Epoxyficosatrienoic acids (EETs) inhibit the formation of prostaglandin E₂ by smooth muscle cells

Epoxyeicosatrienoic acids (EETs) and prostaglandins (PG) are eicosanoids derived from arachidonic acid (AA) by cytochrome P450 epoxygenase and cycloxygenase metabolism, respectively. EETs were previously reported to inhibit PG production by platelets and blood vessels. To determine whether EETs can inhibit PG production by vascular smooth muscle cells (SMC), porcine aortic SMC were incubated with [³H]AA in the presence and absence of EETs, and PG production in the medium was determined by reverse-phase HPLC and radioimmunoassay (RIA). The formation of PGE₂, the major PG produced by SMC, was inhibited in concentration-dependent fashion by 14,15-EET. In the presence of 1 μM 14,15-EET, basal PGE₂ formation, and PGE₂ formation stimulated by 2 μM calcium ionophore A23187, were reduced by 40-50%. 8,9-EET (1 μM) decreased PGE₂ formation by 30%, whereas 11,12-EET and 5,6-EET were without effect. 14,15-dihydroxyeicosatrienoic acid (DHET), the major metabolite of 14,15-EET, and 15-(S)-hydroxyeicosatetraenoic acid also did not alter PGE₂ production by SMC. 14,15-EET-induced inhibition of PGE₂ production was diminished by the inclusion of 30 μM AA. 4-Phenylchalcone oxide, a potent inhibitor of epoxide hydrolase (the enzyme responsible for conversion of EETs to DHETs), potentiated the 14,15-EET-induced inhibition of PGE₂ production. We conclude that EETs regio-specifically inhibit PGE₂ production by SMC.