Three inhibitors of the release or effects of endothelium-derived relaxing factor (EDRF), N-nitro-L-arginine, methylene blue and oxyhemoglobin, caused further increases in perfusion pressure during vascular constriction with submaximal concentrations of the thromboxane A2-mimetic, U46619 in fetal vessels of human placental lobules perfused in vitro. The results suggest the EDRF, released during constriction of fetal placental vessels in response to thromboxane A2 receptor stimulation, attenuates the vasoconstrictor response. Hence, impairment of EDRF release or function could contribute to the reduced placental blood flow observed in various disease states associated with increased thromboxane A2 production such as pre-eclampsia.