In anesthetized, ventilated pigs we analyzed the involvement of nitric oxide (NO) and prostaglandins (PGs) in the regulation of systemic and pulmonary basal vascular tone. Endogenous release of NO was blocked by NG-nitro-L-arginine methyl ester (L-NAME) and prostanoid biosynthesis by indomethacin. Blocking NO raised pulmonary and systemic arterial pressure and vascular resistances. These effects show that in the pig there is continuous release of minute amounts of NO. Blocking prostanoid biosynthesis did not affect the vasoconstrictor effect of L-NAME on the pulmonary vascular bed, but significantly strengthened the hypertensive effect of L-NAME on the systemic vascular bed. These data show that different mechanisms regulate pulmonary and systemic vascular tone. Administration of a stable analogue of PGI2 to pigs pretreated with indomethacin reversed the systemic vasoconstrictor effect of L-NAME. In conclusion, our data show that NO especially modulates pulmonary vascular tone, while PGI2 preferentially modulates systemic vascular tone.