The pressor effects of porcine (ET-1) and rat (ET-3) endothelins were studied in the pithed rat along with the actions of cyclo-oxygenase inhibitors upon these responses. Indomethacin (15 mumol/kg i.v.) when given prior to endothelin had no effect on the pressor responses to ET-1 or ET-3. However, when indomethacin or piroxicam was administered between two doses of ET-1 or ET-3, the second response was significantly potentiated. This potentiation was abolished when the adrenal glands were excluded from the circulation but partially restored when neuropeptide Y (NPY) (1 nmol/kg i.v.) was administered. Radiolabeled microspheres were used to measure regional blood flow and from these measurements, regional vascular resistance was calculated. From these data, it is evident that ET-1 caused a generalized increase in vascular resistance, and only in the large intestine and epididymal fat pad was this attenuated by indomethacin. In the gastric vasculature, the effects of ET-1 were potentiated by indomethacin. In the bronchial vasculature, ET-1 caused a reduction in vascular resistance possibly due to the bronchoconstrictor actions of ET-1 and the concomitant release of vasodilators such as histamine. When the fraction of the cardiac output received by each vascular bed is taken into account, the gastrointestinal tract, kidneys, and skeletal muscle account for most of the increase in total peripheral resistance induced by ET-1. Prostanoids have a role in the pressor response to ET-1 and ET-3 that is more complex than one of simple physiological antagonism or potentiation at the level of the vascular smooth muscle and possibly act as modulators of other regulatory factors such as NPY.