The generation of vasoactive prostanoids from arachidonic acid by COX-1 and -2 was investigated in anesthetized mice. Intravenous injections of the prostanoid precursor arachidonic acid increased pulmonary and decreased systemic arterial pressures. Pulmonary pressor and systemic depressor responses were attenuated by SC-560 and nimesulide, inhibitors of COX-1 and -2, in doses that did not alter responses to injected prostanoids. Pulmonary pressor responses to arachidonic acid were blocked and a depressor response was unmasked whereas systemic depressor responses were not altered by a thromboxane receptor antagonist. Pulmonary and systemic pressor responses to angiotensin II injections and systemic pressor responses to angiotensin II infusion were not modified by COX-1 or -2 inhibitors but were attenuated by losartan. Systemic depressor responses to arachidonic acid were smaller in COX-1 and -2 knockout mice whereas responses to angiotensin II, norepinephrine, U46619, endothelin-1 and PGE1 were not different in COX-1 and -2 knockout and wild-type control mice. These results suggest that vasoactive prostanoids having pulmonary pressor and systemic vasodepressor activity are formed by COX-1 and -2 and are consistent with Western blot analysis and immunostaining, showing the presence of COX-1 and -2. These data suggest that TXA2 is formed from the precursor by COX-1 and -2 in the lung and are in agreement with immunofluorescence studies showing thromboxane synthase. The present data suggest that COX-1 or -2 derived prostanoids do not modulate responses to angiotensin II or other vasoactive agents and prostanoid responses are similar in CD-1 and C57BL/6 mice and in male and female mice.