Frankfurt am Main Recent findings have indicated a role for cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in acute hypoxic pulmonary vasoconstriction (HPV). Here, we assessed the role of EETs and the soluble epoxide hydrolase (sEH), which metabolizes EETs to less active diols, on pulmonary artery pressure (PAP) and HPV in the buffer-perfused mouse lung.

In lungs from wild-type (WT) mice, hypoxia induced a vasoconstriction and increased 11,12-EET production (1.7-fold) - detected using LC-MS/MS. ACU, a sEH inhibitor, potentiated HPV (2.6-fold), effect abolished by pre-incubation with the CYP epoxygenase inhibitor MSPPOH. Authentic 11,12-EET (0.01?3 mM) increased PAP (1.6-fold) and enhanced HPV (2.2-fold). HPV was greater in lungs from sEH-/- mice than from WT mice and was comparable in ACU-treated lungs from WT mice and in solvent perfused lungs from sEH-/- mice. ACU had no further effect of HPV in sEH-/- mice while MSPPOH decreased the response by 50%. In lungs from WT mice, ketanserin, a 5- hydroxytryptamine (5-HT)2A receptor antagonist, shifted the 11,12-EET dose-response curve to the right and abrogated the effect of sEH inhibition on HPV.

These data demonstrate that CYP-derived EETs are involved in HPV in the mouse lung and that the EET-induced contraction is mediated by a 5-HT2A receptor dependent mechanism.