Characteristics of rat platelets and relative contributions of platelets and blood coagulation to haemostasis.

In order to understand some of the haemostatic mechanisms in rats for the interpretation of toxicological data, basic haemostatic parameters with a special emphasis on platelet functions were first measured in vitro. The results of reactions of rat platelets to many aggregating agents suggest that only ADP may be a consistently significant aggregator. The search for physiologic aggregators revealed ADP to be available from erythrocytes. Adhesion reaction also required ADP. Collagen was not considered to be essential for either reaction. Aggregation and adhesion were probably both reversible in flowing blood, while irreversible thrombi were formed in blood at rest ex vivo. Blood coagulation parameters determined revealed that the intrinsic pathway may be more important than the extrinsic one. The rate of intrinsic coagulation reaction was rapid, and plasma coagulation appeared to be of primary importance while the influence of platelet aggregation was minor. A simple model of rat haemostatic mechanism is proposed based on these results. Additionally, to define the relative contribution of platelets versus other cellular and plasma coagulation in vivo, rats were administered antiplatelet drugs (ticlopidine, suprofen and clopidogrel) and an anticoagulant (warfarin) intraperitoneally. Bleeding times (BTs) were significantly increased in all treated groups. ADP-induced platelet aggregations were significantly depressed by the administration of the three antiplatelet drugs, while kaolon-activated partial thromboplastin time and prothrombin time were greatly increased in the warfarin-treated rats. The increase in BT may be due to the inhibition of platelet activity or blood coagulation defect in rats given antiplatelet drugs or warfarin, respectively. These results suggest that platelets play a key role in haemostasis in the rat. Two possible explanations of the disparity between in vitro and in vivo results may be that functional tests used here are not adequate to cover the properties of rat platelets or that mechanisms leading to the formation of platelet thrombi in rats are ADP-dependent adhesion and ADP-induced aggregation.     

Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes

Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats, a model of the metabolic syndrome, and Zucker Diabetic Fatty (ZDF) rats, a model of type 2 diabetes. Because of their lipid lowering action and antioxidant activity, we predicted that treatment with Rosuvastatin, an HMG-CoA reductase inhibitor (statin) or Enalapril, an angiotensin converting enzyme (ACE) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes. METHODS: 20-week-old Zucker obese and 16-week-old ZDF rats were treated with Rosuvastatin (25 mg/kg/day) or Enalapril (20 mg/kg/day) for 12 weeks. We examined metabolic parameters, indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries (75-175 microm intraluminal diameter) from lean, Zucker obese and ZDF rats (untreated and treated). RESULTS: Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats. Both drugs improved metabolic parameters, oxidative stress, and vascular dysfunction in Zucker obese rats, however, only partial improvement was observed in ZDF rats, suggesting more aggressive treatment is needed when hyperglycemia is involved. CONCLUSION: Vascular dysfunction is improved when Zucker obese and, to a lesser degree, when ZDF rats were treated with Rosuvastatin or Enalapril.     

Some properties of rat platelet aggregation and effects of butylated hydroxytoluene, warfarin and aspirin

The platelet aggregation characteristics of male Sprague-Dawley (Jcl:SD) rats were investigated. Epinephrine, ristocetin, serotonin and platelet-activating factor were ineffective in rat platelets. Heparinized platelet-rich plasma (PRP) was more sensitive than citrated PRP to three aggregating agents, ADP, collagen and arachidonic acid. Butylated hydroxytoluene (BHT) and BHT quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) inhibited ADP- and collagen-induced aggregation at concentrations over 10(-3) M in vitro. The ADP-, collagen- and arachidonic acid (0.5-2.0 mM)-induced aggregations of PRP obtained from rats given 1.20% BHT in the diet for 7 days were normal, while arachidonic acid (3.9 mM)-induced aggregation of PRP from BHT-fed rats was significantly lower than control. PRP from rats given aspirin and warfarin also aggregated normally with ADP or collagen addition. These results suggest that heparinized PRP may be preferable in platelet aggregation analyses in rats and reaffirmed that effects on platelet aggregation may not play a key role in BHT-induced bleeding. Platelet aggregation capacity also does not necessarily reduce in haemorrhages induced by aspirin or warfarin.     

Specific inhibition of ADP-induced platelet aggregation by clopidogrel in vitro

1. The thienopyridine clopidogrel is a specific inhibitor of ADP-induced platelet aggregation ex vivo. No direct effects of clopidogrel (< or = 100 microM) on platelet aggregation in vitro have been described so far. 2. Possible in vitro antiaggregatory effects (turbidimetry) of clopidogrel were studied in human platelet-rich plasma and in washed platelets. 3. Incubation of platelet-rich plasma with clopidogrel (< or = 100 microM) for up to 8 h did not result in any inhibition of ADP (6 microM)-induced platelet aggregation. 4. Incubation of washed platelets with clopidogrel resulted in a time- (maximum effects after 30 min) and concentration-dependent (IC50 1.9+/-0.3 microM) inhibition of ADP (6 microM)-induced platelet aggregation. Clopidogrel (30 microM) did not inhibit collagen (2.5 microg ml(-1))-, U46619 (1 microM)- or thrombin (0.1 u ml(-1))-induced platelet aggregation. The inhibition of ADP-induced aggregation by clopidogrel (30 microM) was insurmountable indicating a non-equilibrium antagonism of ADP actions. The R enantiomer SR 25989 C (30 microM) was significantly less active than clopidogrel (30 microM) in inhibiting platelet aggregation (32+/-5% vs 70+/-1% inhibition, P < 0.05, n = 5). 5. In washed platelets, clopidogrel (< or = 30 microM) did not significantly reverse the inhibition of prostaglandin E1 (1 microM)-induced platelet cyclic AMP formation by ADP (6 microM). 6. The antiaggregatory effects of clopidogrel were unchanged when the compound was removed from the platelet suspension. However, platelet inhibition by clopidogrel was completely abolished when albumin (350 mg ml(-1)) was present in the test buffer. 7. It is concluded that clopidogrel specifically inhibits ADP-induced aggregation of washed platelets in vitro without hepatic bioactivation. Inhibition of ADP-induced platelet aggregation by clopidogrel in vitro occurs in the absence of measurable effects on the reversal of PGE1-stimulated cyclic AMP by ADP.     

Inhibition of intravascular platelet aggregation in the rat by adrenaline

Intravascular platelet aggregation to adenosine diphosphate (ADP) was measured in anesthetized rats using 111indium-labelled platelets. Acute adrenalectomy increased the aggregatory effect of ADP in vivo, whereas infusions of low concentrations of adrenaline into adrenalectomized rats suppressed ADP-induced platelet aggregation. Similar antiaggregatory effects were seen with the alpha 2 agonist B-HT 933 and the alpha 1 agonist methoxamine, but not with isoprenaline. The effect of adrenaline was inhibited by phentolamine, yohimbine, the selective alpha 2 adrenoceptor antagonist WY 26392 and by indomethacin, but not by propranolol or prazosin. Adrenaline thus inhibits ADP-induced aggregation in vivo by a mechanism that may involve stimulation of an alpha 2 adrenoreceptor and may be dependent on activation of cyclooxygenase enzyme.     

Inhibitory mechanism of ifenprodil tartrate on rabbit platelet aggregation

The effects of dl-erythro-4-benzyl-alpha-(4-hydroxyphenyl)-beta-methyl-l-piperidine-eth anol tartrate (ifenprodil tartrate) on rabbit platelet aggregation in vitro and ex vivo were studied. Ifenprodil tartrate inhibited platelet aggregation in vitro induced by ADP, collagen and epinephrine. It also inhibited 5-hydroxytryptamine (5-HT) uptake into platelets and 5-HT release from platelets. Since these inhibitory effects of ifenprodil tartrate on the functions of rabbit platelets were similar to the effects of imipramine, the effects of ifenprodil tartrate may be due to the stabilizing action of ifenprodil tartrate on the platelet membrane. The platelet aggregation by ADP was significantly inhibited in rabbits after oral administration of ifenprodil tartrate, the maximal plasma level of ifenprodil being reached at 20 ng/ml ex vivo, while the maximal level was only 1/40 of the minimal concentration of ifenprodil tartrate necessary to inhibit platelet aggregation in vitro. These results indicate that factors other than ifenprodil tartrate acting directly on the platelets (e.g., PGI2 which is an endogenous inhibitor of platelet aggregation) are involved in inducing the inhibitory effects of ifenprodil tartrate on platelet aggregation ex vivo. The effects of ifenprodil tartrate on both PGI2 release from the aorta and the inhibitory effects of PGI2 on platelet aggregation in vitro were investigated: PGI2 was found to intensify the inhibitory effects of ifenprodil tartrate on platelet aggregation in vitro, but there was little effect, if any, on PGI2 release. Therefore, it is considered that the ex vivo effects of ifenprodil tartrate might be due to its interaction with endogenous PGI2 in the blood.     

The cannabinoid receptor-1 antagonist rimonabant inhibits platelet activation and reduces pro-inflammatory chemokines and leukocytes in Zucker rats

BACKGROUND AND PURPOSE: We investigated the effect of rimonabant on inflammation and enhanced platelet reactivity in type 2 diabetic Zucker rats, an experimental model of impaired glucose tolerance and the metabolic syndrome. EXPERIMENTAL APPROACH: Rimonabant (10 mg kg(-1) by gavage) was fed for 2 weeks to 3-month-old male obese Zucker rats as an impaired glucose tolerance model and for 10 weeks to 6-month-old male obese Zucker rats as a model of the metabolic syndrome. RANTES (Regulated upon Activation, Normal T cell Expressed, and Secreted) and MCP-1 (monocyte chemotactic protein-1) serum levels were determined by ELISA. Leukocyte populations were quantitatively assessed using a veterinary differential blood cell counter. Platelet activation was assessed by flow-cytometry, platelet aggregation, and adhesion of isolated platelets to immobilized fibrinogen. KEY RESULTS: RANTES and MCP-1 serum levels were increased in obese vs lean Zucker rats and significantly reduced by long-term treatment with rimonabant, which slowed weight gain in rats with the metabolic syndrome. Neutrophils and monocytes were significantly increased in young and old obese vs lean Zucker rats and lowered by rimonabant. Platelet-bound fibrinogen was significantly enhanced in obese vs lean Zucker rats of both age, and was reduced by rimonabant. Platelets from obese rats were more sensitive to thrombin-induced aggregation and adhesion to fibrinogen, which were both attenuated by rimonabant therapy. CONCLUSIONS AND IMPLICATIONS: We demonstrate positive modulation of circulating neutrophil and monocyte numbers, reduced platelet activation and lower RANTES and MCP-1 levels by rimonabant in Zucker rats. This may potentially contribute to a reduction of cardiovascular risk.     

ATP induces contraction mediated by the P2Y(2) receptor in rat intestinal subepithelial myofibroblasts

The role of endogenous nitric oxide in regulating platelet function in vivo is incompletely understood. The enzymic and anatomic sources of bioactive NO remain unclear and the consequences of the differences in endothelial function between males and females to platelet responsiveness are not known. We employed a mouse model of platelet thromboembolism to assess platelet aggregation in vivo along with supporting in vitro studies to investigate these issues. Pharmacological nitric oxide synthase (NOS) inhibition protracted the duration of thromboembolic responses to ADP (adenosine diphosphate) and enhanced in vivo platelet aggregation following activation of the coagulation cascade. Collagen induced in vivo platelet aggregation was enhanced in female eNOS(-/-) mice and the NOS inhibitor L-NAME (Nω-Nitro-l-arginine methyl ester hydrochloride) potentiated collagen induced thromboembolism although selective iNOS and nNOS antagonists had no effect. None of the NOS inhibitors tested had significant effects on platelet aggregation in isolated whole blood. In conclusion, endogenous NO derived from eNOS in the vascular endothelium is a critical regulator of platelet function in vivo in both males and females with negligible roles of iNOS and nNOS. Despite the expression of NOS enzymes in circulating blood elements, there is no evidence of a functional role of endogenous NO from these cells in regulating platelets. eNOS and its up- and down-stream mediators are therefore potential anti-thrombotic targets.     

The suppressive effect of pyrrole-2-carboxylic acid on platelet aggregation

In the course of a search for novel antibiotics, an antiplatelet substance was isolated from the fermentation broth of Streptomyces sp. No. 82-85. Thereafter, the active substance was identified as pyrrole-2-carboxylic acid (P2C) by structural studies. The effects of P2C on adenosine diphosphate (ADP)-, arachidonic acid-, collagen- or tumor cell-induced platelet aggregation were examined in vitro and ex vivo. In in vitro studies, P2C (25-100 micrograms/ml) suppressed the aggregation of platelets of normal Wistar rats. The intraperitoneal administration of P2C (200 mg/kg) to rats and rabbits suppressed platelet aggregation induced by ADP, arachidonic acid and collagen when examined for 0.5-3 hours after administration. The agent also suppressed platelet aggregation induced by both mouse syngenic tumors, Meth-A fibrosarcoma and IMC carcinoma in vitro.     

Inhibition of rat platelet aggregation by a Prudhoe Bay crude oil and its aliphatic,aromatic, and heterocyclic fractions

Wasjed platelets isolated from rats 24 hr after oral treatment with a Prudhoe Bay crude oil (PBCO) showed a substantial inhibition of aggregation induced by ADP, arachidonic acid, or epinephrine. In vitro addition of a dimethyl sulfoxide extract of PBCO or its aliphatic, aromatic, or heterocyclic fractions to washed platelets also resulted in an inhibition of aggregation. ADP release was inhibited in platelets to which an extract of PBCO or its fractions were added in vitro or in platelets isolated from rats treated in vivo with PBCO. Thromboxane B₂ release was increased in platelets isolated from rats intubated with PBCO or in platelets to which a dimethyl sulfoxide extract of the aromatic or heterocyclic fraction was added. However, thromboxane B₂ release was inhibited in platelets to which PBCO or the aliphatic fraction extracts were added. The results indicate that PBCO inhibits platelet aggregation presumably by bringing about alterations in the platelet plasma membrane. Inhibition of ADP release could contribute to the inhibition of aggregation but thromboxane B₂ is believed not to play a significant role.     

Inhibition of collagen- and ADP-induced platelet aggregation by substance P in vivo: involvement of endothelium-derived relaxing factor.

We examined the effect of substance P, a potent stimulator of endothelium-derived relaxing factor (EDRF) release, on responses to collagen and adenosine 3',5'-diphosphate (ADP) in an in vivo model of platelet aggregation. Substance P inhibited platelet aggregation induced in vivo by both collagen and ADP. This anti-platelet effect was particularly pronounced against collagen-induced aggregation and was prevented by prior administration of haemoglobin (Hb), a known inhibitor of EDRF-mediated responses. Collagen-induced platelet aggregation in vitro was unaffected by a concentration of substance P equivalent to that achieved in plasma following in vivo administration. This study provides a clear demonstration of the anti-platelet activity of EDRF in vivo and an indication that its effectiveness may depend on the aggregating agent used.     

Studies on the antiplatelet effect of the stable epoprostenol analogue beraprost sodium and its mechanism of action in rats

Baraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a.8b- tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6- 1H-cyclopenta[b]benzo-furan-5-butyrate, TRK-100) is a novel stable epoprostenol (prostaglandin I2, PGI2) analogue having antiplatelet and vasodilating actions. Its effect on platelet aggregation in whole blood ex vivo and platelet suspension in vitro, formation of cyclic AMP(cAMP), production of malondialdehyde(MDA), and 45Ca++-influx into platelets were studied in rats. Oral administration of TRK-100 (0.3-1 mg/kg) showed a dose-dependent inhibition of platelet aggregation induced by ADP and collagen in whole blood and also inhibited in vitro thrombin-induced aggregation of platelet suspension in the presence or absence of external Ca++. Oral TRK-100 (0.3-3 mg/kg) dose-dependently increased plasma cAMP levels and this action was confirmed in vitro with platelet rich plasma in the presence or absence of theophylline. 45Ca++-influx into platelets stimulated by thrombin was dose-dependently inhibited by TRK-100 (3-100 nmol/l). TRK-100 (3-100 nmol/l) also suppressed MDA production induced by thrombin in platelet suspension but not that induced by arachidonic acid. From these results, TRK-100 which is orally active was suggested to exert its antiplatelet action through the increase of cAMP in platelets by activation of adenylate cyclase, concomitantly followed by the inhibition of Ca++-influx and thromboxane A2 formation.     

Effects of AVS (1,2-bis(nicotinamido)propane) on platelet function and vascular endothelium

The effects of 1,2-bis(nicotinamido)propane (AVS) on platelet function and vascular endothelium were investigated using various experimental thrombosis and vascular endothelial injury models. Neither in vitro platelet aggregation induced by ADP, collagen or arachidonate nor ex vivo platelet aggregation by ADP or collagen could be antagonized by AVS. On the other hand, AVS prevented mice, rats and rabbits from death induced by acute cerebral or pulmonary thromboembolism following the injection of arachidonate or collagen. These activities were as potent as those of acetylsalicylic acid. The disrupting actions of citrate and/or lipidperoxide (13-hydroperoxy linoleic acid) on endothelium were well inhibited by the pretreatment of AVS. AVS did not inhibit cyclooxygenase, increased prostacyclin (PGI2)/thromboxane A2 (TXA2) ratio in the coupled system of platelets and aortic microsomes. In conclusion, AVS inhibited thrombus formation in vivo while it was ineffective in vitro platelet alone system, which may result from the actions of this agent on both platelets and vascular endothelium. The above-mentioned results clearly show that AVS may be a new potent anti-vascular damaging agent with both endothelium stabilizing and PGI2 enhancing activities.     

Effects of plumbagin on platelet aggregation and platelet-neutrophil interactions

The effects of plumbagin were investigated on platelet aggregation in vitro and ex vivo, on the binding of thrombin-stimulated platelets to neutrophils, and platelet aggregation induced by intact neutrophils and N-formyl-methionyl-leucyl-phenylalanine (fMLP) or platelet activating factor (PAF) activated neutrophils, by use of the methods of Hamburger, McEver and Born, respectively. The results showed that plumbagin in vitro significantly inhibited adenosine diphosphate (ADP)-, arachidonic acid (AA)-, or platelet activating factor (PAF)-induced platelet aggregation, in a concentration-dependent manner. The medium inhibitory concentrations (IC 50 ) were 39.4, 82.7 and 38.1 microM, respectively. Intragastric plumbagin at 10 mg/kg markedly suppressed platelet aggregation induced by ADP, AA, or PAF. Plumbagin decreased the binding between thrombin-stimulated platelets and neutrophils with an IC 50 of 62.9 microM. Plumbagin significantly inhibited washed platelet aggregation stimulated by fMLP- or PAF-activated neutrophils. The IC 50 values were 54.3 and 47.6 microM, respectively. On the other hand, plumbagin and aspirin increased the inhibition of intact neutrophils on AA-induced platelet aggregation. It is suggested that plumbagin inhibited platelet aggregation in vitro and ex vivo, suppressed the binding of activated platelets to neutrophils, inhibited platelet aggregation induced by activated neutrophils, and increased inhibition of intact neutrophils on platelet reactivity. Abbreviations. DMSO:dimethyl sulphoxide fMLP: N-formyl-methionyl-leucyl-phenylalanine ADP:adenosine diphosphate AA:arachidonic acid PAF:platelet activating factor     

咪苯嗪酮对血小板聚集、血栓形成和血小板环磷酸腺苷含量的影响

本文观察了新型强心剂咪苯嗪酮(Cl-914)对血小板聚集、血栓形成和血小板cAMP含量的影响。用比浊法测定Cl-914体外抑制AA,ADP和胶原诱导兔血小板聚集的IC_(50),分别为2.6,8.9和15.8μM;大鼠iv Cl-914 1.25mg/kg能抑制实验性血栓形成,20 mg/kg能抑制上述三种诱导剂引起的血小板聚集。在体外,用竞争性蛋白结合法测定,CI-914可使洗涤兔血小板cAMP含量明显升高。CI-914能以剂量依赖方式协同PGE_1抑制血小板聚集和升高血小板cAMP的含量。提示CI-914升高血小板cAMP含量可能是其抑制血小板聚集和抗血栓形成的主要机理。     

Inhibition of platelet aggregation following chronic in vivo treatment of rats with nicotine: prevention by simultaneous application of propranolol

Platelet aggregability is known to be enhanced and platelet-survival time shortened in smokers when compared with nonsmokers. Up to now it is unknown which of the substances in tobacco smoke are responsible for these effects. To evaluate a possible role of nicotine, rats were chronically treated with the alkaloid (10 mg/kg/day), continuously released from subcutaneously implanted osmotic minipumps. Surprisingly, after 8 weeks, platelet sensitivity toward the aggregating stimulus adenosine 5'-diphosphate (ADP) was markedly reduced. The mean ADP concentration required to induce half the maximum rate of aggregation (EC50) was 0.88 mumol/L in nicotine-treated animals, as compared with 0.67 mumol/L in controls (p less than 0.002). Platelet aggregability remained normal when the rats were treated simultaneously with nicotine and the beta blocker propranolol (3.5 mg/kg/day); for these animals, the mean EC50 for ADP was 0.73 mumol/L. These results are suggestive of a catecholamine-mediated action of nicotine. However, neither the basal levels of cAMP in platelet-rich plasma, nor the cAMP levels attained after stimulation of platelet adenylate cyclase with prostaglandin E1 (PGE1), were affected by 8 weeks of treatment with nicotine or nicotine plus propranolol. No effect on platelet aggregation was observed when the rats were treated with nicotine for only 2 weeks, or when nicotine or nicotine plus cotinine were added to platelet-rich plasma in vitro in concentrations equal to those attained in vivo after 8 weeks. Thus, prolonged application of nicotine in vivo caused an inhibition of ADP-induced rat platelet aggregation presumably mediated by beta-catecholaminergic stimulation of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of fibrinopeptides A and B on human and rat platelet aggregation in vitro

The effect of fibrinopeptides on platelet aggregation is reported. Fibrinopeptide A (minimal effective concentration, 0.65 microM) aggregated human (but not rat) platelets suspended in plasma and at lower concentrations (0.01-0.1 microM) potentiated platelet aggregation due to ADP and collagen in both species. Fibrinogen mimicked these effects of fibrinopeptide A. P-bromophenacyl bromide (100 microM), mepacrine (10 microM), indomethacin (10 microM) and dazoxiben (10 microM) inhibited human platelet aggregation induced by fibrinopeptide A and fibrinogen. In both species, fibrinopeptide B (0.65-6.5 microM) antagonised the platelet inhibitory effect of PGI2 and PGD2 but not adenosine. Antagonism was non-competitive in nature. The concentration of fibrinopeptide A required to potentiate platelet aggregation occurs naturally in the plasma of patients with thrombotic disease suggesting this effect may be of physiological significance during the formation of a thrombus. The novel action of fibrinopeptide B to reduce the platelet inhibitory effect of PGI2 and PGD2 may also contribute to the control of thrombus formation.     

Inhibition of platelet function by administration of MRS2179, a P2Y1 receptor antagonist

The effects of a potent P2Y1 receptor antagonist, N6-methyl-2'-deoxyadenosine-3',5'-bisphosphate (MRS2179) on adenosine-5'-diphosphate (ADP)-induced platelet aggregation in vitro, ex vivo and on the bleeding time in vivo were determined. In suspensions of washed platelets, MRS2179 inhibited ADP-induced platelet shape change, aggregation and Ca2+ rise but had no effect on ADP-induced inhibition of adenylyl cyclase. Binding studies using the new radioligand [33P]MRS2179 showed that washed human platelets displayed 134+/-8 binding sites per platelet with an affinity (Kd) of 109+/-18 nM. Finally, intravenous injection of MRS2179 resulted in inhibition of rat platelet aggregation in response to ADP and prolonged the bleeding time, in rats or mice, as compared to controls. These results suggest this potent P2Y1 receptor antagonist to be a promising tool to evaluate the in vivo effects of pharmacologically targeting the P2Y1 receptor with a view to antithrombotic therapy.     

Increased platelet aggregation responses to 5-hydroxytryptamine in patients taking chlorpromazine.

1 The aggregation response of platelets induced by 5-HT was greatly increased in psychiatric patients receiving chlorpromazine therapy when compared with normal volunteers and psychiatric patients not receiving chlorpromazine. 2 Platelet aggregation responses to ADP were normal during chlorpromazine therapy, but 5-HT induced aggregation was increased in rate and the typical transient reversible response was converted to an irreversible response in all subjects. This was usually indistinguishable from the ADP response. 3 When chlorpromazine therapy was stopped, plasma concentrations of chlorpromazine, monodesmethylchlorpromazine and chlorpromazine sulphoxide fell rapidly within one week, whereas 5-HT induced platelet aggregation responses became normal after three weeks. The enhanced responses returned when chlorpromazine therapy was re-instituted. 4 It is possible that platelet aggregation responses to 5-HT in vitro could prove to be a useful index of the pharmacological effect of chlorpromazine in vivo.     

奥沙普嗪对血小板聚集和血栓形成的影响

目的:研究奥沙普嗪对家兔和大鼠血小板聚集和血栓形成的影响.方法:麻醉动物颈动脉取血,制备富含血小板血浆(PRP),加入奥沙普嗪,用多功能血小板聚集仪测定二磷腺苷(ADP)诱导的血小板聚集作用.结果:奥沙普嗪能明显抑制ADP诱导动物体内外血小板聚集和降低胶原 肾上腺素静脉注射所致的小鼠死亡率.结论:初步证实奥沙普嗪具有类似阿司匹林抑制血小板聚集作用.