ANTIPLATELET ACTIVITY OF FENOFIBRATE, A PPARALPHA AGONIST, WAS MEDIATED BY BLOCKING OF CYTOSOLIC CALCIUM MOBILIZATION AND THROMBOXANE A2 RECEPTOR

1985 ◽

Vol 249 (1) ◽

pp. H8-H13

Author(s):

L. D. Brace ◽

D. L. Venton ◽

G. C. Le Breton

Keyword(s):

Receptor Antagonist ◽

Calcium Release ◽

Shape Change ◽

Thromboxane A2 ◽

Cytosolic Calcium ◽

Human Platelets ◽

Calcium Mobilization ◽

Receptor Interaction ◽

Calcium Sequestration ◽

Platelet Shape

We previously demonstrated that thromboxane A2 and/or prostaglandin H2 (TXA2/PGH2), ADP, and A23187 cause calcium mobilization in intact human platelets. Other studies have also shown that platelet shape change and aggregation induced by a variety of platelet agonists can be reversed by specific antagonists. In the present study, we used the fluorescent calcium probe chlortetracycline to evaluate whether the reversal of platelet activation involves a resequestration of intraplatelet calcium. It was found that the TXA2/PGH2 receptor antagonist 13-azaprostanoic acid (13-APA) reversed calcium mobilization and shape change induced by AA but not that induced by ADP. A similar specificity of action was observed using the specific ADP receptor antagonist, ATP, in that ATP only reversed ADP-induced calcium release and shape change. In contrast, prostacyclin reversed both AA and ADP-induced calcium redistribution and shape change. In the latter experiments, a net calcium sequestration was actually observed on prostacyclin addition. These findings indicate that the resequestration of released calcium leads to platelet deactivation. Furthermore, there appear to be at least two mechanisms by which a reduction in cytosolic calcium can be produced: specific interruption of the agonist-receptor interaction, for example, 13-APA antagonism of TXA2/PGH2; and stimulation of platelet adenosine 3',5'-cyclic monophosphate production by prostacyclin and consequent calcium sequestration.

Download Full-text

Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane A2 receptor

Acta Pharmacologica Sinica ◽

10.1038/aps.2009.195 ◽

2010 ◽

Vol 31 (2) ◽

pp. 150-159 ◽

Cited By ~ 9

Author(s):

Harold J Ting ◽

Wallace J Murray ◽

Fadi T Khasawneh

Keyword(s):

Thromboxane A2 ◽

Antiplatelet Activity ◽

Thromboxane A2 Receptor

Download Full-text

Antiplatelet activity of carnosol is mediated by the inhibition of TXA2 receptor and cytosolic calcium mobilization

Vascular Pharmacology ◽

10.1016/j.vph.2006.04.003 ◽

2006 ◽

Vol 45 (3) ◽

pp. 148-153 ◽

Cited By ~ 17

Author(s):

Jung-Jin Lee ◽

Yong-Ri Jin ◽

Yong Lim ◽

Jin-Tae Hong ◽

Tack-Joong Kim ◽

...

Keyword(s):

Cytosolic Calcium ◽

Calcium Mobilization ◽

Antiplatelet Activity ◽

Txa2 Receptor

Download Full-text

Hypersensitivity to Thromboxane A2 in Cholesterol-Rich Human Platelets

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647364 ◽

1990 ◽

Vol 64 (04) ◽

pp. 594-599 ◽

Cited By ~ 16

Author(s):

Takuya Tomizuka ◽

Kyohei Yamamoto ◽

Aizan Hirai ◽

Yasushi Tamura ◽

Sho Yoshida

Keyword(s):

Calcium Concentration ◽

Binding Capacity ◽

Thromboxane A2 ◽

Cytosolic Calcium ◽

Cholesterol Content ◽

Human Platelets ◽

Dissociation Rate ◽

Platelet Membrane ◽

Maximal Concentration ◽

Equilibrium Dissociation

SummaryThe effect of changes in platelet membrane cholesterol content on thromboxane A2 (TXA2)-induced platelet activation was studied. Concentrations of 9,ll-epithio-ll,12-methano-TXA2 (STA2), a stable analogue of TXA2 which can cause half-maximal aggregation and release of [14C]serotonin in cholesterol-rich platelets were significantly lower than those in cholesterol-normal platelets. STA2-induced increase in cytosolic calcium concentration and [32P]phosphatidic acid formation in cholesterol-rich platelets were significantly greater than those in cholesterol-normal platelets. The maximal concentration of binding site (Bmax) for SQ29548 was significantly increased in cholesterol-rich platelets compared with cholesterol-normal platelets, while the equilibrium dissociation rate constant (Kd) for SQ29548 did not differ between cholesterol-rich and cholesterol-normal platelets. The present study suggested that sensitivity to TXA2 was increased by the incorporation of cholesterol into platelet membrane and that the cause of hypersensitivity to TXA2 in cholesterol-rich platelets may be partly explained by an increase in binding capacity for TXA2.

Download Full-text