On the Mechanism of Thrombolytic Action of Thromboxane Synthetase Inhibitors

1987 ◽  
Vol 58 (03) ◽  
pp. 827-830 ◽  
Author(s):  
R Korbut ◽  
A Dembińska-Kieć ◽  
J Świȩs ◽  
A Źmuda ◽  
R J Gryglewski
Keyword(s):  
Extracorporeal Circulation ◽  
Vascular Endothelium ◽  
Platelet Rich Plasma ◽  
In Vivo Model ◽  
Platelet Poor Plasma ◽  
Arterial Blood ◽  
Thrombolytic Action ◽  
Thromboxane Synthetase ◽  
Isolated Rat

SummaryUsing our in vivo model for studying drugs which prevent deposition of thrombi or dissipate thrombi formed in extracorporeal circulation over a collagen strip superfused with arterial blood of anaesthetized and heparinized cats, we have found that dazoxiben - a thromboxane synthetase inhibitor - possesses not only antithrombotic but also thrombolytic potency in vivo (ED50 = 3.8 mg/kg i.v.). The thrombolytic potency of dazoxiben was antagonized by aspirin at a dose of 50 mg/kg i.v. Moreover, dazoxiben stimulated the generation of prostacyclin in isolated rat aortic slices incubated in platelet rich plasma, but not in platelet poor plasma. It is suggested that the thrombolytic potency of thromboxane synthetase inhibitors after their systemic administration is associated with the release of prostacyclin and/or prostacyclin-stable metabolites by the vascular endothelium owing to feeding of prostacyclin synthetase with prostaglandin endoperoxides acumulated in platelets following the inhibition of thromboxane synthetase.

scholarly journals Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling

2015 ◽  
Vol 112 (41) ◽  
pp. 12812-12817 ◽  
Author(s):  
Shira Landskroner-Eiger ◽  
Cong Qiu ◽  
Paola Perrotta ◽  
Mauro Siragusa ◽  
Monica Y. Lee ◽  
...  
Keyword(s):  
Blood Flow ◽  
Wnt Signaling ◽  
Critical Role ◽  
Arterial Blood Flow ◽  
In Vivo Model ◽  
Mirna Regulation ◽  
Arterial Blood ◽  
Specific Deletion

The contribution of endothelial-derived miR-17∼92 to ischemia-induced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemia-triggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery. Individual cluster components positively or negatively regulate endothelial cell (EC) functions in vitro, and, remarkably, ECs lacking the cluster spontaneously form cords in a manner rescued by miR-17a, -18a, and -19a. Using both in vitro and in vivo analyses, we identified FZD4 and LRP6 as targets of miR-19a/b. Both of these targets were up-regulated in 17∼92 KO ECs compared with control ECs, and both were shown to be targeted by miR-19 using luciferase assays. We demonstrate that miR-19a negatively regulates FZD4, its coreceptor LRP6, and WNT signaling, and that antagonism of miR-19a/b in aged mice improves blood flow recovery after ischemia and reduces repression of these targets. Collectively, these data provide insights into miRNA regulation of arterialization and highlight the importance of vascular WNT signaling in maintaining arterial blood flow.

Platelets Do Not Alter Flow-Mediated Dilation or Arterial Conduction in vivo

2021 ◽  
pp. 1-6
Author(s):  
Therese Ruane-O’Hora ◽  
Farouk Markos
Keyword(s):  
Shear Stress ◽  
Platelet Count ◽  
Platelet Rich Plasma ◽  
Flow Mediated Dilation ◽  
Vascular Conductance ◽  
Arterial Blood ◽  
Vascular Bed ◽  
Before And After

The aim of this study was to investigate whether platelets contribute to shear stress and vascular conductance in the iliac vascular bed in vivo. Flow-mediated dilation of pig iliac was induced by downstream injection of acetylcholine (50 μg), and separately, conductance (ΔF/ΔP) was calculated. This was carried out before and after removal of 1 L of arterial blood in 240 mL increments, and each 240 mL was spun in a centrifuge (1,500 rcf for 7 min); platelet-rich plasma was replaced with equal volume of heparinised saline and reinjected. The circulating platelet count fell from 369 × 10<sup>9</sup>/L (<i>n</i> = 5) to 165 × 10<sup>9</sup>/L (<i>p</i> = 0.01; <i>n</i> = 4; Student’s unpaired <i>t</i>). An increase in flow led to an increase in the iliac diameter by 0.49 ± 0.03 mm (mean ± SEM) before platelet reduction and 0.55 ± 0.05 mm after (<i>p</i> = 0.36, Student’s paired <i>t</i>, <i>n</i> = 5); the change in arterial conductance was also not significantly affected by platelet reduction, control: 1.44 ± 0.34 mL/min/mm Hg, after platelet reduction: 1.39 ± 0.04 mm (<i>p</i> = 0.55, Student’s paired <i>t</i>, <i>n</i> = 4). Therefore, platelets do not contribute to shear stress or conductance in vivo.

scholarly journals NPP4 is a procoagulant enzyme on the surface of vascular endothelium

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4432-4440 ◽  
Author(s):  
Ronald A. Albright ◽  
William C. Chang ◽  
Donna Robert ◽  
Deborah L. Ornstein ◽  
Wenxiang Cao ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Vascular Endothelium ◽  
Platelet Rich Plasma ◽  
Dense Granule ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Phosphodiesterase 4 ◽  
Adp Receptors

Abstract Ap3A is a platelet-dense granule component released into the extracellular space during the second wave of platelet aggregation on activation. Here, we identify an uncharacterized enzyme, nucleotide pyrophosphatase/phosphodiesterase-4 (NPP4), as a potent hydrolase of Ap3A capable of stimulating platelet aggregation and secretion. We demonstrate that NPP4 is present on the surface of vascular endothelium, where it hydrolyzes Ap3A into AMP and ADP, and Ap4A into AMP and ATP. Platelet aggregation assays with citrated platelet-rich plasma reveal that the primary and secondary waves of aggregation and dense granule release are strongly induced by nanomolar NPP4 in a concentration-dependent manner in the presence of Ap3A, while Ap3A alone initiates a primary wave of aggregation followed by rapid disaggregation. NPP2 and an active site NPP4 mutant, neither of which appreciably hydrolyzes Ap3A, have no effect on platelet aggregation and secretion. Finally, by using ADP receptor blockade we confirm that NPP4 mediates platelet aggregation via release of ADP from Ap3A and activation of ADP receptors. Collectively, these studies define the biologic and enzymatic basis for NPP4 and Ap3A activity in platelet aggregation in vitro and suggest that NPP4 promotes hemostasis in vivo by augmenting ADP-mediated platelet aggregation at the site of vascular injury.

scholarly journals Cold Atmospheric Plasma, Platelet-Rich Plasma, and Nitric Oxide Synthesis Inhibitor: Effects Investigation on an Experimental Model on Rats

2022 ◽  
Vol 12 (2) ◽  
pp. 590
Author(s):  
Bogdan Caba ◽  
Ioannis Gardikiotis ◽  
Ionut Topala ◽  
Ilarion Mihaila ◽  
Cosmin Teodor Mihai ◽  
...  
Keyword(s):  
Platelet Rich Plasma ◽  
Skin Flap ◽  
Atmospheric Plasma ◽  
In Vivo Model ◽  
Control Group ◽  
Synthesis Inhibitor ◽  
Cold Atmospheric Plasma ◽  
Flap Survival ◽  
Surgery Research

The evolution of reconstructive methods for defects of the human body cannot yet replace the use of flap surgery. Research is still preoccupied with the ideal techniques for offering the best chances of survival of the flaps. In our study, we investigated the effects of cold atmospheric plasma (CAP), N-nitro-L-arginine methyl ester (L-NAME), and platelet-rich plasma (PRP) injectable solutions on flap survival using an in vivo model. Twenty-four Wistar rats (four groups) had the McFarlane flap raised and CAP, L-NAME, and PRP substances tested through a single dose subcutaneous injection. The control group had only a saline solution injected. To the best of our knowledge, this is the first study that evaluated a CAP activated solution through injection on flaps. The flap survival rate was determined by clinical examination (photography documented), hematology, thermography, and anatomopathological tests. The image digital analysis performed on the flaps showed that the necrosis area (control—49.64%) was significantly lower for the groups with the three investigated solutions: CAP (14.47%), L-NAME (18.2%), and PRP (23.85%). Thermography exploration revealed less ischemia than the control group on the CAP, L-NAME, and PRP groups as well. Anatomopathological data noted the best degree of angiogenesis on the CAP group, with similar findings on the L-NAME and PRP treated flaps. The blood work did not indicate infection or a strong inflammatory process in any of the subjects. Overall, the study shows that the CAP activated solution has a similar (better) impact on the necrosis rate (compared with other solutions with known effects) when injected on the modified dorsal rat skin flap, and on top of that it can be obtained fast, in unlimited quantities, non-invasively, and through a standardized process.

Effect of varying nitric oxide release to prevent platelet consumption and preserve platelet function in an in vivo model of extracorporeal circulation

Perfusion ◽  
2007 ◽  
Vol 22 (3) ◽  
pp. 193-200 ◽  
Author(s):  
Amy M. Skrzypchak ◽  
Nathan G. Lafayette ◽  
Robert H. Bartlett ◽  
Zhengrong Zhou ◽  
Megan C. Frost ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Platelet Function ◽  
Extracorporeal Circulation ◽  
In Vivo Model ◽  
Nitric Oxide Release

A small-molecule inhibitor of integrin α2β1 introduces a new strategy for antithrombotic therapy

2010 ◽  
Vol 103 (02) ◽  
pp. 387-397 ◽  
Author(s):  
Jarmo Käpylä ◽  
Marika Ojala ◽  
Jonna Nieminen ◽  
Anu Lipsanen ◽  
Heli Lappalainen ◽  
...  
Keyword(s):  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Blood Platelets ◽  
In Vivo Model ◽  
Antiplatelet Activity ◽  
Collagen Binding ◽  
Molecule Inhibitor ◽  
New Strategy ◽  
Α2β1 Integrin

SummaryInteraction of blood platelets with vascular collagen is an initiating event in haemostasis and thrombus formation. Based on molecular modelling of human integrin α2I domain and cell-based screening assays we have developed sulfonamide derivatives, a mechanistically novel class of molecules. These molecules show antiplatelet efficacy by selectively inhibiting α2β1 integrin-mediated collagen binding. One sulfonamide derivative, named BTT-3016, showed inhibitory capacity in several assessments of human platelet interaction with collagen. It inhibited about 90% of the aggregation of gel-filtered magnesium-supplemented platelets and 70% of aggregation in PPACK-anticoagulated platelet-rich plasma when stimulated with collagen but not with ADP. The antiplatelet activity of BTT-3016 was dependent on α2β1 integrin, since in collagen binding test BTT-3016 had no effect on the platelets derived from α2 integrin null mice. When tested in an in vivo model in mice, BTT-3016 clearly reduced thrombus formation on the vessel wall after vascular injury. Furthermore, BTT-3016 prolonged tail-bleeding time in a manner comparable to aspirin. We show that new α2β1 inhibitors exert collagen-specific antiplatelet activity and regulate thrombus growth in vivo without compromising primary haemostasis more than aspirin. We suggest that the α2β1 inhibiting strategy could be further developed for the prevention and treatment of arterial thrombosis.

Doxorubicin-induced vascular toxicity: Targeting potential pathways to reduce procoagulant activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13080-e13080
Author(s):  
Hadas Bar-Joseph ◽  
Irit Ben-Aharon ◽  
Moran Tzabari ◽  
Naftaly Savion ◽  
Ruth Shalgi ◽  
...  
Keyword(s):  
Blood Flow ◽  
Real Time ◽  
Platelet Adhesion ◽  
Platelet Rich Plasma ◽  
Fold Increase ◽  
Acute Effect ◽  
Arterial Blood Flow ◽  
Vascular Toxicity ◽  
Arterial Blood

e13080 Background: In a former study in mice using the gonads as an end-organ prototype, we have characterized by real-time intravital imaging an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets’ function and to use potentially protectants to reduce DXR acute effect on the blood flow. Methods: 100 µg/mouse 24 hours and 1 hour prior to DXR treatment (8 mg/kg), or with eptifibatide (integrilin,75µg/mouse) 90min prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound. Platelet adhesion to confluent endothelial cells (EC) was evaluated following exposure of EC to DXR (100 µM) for 4h followed by exposure to whole blood under defined shear rates. Fixed platelets were immunostained by anti- CD41a antibody. DXR effect on platelet adhesion was determined by pre-incubation of platelet rich plasma for 15min with increasing concentrations of DXR and induction of aggregation by ADP. For in vivo study, mice were injected with either LMWH (Enoxaparin; Clexane). Results: There was a significant 3.6-fold increase in platelet adhesion to DXR-exposed EC (p<0.002) reflecting the toxic effect of DXR on EC. Yet, significant DXR- dose dependent decrease in platelet aggregation was observed reaching up to 40% inhibition at 100 µM (p<0.001). Testicular arterial blood flow was preserved as a result of pre-treatment with LMWH or eptifibatide prior to DXR (P<0.01). Conclusions: DXR-induced acute vascular toxicity may trigger the coagulation pathway while enhancing platelet adhesion yet inhibiting massive aggregation, which result in compromised blood flow due to microthrombi formation. Anti-platelet/anti-coagulant agents appear to be effective in reducing the detrimental effect of DXR on the vasculature.

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