New Trends in Thromboxane and Prostacyclin Modulators

Abstract

Thromboxane A2 (TXA2) and prostacyclin (PGI2) are two labile products formed from arachidonic acid by the way of cyclooxygenase. An overproduction of thromboxane A2 has been detected in a series of diseases whereby this prostanoid is assumed to contribute to the underlying pathomechanisms by its potent stimulation of platelet aggregation and smooth muscle contraction. This increased TXA2 biosynthesis is frequently accompanied by a stimulation of prostacyclin formation which is one of the most potent inhibitors of platelet aggregation and smooth muscle contraction. Therefore, TXA2 / prostaglandin endoperoxide H2 receptor antagonists, thromboxane synthase inhibitors and drugs which combine both activities have been developed with the aim to suppress the formation and/or the action of thromboxane A2. Since prostacyclin has been demonstrated to counterbalance the pathological effects of TXA2, several PGI2 agonists have also been developed. This review will highlight the evolution and some of the latest findings in the field of prostacyclin and thromboxane A2 modulators mainly those which are under clinical evaluation or marketed.

Protein Kinase A-mediated Phosphorylation of Serine 357 of the Mouse Prostacyclin Receptor Regulates Its Coupling to Gs-, to Gi-, and to Gq-coupled Effector Signaling

“…Prostacyclin is central to the regulation of vascular hemostasis and may also mediate other somewhat diverse cellular actions under both physiologic and pathophysiologic settings (3,8,35). Mice deficient in the IP exhibit altered pain perception and inflammatory reactions as well as exhibiting an impaired response to thrombotic stimuli (4).…”

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

“…‫,ء‬ P Ͻ 0.05 compared with the vehicle-treated group. firmed the greater interest for coadministration of both thromboxane modulators than their independent use (Dogné et al, 2000(Dogné et al, , 2003.…”

Superoxide as a Messenger of Endothelial Function

“…The vasospasm in segments treated with LPS could be fully blocked with SQ 29548, a selective antagonist of the TxA 2 /PGH 2 receptor (Dogne et al, 2000), whereas the TxA 2 synthase inhibitor CGS 1380 was without effect ( fig. 6.9).…”