Arachidonic acid (AA) (100 and 200 microgram/kg) and prostacyclin (PGI2) (0.25, 0.5, 1,2 and 3 microgram/kg) were administered by bolus injection into the inferior vena cava (i.v.) and left ventricle (i.a.) in spontaneously breathing anesthesized dogs (25). PGI2 like its precursor AA, decreased arterial diastolic pressure in a dose-dependent manner. The depressor responses after i.a. administration of a given dose of either AA or PGI2 did not differ significantly when the same dose was given i.v.; the i.v./i.a. ratio was 1. In comparison, the vasodepressor response to PGE2 (1, 2 and 3 microgram/kg i.v.) was reduced 12- to 40-fold by passage through the dog lung. The vasopressor response to PGF2alpha (1, 2, 3 and 5 microgram/kg i.v.) was diminished 5- to 8-fold by lung transit. Similarly, the pressor response to norepinephrine was also reduced by pulmonary transit. These studies support the view that (1) the lung plays a minor role in the systemic depressor response to AA and PGI2 and (2) the lack of an i.v./i.a. difference for AA and PGI2 indicates that the depressor response to AA may be due to generation of PGI2 by the vessel wall.