Abstract 662: The Acute Hypoxic Pulmonary Vasoconstrictor Response And Pulmonary Artery Pressure Are Modified By The Soluble Epoxide Hydrolase And Epoxyeicosatrienoic Acids.
Recent findings have indicated a role for cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in acute hypoxic pulmonary vasoconstriction (HPV). As the intracellular concentration of EETs is largely determined by the expression and activity of the soluble epoxide hydrolase (sEH) which metabolizes EETs to their less active diols, we assessed the role of the sEH on pulmonary artery pressure (PAP) and HPV in the isolated, buffer-perfused mouse lung. In lungs from wild-type mice, hypoxia induced a pronounced pulmonary vasoconstriction and increased 11,12-EET production (1.7-fold). The sEH inhibitor 1-adamantyl–3-cyclohexylurea (ACU), potentiated HPV (2.6-fold, P<0.01), an effect that was abolished by pre-incubation with the CYP epoxygenase inhibitor MSPPOH and the EET antagonist 14,15-EEZE. HPV was significantly greater in lungs from sEH−/ − mice than from wild-type mice and responses were comparable in ACU-treated lungs from wild-type mice and in solvent-perfused lungs from sEH−/ − mice. ACU had no further effect on HPV in sEH−/ − mice while MSPPOH and 14,15-EEZE decreased the response by approximately 50%. In lungs from wild-type mice authentic 11,12-EET increased PAP in a concentration-dependent manner and significantly enhanced HPV (2.2-fold, P<0.01). Ritanserin (5-HT2A receptor antagonist) and Y27632 (Rho kinase inhibitor) shifted the 11,12-EET dose-response curve to the right and markedly decreased HPV after 11,12-EET application. Furthermore, in cultured murine lung endothelial cells 11,12-EET elicited the release of 5-HT while in lungs from wild-type mice ritanserin abrogated the effect of sEH inhibition on acute hypoxic pulmonary vasoconstriction. Taken together, these data demonstrate that CYP-derived EETs are involved in HPV and that EET-induced pulmonary contraction under normoxic and hypoxic conditions involves the 5-HT2A receptor as well as the Rho kinase.