

复方丹参片与丹参片对冠状动脉粥样硬化患者血小板活化抑制作用的比较

目的:比较复方丹参片与丹参片对冠状动脉粥样硬化患者血小板活化的抑制作用。方法:90例冠状动脉粥样硬化确诊患者随机分为复方丹参片组、丹参片组和对照组,疗程2个月;另设正常组30例。分别采用放射免疫法和realtime PCR法检测血浆中环磷酸腺苷(cAMP)、血栓素A(2TXA2)、前列环素(PGI2)及前列腺环素合酶(PTGIS)mRNA的表达情况,并与正常组比较。结果:相对于正常组,冠状动脉粥样硬化患者血浆中cAMP、PGI2、PTGIS mRNA表达明显降低,TXA2表达明显升高。复方丹参片组和丹参片组能明显升高冠状动脉粥样硬化患者血浆中cAMP、PGI2、PTGIS mRNA表达,降低血浆中TXA2的表达,其中复方丹参片组的升高或降低作用显著大于丹参片组。结论:复方丹参片与丹参片均能抑制血小板活化,对冠状动脉粥样硬化患者急性冠脉综合征均有防治作用,但复方丹参片的防治效果强于丹参片。     

硬膜外阻滞行剖宫产对产妇及胎儿TXA_2和PGI_2的影响

观察25例硬膜外阻滞行剖宫产的正常产妇及胎儿脐血内TXA_2及PGI_2的变化。发现母体在胎儿娩出及术毕时与麻醉前相比,TXA_2及PGI_2均无统计学的改变(P>0.05),胎儿脐血内含量在母体范围内。表明局麻药利多卡因及丁卡因经硬膜外用药后,对TXA_2和PGI_2的平衡无明显影响,可能是由于硬膜外阻滞有效地抑制手术伤害刺激所致的应激反应。     

Thromboxane synthase inhibitors, thromboxane receptor antagonists and dual blockers in thrombotic disorders.

Thromboxane A2 (TXA2) plays a pivotal role in platelet activation and is involved in the development of thrombosis. Thromboxane synthase inhibitors suppress TXA2 formation and increase the synthesis of the antiaggregatory prostaglandins PGI2 and PGD2; however, accumulated PGH2 may interact with the platelet and vessel wall TXA2 receptor, thus reducing the antiplatelet effects of this class of drug. TXA2 receptor antagonists block the activity of both TXA2 and PGH2 on platelets and the vessel wall. Very recently, drugs possessing both thromboxane synthase-inhibitory and thromboxane receptor-antagonist properties have been developed. Paolo Gresele and colleagues explain here why these drugs can be more efficacious than traditional antiplatelet agents and review the available experimental studies involving these drugs.