5-Hydroxytryptamine dominates over thromboxane A2 in reducing collateral blood flow by activated platelets

1993 ◽  
Vol 265 (1) ◽  
pp. H158-H164 ◽  
Author(s):  
W. Loots ◽  
F. De Clerck
Keyword(s):  
Blood Flow ◽  
Platelet Activation ◽  
Perfusion Defect ◽  
Activation Process ◽  
Collateral Blood Flow ◽  
Peripheral Vascular ◽  
Similar Extent ◽  
Receptor Antagonism ◽  
Prostaglandin Endoperoxide ◽  
Activated Platelets

Intra-aortic infusion of collagen (100 micrograms/kg in 1 min) elicited an extensive platelet activation and transient but marked reductions of blood flow and increases of peripheral vascular resistance, both responses being more pronounced in collaterals than in normal arterial beds in feline hind legs. Blockade of 5-hydroxytryptamine (5-HT) subtype 2 (5-HT2) receptors for 5-HT (ketanserin or ritanserin, 0.63 mg/kg iv, -10 min) or amine depletion (reserpine, 0.1 mg/kg im, -10 days, + parachlorophenylalanine 100 mg/kg sc daily for 3 days), but not cyclooxygenase inhibition (indomethacin, 5 mg/kg iv) or thromboxane (Tx) A2/prostaglandin endoperoxide receptor antagonism (sulotroban, 2.5 mg/kg iv), largely prevented the collagen-induced perfusion defect without interfering substantially with the platelet activation process. TxA2 synthase inhibition, alone (dazoxiben, 5 mg/kg iv) or combined with TxA2-prostaglandin endoperoxide receptor antagonism (ridogrel, 2.5 mg/kg iv), partially reduced the collagen-induced perfusion defect and limited to a similar extent the initial platelet aggregation and release of 5-hydroxyindoles and TxB2 while increasing plasma levels of prostacyclin. These results suggest that platelet-derived 5-HT dominates over TxA2 in reducing blood flow in collateral-dependent tissue of the cat hindlimb.

Multiscale Modeling of Flow Induced Thrombogenicity Using Dissipative Particle Dynamics and Molecular Dynamics

2013 ◽  
Author(s):  
Danny Bluestein ◽  
João S. Soares ◽  
Peng Zhang ◽  
Chao Gao ◽  
Seetha Pothapragada ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Blood Flow ◽  
Red Blood Cells ◽  
Platelet Activation ◽  
Blood Cells ◽  
Dissipative Particle Dynamics ◽  
Particle Dynamics ◽  
Coagulation Cascade ◽  
Shear Stresses ◽  
Activated Platelets

The coagulation cascade of blood may be initiated by flow induced platelet activation, which prompts clot formation in prosthetic cardiovascular devices and arterial disease processes. While platelet activation may be induced by biochemical agonists, shear stresses arising from pathological flow patterns enhance the propensity of platelets to activate and initiate the intrinsic pathway of coagulation, leading to thrombosis. Upon activation platelets undergo complex biochemical and morphological changes: organelles are centralized, membrane glycoproteins undergo conformational changes, and adhesive pseudopods are extended. Activated platelets polymerize fibrinogen into a fibrin network that enmeshes red blood cells. Activated platelets also cross-talk and aggregate to form thrombi. Current numerical simulations to model this complex process mostly treat blood as a continuum and solve the Navier-Stokes equations governing blood flow, coupled with diffusion-convection-reaction equations. It requires various complex constitutive relations or simplifying assumptions, and is limited to μm level scales. However, molecular mechanisms governing platelet shape change upon activation and their effect on rheological properties can be in the nm level scales. To address this challenge, a multiscale approach which departs from continuum approaches, may offer an effective means to bridge the gap between macroscopic flow and cellular scales. Molecular dynamics (MD) and dissipative particle dynamics (DPD) methods have been employed in recent years to simulate complex processes at the molecular scales, and various viscous fluids at low-to-high Reynolds numbers at mesoscopic scales. Such particle methods possess important properties at the mesoscopic scale: complex fluids with heterogeneous particles can be modeled, allowing the simulation of processes which are otherwise very difficult to solve by continuum approaches. It is becoming a powerful tool for simulating complex blood flow, red blood cells interactions, and platelet-mediated thrombosis involving platelet activation, aggregation, and adhesion.

scholarly journals Tyrosine phosphatase inhibition augments collateral blood flow in a rat model of peripheral vascular disease

2004 ◽  
Vol 287 (1) ◽  
pp. H268-H276 ◽  
Author(s):  
Andrew N. Carr ◽  
Michael G. Davis ◽  
Elaine Eby-Wilkens ◽  
Brian W. Howard ◽  
Bryan A. Towne ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Disease ◽  
Peripheral Vascular Disease ◽  
Rat Model ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Collateral Blood Flow ◽  
Peripheral Vascular ◽  
Phosphatase Inhibition

During embryonic development, the growth of blood vessels requires the coordinated activation of endothelial receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie-2. Similarly, in adulthood, activation of endothelial RTKs has been shown to enhance development of the collateral circulation and improve blood flow to ischemic tissues. Recent evidence suggests that RTK activation is negatively regulated by protein tyrosine phosphatases (PTPs). In this study, we used the nonselective PTP inhibitor bis(maltolato)oxovanadium IV (BMOV) to test the potential efficacy of PTP inhibition as a means to enhance endothelial RTK activation and improve collateral blood flow. In cultured endothelial cells, pretreatment with BMOV augmented VEGFR-2 and Tie-2 tyrosine phosphorylation and enhanced VEGF- and angiopoietin-1-mediated cell survival. In rat aortic ring explants, BMOV enhanced vessel sprouting, a process that can be influenced by both VEGFR-2 and Tie-2 activation. Moreover, 2 wk of BMOV treatment in a rat model of peripheral vascular disease enhanced collateral blood flow similarly to VEGF, and after 4 wk, BMOV was superior to VEGF. Taken together, these studies provide evidence that PTPs are important regulators of endothelial RTK activation and for the first time demonstrate the potential utility of phosphatase inhibition as a means to promote collateral development and enhance collateral blood flow to ischemic tissue.

Improvement of Collateral Circulation after Arterial Thrombosis with Indomethacin Therapy

1980 ◽  
Vol 44 (02) ◽  
pp. 069-071 ◽  
Author(s):  
Cecelia Helenski ◽  
Robert G Schaub ◽  
Royce Roberts
Keyword(s):  
Blood Flow ◽  
Platelet Activation ◽  
Arterial Thrombosis ◽  
Collateral Circulation ◽  
Thromboxane A2 ◽  
Collateral Flow ◽  
Collateral Blood Flow ◽  
Vasoactive Substance ◽  
Aortic Thrombosis ◽  
Platelet Counts

SummaryWe compared development of feline hindlimb collateral circulation and coagulation changes 3 hours following aortic thrombosis in five non-treated and five indomethacin treated (20 mg/kg) cats. Coagulation changes were monitored with the one stage prothrombin time (OSPT), partial thromboplastin time (PTT), protamine sulfate dilution test for fibrin monomer (PSD), and platelet counts. Collateral circulation was assessed with aortograms. Significant changes in coagulation parameters with the exception of platelet counts were not observed in either group. Platelet counts of non-treated cats were reduced to 63 ± 5% of control while platelet counts of treated cats were 96 ± 3% of control. Aortograms of non-treated cats indicated poor hindlimb perfusion around the thrombus, while aortograms of indomethacin treated animals indicated significant blood flow to the hindlimbs through collateral channels. These results support a role for the platelet in post thrombosis vasospasms and suggest that anti-platelet therapy could have positive effects in reducing the extent of ischemic damage which follows arterial thrombosis.Several studies, using cat and dog models, have demonstrated a significant reduction of collateral blood flow can occur following formation of an occlusive arterial thrombus (1–5). The collateral flow which developed after thrombosis was significantly less than when occlusion was accomplished with mechanical methods such as ligation (1, 3, 4). This suggested the presence of a thrombus produced effects on blood vessels more complex than simple mechanical obstruction. Imhoff originally suggested that the inhibition of collateral flow which followed thrombosis was related to the release or formation of a vasoactive substance which would induce constriction of collateral source or re-entry vessels (1). Butler, in later studies, suggested that it was serotonin which was responsible for the post thrombosis inhibition of collateral blood flow (2). The involvement of serotonin would seem logical, since the majority of blood serotonin is found in the platelet (6), is released upon platelet activation (7-9), and is a potent vasoconstrictor (10). A mechanism for serotonin involvement has proposed that the platelets in the flowing blood come into contact with the thrombus, are activated and release serotonin (2–4). Consideration of the biochemistry of platelet activation makes it apparent that serotonin is neither the only nor the most powerful vasoactive substance released by the platelet. Thromboxane A2 (TxA) is a critical substance in the activation, release, and aggregation of platelets (11, 12, 13). Thromboxane A2 is a particularly powerful vasoconstrictor which would be a more likely candidate to produce the type of long lasting vasospasm necessary to reduce collateral flow in the post thrombosis state (11, 12, 13). The relationship between thromboxane A2 and serotonin is suggested by recent studies which demonstrate that serotonin can initiate thromboxane A2 release from canine and feline platelets (14). Therefore, serotonin could be an intermediate mechanism in the process of collateral inhibition.If this hypothesis is correct, then inhibition of TxA synthesis should prove as beneficial in improving collateral flow after thrombosis as serotonin antagonists. To test this hypothesis we examined the effect of indomethacin treatment on development of collateral circulation following aortic thrombosis. Indomethacin is a non-steroidal, anti-inflammatory drug which inhibits cyclooxygenase, the major enzyme in the PG and TxA synthetic pathway (15–19).

Platelet Inhibitory Drugs Improve Collateral Blood Flow After Aortic Thrombosis

1981 ◽  
Author(s):  
R Schaub ◽  
C Helenski ◽  
K Gates ◽  
R Roberts
Keyword(s):  
Blood Flow ◽  
Contrast Media ◽  
Blood Vessels ◽  
Platelet Activation ◽  
Treated Group ◽  
Collateral Blood Flow ◽  
Clotting Factors ◽  
Iliac Arteries ◽  
Platelet Counts ◽  
Intermediate Response

Complete occlusion of the feline caudal aorta with a thrombus inhibits opening of collateral blood vessels to the hindlimbs. Our previous studies suggest this inhibition results from platelet activation. To test this hypothesis we evaluated the effect of indomethacin (I), aspirin (ASA), and prostacyclin (PGI) on collateral inhibition. Prothrombin times (OSPT), thromboplastin times (PTT), fibrin monomer (FM), and platelet counts were measured in 20 cats before the aortas were occluded by thrombosis. Five cats were untreated. Treatment of the others was started 1 hour prior to thombosis. Five cats received I (20 mg/kg i.v.), 6 cats received ASA (650 mg orally), and 4 cats received an i.v. infusion of PGI (50 ug/kg/hr). Cats were maintained 3 hours post-operatively. Coagulation parameters were measured after the 3 hour period and calculated as a percent of pre-thrombosis values. Collateral circulation was assessed as the time necessary for contrast media to appear in the iliac arteries caudal to the thrombus during aortography. All treated groups were statistically compared to the non-treated group. The OSPT, PTT, and FM values were not significantly changed in any group except for a prolonged PTT in the ASA group. Platelet counts were significantly reduced in non- treated cats (66 ± 4%) compared to treated cats I (96 ± 3%), ASA (97 ± 10), and PGI (97 ± 9%). Contrast media did not appear in the iliac arteries of non-treated cats until 8 seconds injection. In 4 I treated and all ASA treated cats contrast media appeared in the iliac arteries within 2 seconds after injection. The PGI treated cats had an intermediate response. Contrast media appeared in the iliac arteries 4 seconds after injection. These results suggest: (1) Some consequences of arterial thrombosis may be due to humoral inhibition of collateral blood flow. (2) This inhibition is related to platelet activation with release of vasoactive and aggregating agents and not to gross alteration of other clotting factors. (3) Platelet thromboxane A2 maY be the factor promoting collateral inhibition since prostaglandin synthesis inhibitors and antagonists are effective. (4) Inhibition of platelet function prior to thombosis could reduce ischemic damage by enhancing development of collateral blood vessels.

Multiscale Modeling of Flow Induced Thrombogenicity With Dissipative Particle Dynamics (DPD) and Molecular Dynamics (MD)

2013 ◽  
Author(s):  
Danny Bluestein ◽  
João S. Soares ◽  
Peng Zhang ◽  
Chao Gao ◽  
Seetha Pothapragada ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Blood Flow ◽  
Red Blood Cells ◽  
Platelet Activation ◽  
Blood Cells ◽  
Dissipative Particle Dynamics ◽  
Particle Dynamics ◽  
Coagulation Cascade ◽  
Shear Stresses ◽  
Activated Platelets

The coagulation cascade of blood may be initiated by flow induced platelet activation, which prompts clot formation in prosthetic cardiovascular devices and arterial disease processes. While platelet activation may be induced by biochemical agonists, shear stresses arising from pathological flow patterns enhance the propensity of platelets to activate and initiate the intrinsic pathway of coagulation, leading to thrombosis. Upon activation platelets undergo complex biochemical and morphological changes: organelles are centralized, membrane glycoproteins undergo conformational changes, and adhesive pseudopods are extended. Activated platelets polymerize fibrinogen into a fibrin network that enmeshes red blood cells. Activated platelets also cross-talk and aggregate to form thrombi. Current numerical simulations to model this complex process mostly treat blood as a continuum and solve the Navier-Stokes equations governing blood flow, coupled with diffusion-convection-reaction equations. It requires various complex constitutive relations or simplifying assumptions, and is limited to μm level scales. However, molecular mechanisms governing platelet shape change upon activation and their effect on rheological properties can be in the nm level scales. To address this challenge, a multiscale approach which departs from continuum approaches, may offer an effective means to bridge the gap between macroscopic flow and cellular scales. Molecular dynamics (MD) and dissipative particle dynamics (DPD) methods have been employed in recent years to simulate complex processes at the molecular scales, and various viscous fluids at low-to-high Reynolds numbers at mesoscopic scales. Such particle methods possess important properties at the mesoscopic scale: complex fluids with heterogeneous particles can be modeled, allowing the simulation of processes which are otherwise very difficult to solve by continuum approaches. It is becoming a powerful tool for simulating complex blood flow, red blood cells interactions, and platelet-mediated thrombosis involving platelet activation, aggregation, and adhesion.

Multiscale Modeling of Flow Induced Thrombogenicity Using Dissipative Particle Dynamics and Coarse Grained Molecular Dynamics

2013 ◽  
Author(s):  
Peng Zhang ◽  
Jawaad Sheriff ◽  
João S. Soares ◽  
Chao Gao ◽  
Seetha Pothapragada ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Blood Flow ◽  
Red Blood Cells ◽  
Platelet Activation ◽  
Blood Cells ◽  
Dissipative Particle Dynamics ◽  
Particle Dynamics ◽  
Coarse Grained ◽  
Activated Platelets ◽  
Coarse Grained Molecular Dynamics

The coagulation cascade of blood may be initiated by flow induced platelet activation, which prompts clot formation in prosthetic cardiovascular devices and arterial disease processes. While platelet activation may be induced by biochemical agonists, shear stresses arising from pathological flow patterns enhance the propensity of platelets to activate and initiate the intrinsic pathway of coagulation, leading to thrombosis. Upon activation platelets undergo complex biochemical and morphological changes: organelles are centralized, membrane glycoproteins undergo conformational changes, and adhesive pseudopods are extended. Activated platelets polymerize fibrinogen into a fibrin network that enmeshes red blood cells. Activated platelets also cross-talk and aggregate to form thrombi. Current numerical simulations to model this complex process mostly treat blood as a continuum and solve the Navier-Stokes equations governing blood flow, coupled with diffusion-convection-reaction equations. It requires various complex constitutive relations or simplifying assumptions, and is limited to μm level scales. However, molecular mechanisms governing platelet shape change upon activation and their effect on rheological properties can be in the nm level scales. To address this challenge, a multiscale approach which departs from continuum approaches, may offer an effective means to bridge the gap between macroscopic flow and cellular scales. Coarse Grained Molecular dynamics (CGMD) and discrete/dissipative particle dynamics (DPD) methods have been employed in recent years to simulate complex processes at the molecular scales, and various viscous fluids at low-to-high Reynolds numbers at mesoscopic scales. Such particle methods possess important properties at the mesoscopic scale: complex fluids with heterogeneous particles can be modeled, allowing the simulation of processes which are otherwise very difficult to solve by continuum approaches. It is becoming a powerful tool for simulating complex blood flow, red blood cells interactions, and platelet-mediated thrombosis involving platelet activation, aggregation, and adhesion.

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