The Inhibitory Effect of GR32191, a Thromboxane Receptor Blocking Drug, on Human Platelet Aggregation, Adhesion and Secretion

1989 ◽  
Vol 61 (03) ◽  
pp. 429-436 ◽  
Author(s):  
E J Hornby ◽  
M R Foster ◽  
P J McCabe ◽  
L E Stratton
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Rabbit Aorta ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Camp Phosphodiesterase ◽  
Platelet Protein ◽  
Thromboxane Receptor ◽  
Serotonin Secretion

SummaryGR32191, a potent selective thromboxane receptor antagonist, has been shown to inhibit completely prostaglandin endoperoxide and thromboxane A2 (TxA2)-induced platelet aggregation, [14C]-serotonin secretion and β-thromboglobulin secretion. Deposition of human platelets onto damaged rabbit aorta in vitro is reduced in the presence of GR32191 which appears to inhibit aggregation of platelets but not direct adhesion of platelets to subendothelium. The effects of non-prostanoid platelet activating agents whose mode of action requires the biosynthesis of TxA2 are also inhibited by GR32191. Prostanoids which inhibit platelet function, such as prostacyclin or PGD2, retain their inhibitory properties in the presence of GR32191 which does not inhibit phospholipase A2, prostaglandin cyclooxygenase, thromboxane synthase, 12-lipoxygenase or cAMP phosphodiesterase activity. The inhibitory action of GR32191 on platelet aggregation, mural thrombus formation and platelet protein storage granule secretion suggests that it has potential in treatingthrombotic disease in man.

Inhibitory Effect of Piracetam on Platelet-rich Thrombus Formation in an Animal Model

1998 ◽  
Vol 79 (01) ◽  
pp. 222-227 ◽  
Author(s):  
F. Stockmans ◽  
W. Deberdt ◽  
Å. Nyström ◽  
E. Nyström ◽  
J. M. Stassen ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Peak Plasma ◽  
Thrombus Formation ◽  
Plasma Concentrations ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Cell Deformability

SummaryIntravenous administration of piracetam to hamsters reduced the formation of a platelet-rich venous thrombus induced by a standardised crush injury, in a dose-dependent fashion with an IC50 of 68 ± 8 mg/kg. 200 mg/kg piracetam also significantly reduced in vivo thrombus formation in rats. However, in vitro aggregation of rat platelets was only inhibited with piracetam-concentrations at least 10-fold higher than plasma concentrations (6.2 ± 1.1 mM) obtained in the treated animals. No effects were seen on clotting tests.In vitro human platelet aggregation, induced by a variety of agonists, was inhibited by piracetam, with IC50’s of 25-60 mM. The broad inhibition spectrum could be explained by the capacity of piracetam to prevent fibrinogen binding to activated human platelets. Ex vivo aggregations and bleeding times were only minimally affected after administration of 400 mg/kg piracetam i.v. to healthy male volunteers, resulting in peak plasma levels of 5.8 ± 0.3 mM.A possible antiplatelet effect of piracetam could be due to the documented beneficial effect on red blood cell deformability leading to a putative reduction of ADP release by damaged erythrocytes. However similarly high concentrations were needed to prevent stirring-induced “spontaneous” platelet aggregation in human whole blood.It is concluded that the observed antithrombotic action of piracetam cannot satisfactorily be explained by an isolated direct effect on platelets. An additional influence of piracetam on the rheology of the circulating blood and/or on the vessel wall itself must therefore be taken into consideration.

Antiplatelet Effect Of A New Compound, Imidazo[1,2-a]- Thienopyrimidin-2-One : A Cyclic AMP Mediated Phenomenon

1981 ◽  
Author(s):  
S Ashida ◽  
K Sakuma ◽  
Y Abiko
Keyword(s):  
Platelet Aggregation ◽  
Membrane Fraction ◽  
Close Correlation ◽  
Inhibitory Effect ◽  
Camp Level ◽  
Camp Phosphodiesterase ◽  
Pde Inhibitors ◽  
Camp Metabolism ◽  
Oral Doses

The effect of a new compound, 1,2,3,5,6,7,8,9-Octahydro- [1]benzothieno[2,3-d]imidazo[1,2-a]pyrimidin-2-one hydrochloride (DH-6471), on cAMP metabolism and aggregation of platelets was studied. In vitro. DH-6471 inhibited platelet aggregation (both the 1st and 2nd phases) induced by ADP, collagen, thrombin, arachidonic acid and PGG2-TXA2 mixture in PRP from various animal species including human at concentrations (IC50) ranging from 0.07 to 8 μH. It inhibited ADP- and collagen-induced platelet aggregation ex vivg in rats following oral doses as low as 0.3- 1 mg/kg.The compound was found to be a highly selective inhibitor of platelet low Km cAMP phosphodiesterase (Ki=0.025 μM), when tested with enzyme fractions separated by DEAE-cellu-lose chromatography. It did not significantly affect basal or PGE1(0.1-1 μM)-stimulated cAMP level of platelets at a concentration of 1 μM where platelet aggregation and the low Km PDE were markedly inhibited. However, both basal and PGE1-stimulated accumulations of cAMP in the platelet membrane fraction were increased by DH-6471 at 1 μM when the isolated membrane fraction was incubated with ATP-Mg2+.Studies with several PDE inhibitors including papaverine, dipyridamole and DH-6471-related compounds showed a close correlation between their ability to inhibit the low Km PDE or to increase cAMP accumulation in the membrane fraction and their inhibitory effect on platelet aggregation. On the other hand, their potency to inhibit high Km cAMP-PDE(cGMP-PDE) and to increase cAMP level in whole platelets was poorly correlated to their inhibitory activity in platelet aggregation.These results suggest that some small but local changes in platelet cAMP may be involved in the regulation of platelet aggregation, particularly primary aggregation.

Effect of Heparin on Aggregation, Release Reaction and Thromboxane A2synthesis in Human Platelets

1979 ◽  
Author(s):  
H.Y.K. Chuang ◽  
S.F. Mohammad ◽  
R.G. Mason
Keyword(s):  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Thromboxane A2 ◽  
Rabbit Aorta ◽  
Human Platelets ◽  
Appreciable Effect ◽  
Layer Chromatography ◽  
Aggregation Of Platelets ◽  
Platelet Functions

Studies on the effect of heparin on platelet functions have resulted in conflicting observations: heparin has been reported to cause aggregation of platelets, potentiate aggregation induced by various aggregating agents, or cause inhibition of aggregation. Using paritally purified heparin (beef lung or porcine mucosa) we observed that addition of heparin to citrated platelet rich plasma(C-PRP)potentiated the aggregation of platelets induced by ADP, epinephrine, or arachidonic acid. Presence of heparin in C-PRP results in complete inhibition of thrombin induced effects and partial inhibition of platelet aggregation induced by collagen. Presence of heparin in C-PRP also resulted in release of significantly higher concentrations of 14C-serotonin when platelets were challenged by appropriate aggregating agents. Those concentrations of heparin that resulted in potentiation of aggregation had no appreciable effect on c-AiMP or c-GMP levels of platelets. However, the presence of heparin results in a significant elevation of thromboxane A2 as determined by contraction of rabbit aorta or after conversion to thromboxane B2 by thin layer chromatography. These observations are of interest since increased production of thromboxane A2 in the presence of heparin may explain in part, the potentiation of platelet aggregation in vitro or thrombocytopenia observed frequently in patients receiving heparin intravenously Supported in part by grants HL22583 & 20679 from NHLBI of NIH.

The Inhibitory Effect Of Dilazep On Adhesion And Aggregation Of Platelet Following Aortic Intimal Injury In Rabbit

1981 ◽  
Author(s):  
A Sumiyoshi ◽  
T Hayashi ◽  
M Fujii
Keyword(s):  
Platelet Aggregation ◽  
Platelet Adhesion ◽  
Rabbit Aorta ◽  
Inhibitory Effect ◽  
Endothelial Injury ◽  
Platelet Adhesion And Aggregation ◽  
Injured Area ◽  
Polyethylene Tubing

The inhibitory effect of dilazep and aspirin on in vivo platelet adhesion and aggregation in rabbit aorta subjected to endothelial injury was investigated. Endothelial injury was induced by insertion of polyethylene tubing from the femoral artery into the aorta. In the beginning before surgery, experimental animals were intravenously given sufficient drug to inhibit platelet aggregation in vitro in response to ADP and collagen. For a quantitative analysis of platelet accumulation on the damaged aortas, 51Cr-labeled platelets were used. For morphological study, the aortas were fixed by perfusion at one hour after injury and examined by light and scanning electron microscopy for platelet adhesion and aggregation in injured area.Radioactivity of damaged aortas in rabbits administered dilazep (50 or 100 μg/kg) or aspirin (10 mg/kg) was significantly lower than in rabbits untreated by drug. Dilazep and aspirin did not prevent completely the adherence of platelets on injured area of the aorta, but inhibited considerably the platelet aggregation to form raised platelet thrombus.

scholarly journals An Antithrombotic Strategy by Targeting Phospholipase D in Human Platelets

2018 ◽  
Vol 7 (11) ◽  
pp. 440 ◽  
Author(s):  
Wan Lu ◽  
Chi Chung ◽  
Ray Chen ◽  
Li Huang ◽  
Li Lien ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Phospholipase D ◽  
Thrombus Formation ◽  
Human Platelets ◽  
Platelet Activity ◽  
Clot Retraction ◽  
First Time

Phospholipase D (PLD) is involved in many biological processes. PLD1 plays a crucial role in regulating the platelet activity of mice; however, the role of PLD in the platelet activation of humans remains unclear. Therefore, we investigated whether PLD is involved in the platelet activation of humans. Our data revealed that inhibition of PLD1 or PLD2 using pharmacological inhibitors effectively inhibits platelet aggregation in humans. However, previous studies have showed that PLD1 or PLD2 deletion did not affect mouse platelet aggregation in vitro, whereas only PLD1 deletion inhibited thrombus formation in vivo. Intriguingly, our data also showed that the pharmacological inhibition of PLD1 or PLD2 does not affect mouse platelet aggregation in vitro, whereas the inhibition of only PLD1 delayed thrombus formation in vivo. These findings indicate that PLD may play differential roles in humans and mice. In humans, PLD inhibition attenuates platelet activation, adhesion, spreading, and clot retraction. For the first time, we demonstrated that PLD1 and PLD2 are essential for platelet activation in humans, and PLD plays different roles in platelet function in humans and mice. Our findings also indicate that targeting PLD may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders.

SELECTIVE ANTAGONISTS OF PAF: INTERFERENCE WITH PLATELET FUNCTION AND EFFECT ON THROMBOGENESIS INDUCED BY SUBENDOTHELIUM.

1987 ◽  
Author(s):  
P Hadvary ◽  
H R Baumgartner
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Blood Platelets ◽  
Rabbit Aorta ◽  
Constant Infusion ◽  
Induced Aggregation

Platelet activating factor (PAF) is a very potent excitatory agonist of blood platelets but the physiological importance of this mediator in platelet thrombus formation is not known. We investigated the effect of two chemically unrelated selective inhibitors of PAF-induced platelet aggregation on thrombogenesis induced by rabbit aorta subendothelium (SE) using an ex vivo perfusion system.Ro 19-3704 is a highly potent inhibitor structurally related to PAF. This compound inhibits PAF-induced aggregation of rabbit platelets in platelet rich plasma in vitro competitively. Against 4 nM PAF, a concentration resulting in submaximal platelet aggre-gregation velocity, the IC50 was 70 nM. Inhibition was highly selective for PAF-induced aggregation, since aggregation induced by collagen (HORM, 5 yg/ml), ADP (1 yM) or thrombin (0.4 U/ml) was not inhibited even at a concentration as high as 10 yM. Bro-tizolam, a triazolobenzodiazepine reported to be a selective inhibitor of PAF-induced platelet activation, had in our system an IC50 of 200 nM. The selective benzodiazepine antagonist Ro 151788 was without effect on inhibition of PAF-induced platelet activation by brotizolam.Ro 19-3704 was given intravenously to rabbits as a bolus of 0.2 mg/kg followed by constant infusion of 0.02 mg/kg/min. This dosage provoked ex vivo a constant right shift ratio of the dose response curve for PAF-induced aggregation (RSR[PAF]) by a factor of 25 to 35. Brotizolam was given orally at a dose of 100 mg/ kg together with 300 mg/kg of Ro 15-1788 (to antagonize the central effects) 90 minutes before starting the perfusion experiment, resulting in a RSR[PAF] of 35 to 135. ADP induced platelet aggregation was not impaired by either compound. SE was exposed to the non-anticoagulated blood withdrawn from the carotid artery for 3 min at 2600 s-1 and for 20 min at 200 s-1 shear rate. Quantitative morphometric evaluation showed that SE coverage by platelets and by fibrin, thrombus area and thrombus height were all unchanged by the PAF antagonists at low and at high shear rates despite a very substantial inhibition of PAF-induced platelet aggregation. Therefore a major role of PAF in SE-induced thrombogenesis seems unlikely.

scholarly journals Selective Inhibition of PAR4 (Protease-Activated Receptor 4)-Mediated Platelet Activation by a Synthetic Nonanticoagulant Heparin Analog

2019 ◽  
Vol 39 (4) ◽  
pp. 694-703 ◽  
Author(s):  
Yu-Chuan Lin ◽  
Yen-Chun Ko ◽  
Shang-Cheng Hung ◽  
Ying-Ting Lin ◽  
Jia-Hau Lee ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Anticoagulant Activity ◽  
Chinese Hamster ◽  
Selective Inhibition ◽  
Human Platelets ◽  
Thrombosis Model ◽  
Promising Target ◽  
New Strategy

Objective— PAR4 (protease-activated receptor 4), one of the thrombin receptors in human platelets, has emerged as a promising target for the treatment of arterial thrombotic disease. Previous studies implied that thrombin exosite II, known as a binding site for heparin, may be involved in thrombin-induced PAR4 activation. In the present study, a heparin octasaccharide analog containing the thrombin exosite II–binding domain of heparin was chemically synthesized and investigated for anti-PAR4 effect. Approach and Results— PAR4-mediated platelet aggregation was examined using either thrombin in the presence of a PAR1 antagonist or γ-thrombin, which selectively activates PAR4. SCH-28 specifically inhibits PAR4-mediated platelet aggregation, as well as the signaling events downstream of PAR4 in response to thrombin. Moreover, SCH-28 prevents thrombin-induced β-arrestin recruitment to PAR4 but not PAR1 in Chinese Hamster Ovary-K1 cells using a commercial enzymatic complementation assay. Compared with heparin, SCH-28 is more potent in inhibiting PAR4-mediated platelet aggregation but has no significant anticoagulant activity. In an in vitro thrombosis model, SCH-28 reduces thrombus formation under whole blood arterial flow conditions. Conclusions— SCH-28, a synthetic small-molecular and nonanticoagulant heparin analog, inhibits thrombin-induced PAR4 activation by interfering with thrombin exosite II, a mechanism of action distinct from other PAR4 inhibitors that target the receptor. The characteristics of SCH-28 provide a new strategy for targeting PAR4 with the potential for the treatment of arterial thrombosis.

A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models

2016 ◽  
Vol 116 (08) ◽  
pp. 285-299 ◽  
Author(s):  
Shiu-Wen Huang ◽  
Heng-Lan Kuo ◽  
Ming-Tsung Hsu ◽  
Yufeng Jane Tseng ◽  
Shu-Wha Lin ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Benzimidazole Derivative ◽  
Antithrombotic Agent ◽  
Hek 293 ◽  
Thromboxane Receptor ◽  
Vascular Physiology ◽  
Thromboxane Receptor Antagonist

SummaryA novel benzimidazole derivative, nstpbp5185, was discovered through in vitro and in vivo evaluations for antiplatelet activity. Thro-maboxane receptor (TP) is important in vascular physiology, haemostasis and pathophysiological thrombosis. Nstpbp5185 concentration-dependently inhibited human platelet aggregation caused by collagen, arachidonic acid and U46619. Nstpbp5185 caused a right-shift of the concentration-response curve of U46619 and competitively inhibited the binding of 3H-SQ-29548 to TP receptor expressed on HEK-293 cells, with an IC50 of 0.1 μM, indicating that nstpbp5185 is a TP antagonist. In murine thrombosis models, nstpbp5185 significantly prolonged the latent period in triggering platelet plug formation in mesenteric and FeCl3-induced thrombi formation, and increased the survival rate in pulmonary embolism model with less bleeding than aspirin. This study suggests nstpbp5185, an orally selective antithrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Derrone Inhibits Platelet Aggregation, Granule Secretion, Thromboxane A2 Generation, and Clot Retraction: An In Vitro Study

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Jung-Hae Shin ◽  
Muhammad Irfan ◽  
Man Hee Rhee ◽  
Hyuk-Woo Kwon
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
In Vitro Study ◽  
Human Platelets ◽  
Clot Retraction ◽  
Traditional Remedy ◽  
Intracellular Calcium Level ◽  
Mitogen Activated Protein ◽  
Granule Secretion

Cudrania tricuspidata (C. tricuspidata) is widespread throughout East Asia and in China and Korea, and it is widely used as a traditional remedy against eczema, mumps, and tuberculosis. With regard to the aforementioned medical efficacy, various studies are continuously being conducted, and it has been reported that C. tricuspidata extract has various actions against inflammation, diabetes, obesity, and tumors. Therefore, we evaluated antiplatelet effects using derrone in C. tricuspidata. We examined the effect of derrone on the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and inositol 1, 4, 5-triphosphate receptor I (IP3RI), and on the dephosphorylation of cytosolic phospholipase A2 (cPLA2), mitogen-activated protein kinases p38 (p38MAPK), and Akt, which affects platelet function and thrombus formation. Various agonists-induced human platelets were inhibited by derrone without cytotoxicity, and it also decreased the intracellular calcium level through the signaling molecule phosphorylations. In addition, derrone inhibited glycoprotein IIb/IIIa (αIIb/β3) affinity. Thus, in the present study, derrone suppressed human platelet aggregation and thrombin-induced clot formation.

Effect of Aspirin and Dipyridamole on the Interaction of Human Platelets with Sub-Endothelium: Studies Using Citrated and Native Blood

1981 ◽  
Vol 45 (02) ◽  
pp. 136-141 ◽  
Author(s):  
Harvey J Weiss ◽  
Vincent T Turitto ◽  
William J Vicic ◽  
Hans R Baumgartner
Keyword(s):  
Shear Rate ◽  
Platelet Adhesion ◽  
Inner Core ◽  
Thrombus Formation ◽  
Human Subjects ◽  
Rabbit Aorta ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Platelet Thrombi

SummaryThe effect of aspirin and dipyridamole ingestion on the interaction of platelets with the subendothelium was studied using both citrated blood and directly sampled (native) blood. After obtained control studies, normal human subjects ingested 0.6 g of aspirin, 150 mg of dipyridamole, or a placebo and studies were repeated 1½ hrs later. Subjects continued on placebo, aspirin (0.6 g b.i.d.) or dipyridamole (100 mg q.i.d.) for 6 days and studies were obtained 1½ hrs after the last dose. Blood was circulated through an annular chamber on whose inner core were mounted everted segments of de-endothelialized rabbit aorta. The wall shear rate was 2,600 sec-1. Surface coverage with adherent platelets and platelet thrombi, as well as several parameters of thrombus dimensions, were evaluated morphometrically. Aspirin ingestion markedly reduced platelet thrombi in citrated blood, – but had a much lesser inhibitory effect in native blood. Platelet adhesion was unaffected in native blood; it was slightly decreased in citrated blood, in contrast to previous findings in which a lower shear rate (800 sec-1) was used. Ingestion of dipyridamole did not inhibit platelet adhesion or thrombi in either citrated or native blood. The studies indicate that, with the flow conditions used, aspirin is a relatively weak inhibitor of platelet thrombus formation in directly sampled human blood.

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