Background—Isoprostanes (iPs) are free radical–catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. Several iPs exert biological effects in vitro and may contribute to the functional consequences of oxidant stress. For example, iPF_2α-III (8-iso PGF_2α) and iPE₂-III modulate platelet function and vascular tone. Although these effects are blocked by antagonists of the receptor (TP) for the cyclooxygenase product thromboxane A₂, it has been speculated that the iPs may activate a receptor related to, but distinct from, the TP.

Methods and Results—Transgenic mice (TPOEs) were generated in which the TP-β isoform was under the control of the preproendothelin promoter. They overexpressed TP-β in the vasculature but not in platelets and exhibited an exaggerated pressor response to infused iPF_2α-III compared with wild-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, both the pressor response to iPF_2α-III and its effects on platelet function were abolished in mice lacking the TP gene. This was also true of the effects of infused iPE₂-III on mean arterial pressure and platelet aggregation.

Conclusions—Both iPF_2α-III and iPE₂-III exert their effects on platelet function and vascular tone in vivo by acting as incidental ligands at membrane TPs rather than via a distinct iP receptor. Activation of TPs by iPs may be of importance in syndromes in which cyclooxygenase activation and oxidant stress coincide, such as in atherosclerosis and reperfusion after tissue ischemia.