Several cannabinoids elicit systemic vasodilation mainly via CB₁ cannabinoid and vanilloid receptors. However, effects in the pulmonary circulation are unknown. Using the isolated, ventilated, buffer-perfused rabbit lung, we show that the endocannabinoids arachidonyl ethanolamide (anandamide) and 2-arachidonyl-glycerol (2-AG) dose-dependently increase pulmonary arterial pressure (+19.9 ± 3.4 mmHg, 5 µM; and +39.5 ± 10.8 mmHg, 0.4 µM, respectively). 2-AG induced lung edema. The CB₁ receptor antagonist AM-251 (0.1 and 5 µM) and the VR₁ vanilloid receptor antagonist capsazepine (10 µM) failed to reduce anandamides effects. The metabolically stable anandamide- and 2-AG-analogues, R-methanandamide and noladin ether, ⁹-tetrahydrocannabinol and the synthetic cannabinoid HU-210, which is no arachidonic acid product, were without effect. The unspecific cyclooxygenase (COX) inhibitor aspirin (100 µM, p<0.001) and the specific COX-2 inhibitor nimesulide (10 µM, p<0.01), completely prevented pulmonary hypertension following 5 µM anandamide. COX-2 RNA was detected in rabbit lungs. The synthetic thromboxane receptor antagonist SQ 29,548 was without effect but the specific EP1 prostanoid receptor antagonist SC 19220 (100 µM) inhibited the pressure increase following anandamide (p<0.05). PCR analysis detected fatty acid amidohydrolase (FAAH), an enzyme that degrades endocannabinoids, in rabbit lung tissue. Furthermore, the specific FAAH inhibitor methyl arachidonyl fluorophosphonate (0.1 µM) blocked pressure effects of anandamide (p<0.01). Finally, anandamide (99 ± 55 pmol/g) and 2-AG (19.6 ± 8.4 nmol/g), were found in native lungs. We conclude that anandamide increases pulmonary arterial pressure via COX-2 metabolites following enzymatic degradation by the FAAH into arachidonic acid products.