Cardiovascular responses to the isoprostanes iPF(2 alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo

Background-Isoprostanes (iPs) are free radical-catalyzed products of arachi donic acid that reflect lipid peroxidation in vivo. Several iPs exert biolo gical effects in vitro and may contribute to the functional consequences of oxidant stress. For example, iPF(2 alpha)-III (8-iso PGF(1 alpha)) and iPE (2)-III modulate platelet function and vascular tone. Although these effect s are blocked by antagonists of the receptor (TP) for the cyclooxygenase pr oduct thromboxane A,, it has been speculated that the iPs may activate a re ceptor related to, but distinct from, the TP. Methods and Results-Transgenic mice (TPOEs) were generated in which the TP- beta isoform was under the control of the preproendothelin promoter. They o verexpressed TP-beta in the vasculature but not in platelets and exhibited an exaggerated presser response to infused iPF(2 alpha)-III compared with w ild-type mice. This was blocked by TP antagonism. The platelet response to the iP was unaltered in TPOEs compared with wild-type mice. By contrast, bo th the presser response to iPF(2 alpha)-III and its effects on platelet fun ction were abolished in mice lacking the TP gene. This was also true of the effects of infused iPE(2)-III on mean arterial pressure and platelet aggre gation. Conclusions-Both iPF(2 alpha)-III and IPE2-III exert their effects on plate let function and vascular tone in vivo by acting as incidental ligands at m embrane TPs rather than via a distinct iP receptor. Activation of Tps by iP s may be of importance in syndromes in which cyclooxygenase activation and oxidant stress coincide, such as in atherosclerosis and reperfusion after t issue ischemia.