Thromboxane receptor aggregation

In both series almost equipotent activities were observed for thromboxane receptor antagonism and thromboxane synthase inhibition (IC50 = 2-30 nM). Upon oral administration to guinea pigs the enantiomers inhibited the ex vivo U-46619-induced platelet aggregation with potencies similar to that of the corresponding racemates. This indicates... 

A more active thromboxane receptor agonist was found in the 9a-homo-9,l 1-epoxy-5,13-prostadienoic acid analogue, SQ 26,538. This compound was 200 times more potent than arachidonic acid in inducing platelet aggregation but was onl> 1/10 as potent as PGH2. This effect was not blocked by inhibitors of cyclo-oxygenas< or of thromboxane synthetase [241]. 

The formation of a platelet aggregate requires the recruitment of additional platelets from the blood stream to the injured vessel wall. This process is executed through a variety of diffusible mediators which act through G-protein-coupled receptors. The main mediators involved in this process are adenosine diphosphate (ADP), thromboxane A2 (TXA2), and thrombin (factor Ila). These mediators of the second phase of platelet activation are formed in different ways. While ADP is secreted from platelets by exocytosis, the release of TXA2 follows its new formation in activated platelets. Thrombin can be formed on the surface of activated platelets (see Fig. 2). 

CoUagen-induced activation of a platelet phospholipase A2 by increased levels of cytosolic Ca results in hberation of arachidonic acid from platelet phospho-hpids, leading to the formation of thromboxane A2 (Chapter 23), which in turn, in a receptor-mediated fashion, can further activate phospholipase C, promot-ing platelet aggregation. 

Higuchi, W., Euse, I., Hattori, A., and Aizawa, Y. (1999) Mutations of the platelet thromboxane A (TXA2) receptor in patients characterized by the absence of TXA2-induced platelet aggregation despite normal TXA2 binding activity. Thromb. Haemost. 82, 1528-1531. 

Thromboxane A2 receptor TBXA2R Agonism Vaso-, bronchoconstriction. platelet aggregation, myocardial ischemia, heart failure. Antagonism could cause bleeding by inhibiting platelet aggregation. 

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