Testosterone treatment increases thromboxane function in rat cerebral arteries

We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane [A.sub.2] (Tx[A.sub.2]) pathway. Therefore, we investigated the effect of chronic testosterone treatment (4 wk) on Tx[A.sub.2] synthase levels and the contribution of Tx[A.sub.2] to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that Tx[A.sub.2] synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that Tx[A.sub.2] synthase protein levels are higher in cerebral vessel homogenates from testosteronetreated orchiectomized (ORX+T) rats compared with orchiectomized (ORX) control animals. Functional consequences of changes in cerebrovascular Tx[A.sub.2] synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the Tx[A.sub.2] mimetic U-46619 were not different between the ORX+T and ORX groups. However, dilator responses to either the selective Tx[A.sub.2] synthase inhibitor furegrelate or the Tx[A.sub.2]-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORX+T compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORX+T groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances Tx[A.sub.2]-mediated tone in rat cerebral arteries by increasing endothelial Tx[A.sub.2] synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular Tx[A.sub.2] synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease. thromboxane synthase; cerebral circulation; vascular smooth muscle; endothelium