Involvement of Rac in thromboxane A2-induced human platelet activation: Regulation of sCD40 ligand release and PDGF-AB secretion

The inter-relationships between receptor occupancy, inositol phospholipid metabolism and elevation of cytosolic free Ca2+ in thromboxane A2-induced human platelet activation were investigated by using the stable thromboxane A2 mimetic, 9,11-epoxymethanoprostaglandin H2, and the thromboxane A2 receptor antagonist, EPO45. 9,11-Epoxymethanoprostaglandin H2 stimulated platelet phosphatidylinositol metabolism as indicated by the rapid accumulation of [32P]phosphatidate and later accumulation of [32P]phosphatidylinositol in platelets pre-labelled with [32P]Pi. These effects of 9,11-epoxymethanoprostaglandin H2 were concentration-dependent and half-maximal [32P]phosphatidate formation occurred at an agonist concentration of 54 +/- 8 nM. With platelets labelled with the fluorescent Ca2+ indicator quin 2, resting cytosolic free Ca2+ was 86 +/- 12 nM. 9,11-Epoxymethanoprostaglandin H2 induced a rapid, concentration-dependent elevation of cytosolic free Ca2+ to a maximum of 300-700 nM. Half-maximal stimulation was observed at an agonist concentration of 80 +/- 23 nM. The thromboxane A2 receptor antagonist EPO45 selectively inhibited 9,11-epoxymethanoprostaglandin H2-induced [32P]phosphatidate formation and elevation of cytosolic free Ca2+, indicating that both events are sequelae of receptor occupancy. Human platelets contain a single class of stereospecific, saturable, high affinity (KD = 70 +/- 13 nM) binding sites for 9,11-epoxymethano[3H]prostaglandin H2. The concentration-response curve for receptor occupancy (9,11-epoxymethano-[3H]prostaglandin H2 binding) is similar to that for 9,11-epoxymethanoprostaglandin H2-induced [32P]phosphatidate formation and for elevation of cytosolic free Ca2+. These observations indicate that human platelet thromboxane A2 receptor occupation is closely linked to inositol phospholipid metabolism and to elevation of cytosolic free Ca2+. Both such events may be necessary for thromboxane A2-induced human platelet activation.

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Effect of Ridogrel on Vascular Contractions Gaused by Vasoactive Substances Released during Platelet Activation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647259 ◽

1990 ◽

Vol 64 (01) ◽

pp. 091-096 ◽

Cited By ~ 6

Author(s):

W J Janssens ◽

F J S Cools ◽

L A M Hoskens ◽

J M Van Nueten

Keyword(s):

Smooth Muscle ◽

Blood Vessel ◽

Platelet Activation ◽

Prostaglandin F2α ◽

Thromboxane A2 ◽

Femoral Arteries ◽

Vasoactive Substances ◽

Caudal Artery ◽

Isolated Rat ◽

Rat Platelets

SummaryRidogrel (6.3 × 10−6 to 10−4 M) inhibited contractions of isolated rat caudal arteries and rabbit femoral arteries caused by U-46619. The slope of an Arunlakshana-Schild plot (pA2-value: 3.4 × 10−6 M) on the caudal artery was slightly higher than one (1.14). This effect was maximal within}D min of incubation of the blood vessel with the compound and easily reversible. Ridogrel antagonised contractions of isolated rabbit femoral arteries caused by prostaglandin Fzo2α in the same concentration range. Ridogrel also inhibited contractions induced by aggregating rat platelets on isolated rat caudal arteries (itt the presence of ketanserin 4 × 10−7 M) and on isolated rabbit pulmonary and femoral arteries (in the absence of ketanserin). Ridogrel had no effect on Ca2+-induced contractions in depolarised isolated rabbit femoral arteries, and at 10−4 M antagonised serotonin-induced contractions in this blood vessel. Its effect on serotonin-induced contractions was statistically significant but very small on isolated rat caudal arteries. These observations indicate that ridogrel is an antagonist of prostaglandin endoperoxide/thromboxane A2 and prostaglandin F2α raCeptors on vascular smooth muscle.

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Current aspects on human platelet activation and responses

European Journal Of Haematology ◽

10.1111/j.1600-0609.1987.tb01434.x ◽

2009 ◽

Vol 38 (5) ◽

pp. 383-399 ◽

Cited By ~ 33

Author(s):

Vidar M. Steen ◽

Holm Holmsen

Keyword(s):

Platelet Activation ◽

Human Platelet

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A role of calcium-activated phospholipid-dependent protein kinase in human platelet activation. Comparison of thrombin and collagen actions.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)33089-8 ◽

1983 ◽

Vol 258 (3) ◽

pp. 2010-2013 ◽

Cited By ~ 24

Author(s):

K Sano ◽

Y Takai ◽

J Yamanishi ◽

Y Nishizuka

Keyword(s):

Protein Kinase ◽

Platelet Activation ◽

Human Platelet ◽

Dependent Protein Kinase ◽

Dependent Protein

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Effect of specific phospholipid molecular species incorporated in human platelet membranes on thromboxane A2/prostaglandin H2 receptors

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)39753-4 ◽

1995 ◽

Vol 36 (1) ◽

pp. 47-56

Author(s):

Y Bayon ◽

M Croset ◽

D Daveloose ◽

F Guerbette ◽

V Chirouze ◽

...

Keyword(s):

Molecular Species ◽

Human Platelet ◽

Thromboxane A2 ◽

Phospholipid Molecular Species ◽

Platelet Membranes ◽

H2 Receptors

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hTRPC1-associated α-actinin, and not hTRPC1 itself, is tyrosine phosphorylated during human platelet activation

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2007.02773.x ◽

2007 ◽

Vol 5 (12) ◽

pp. 2476-2483 ◽

Cited By ~ 5

Author(s):

P. C. REDONDO ◽

A. G. S. HARPER ◽

M. T. HARPER ◽

S. L. BROWNLOW ◽

J. A. ROSADO ◽

...

Keyword(s):

Platelet Activation ◽

Human Platelet

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Synergistic inhibition of platelet activation by plasmin and prostaglandin I2

Blood ◽

10.1182/blood.v69.5.1504.bloodjournal6951504 ◽

1987 ◽

Vol 69 (5) ◽

pp. 1504-1507

Author(s):

AI Schafer ◽

GB Zavoico ◽

J Loscalzo ◽

AK Maas

Keyword(s):

Cyclic Amp ◽

Platelet Activation ◽

Platelet Rich Plasma ◽

Thromboxane A2 ◽

Prostaglandin I2 ◽

Synergistic Inhibition ◽

Tissue Plasminogen ◽

A Site ◽

Induced Aggregation ◽

Inhibition Of Thrombin

Endothelial cell prostacyclin (PGI2) inhibits platelet activation by raising platelet cyclic AMP. Previously, platelet activation was also shown to be blocked by plasmin formed by endothelium-derived tissue plasminogen activator (TPA). We have now studied interactions between PGI2 and plasmin in the control of platelet function. PGI2 and plasmin cause synergistic inhibition of thrombin- and ADP-induced aggregation of washed platelets. Inhibition by PGI2 is similarly potentiated by TPA added to platelet-rich plasma to generate plasmin. Thrombin-stimulated rise in platelet cytosolic Ca2+, measured by fura2 fluorescence, and thromboxane A2 formation, measured by radioimmunoassay (RIA), are likewise synergistically inhibited by PGI2 and plasmin. Plasmin neither increases nor potentiates PGI2-stimulated increases in platelet cyclic AMP. Thus, PGI2 and plasmin cause synergistic inhibition of platelet activation by both cyclic AMP-dependent and independent mechanisms. This interaction between two different endothelium-derived products may play an important role in localizing the hemostatic plug to a site of vascular injury by preventing further thrombin-mediated accrual of platelets.

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