11,12-Epoxyeicasotrienoic acid (EET) can activate large conductance Ca²⁺-activated potassium (BK) channels leading to smooth muscle cell hyperpolarization and relaxation. In the lung, EET contributes to hypoxia-induced pulmonary artery constriction but the role of pulmonary BK channels is unclear. In buffer-perfused mouse lungs, hypoxia increased pulmonary artery pressure and this was significantly enhanced in the presence of nitric oxide synthase and cyclooxygenase inhibitor. Under these conditions a soluble epoxide hydrolase inhibitor (sEH-I; to increase EET levels), further increased the response to hypoxia. Direct administration of EET also increased pulmonary artery pressure, an effect sensitive to iberiotoxin. Neither EET nor the sEH-I increased pulmonary artery pressure in mice lacking the BKb₁ subunit. In pulmonary artery smooth muscle cells, the direct BK channel activator NS1619 induced a significant hyperpolarization irrespective of the presence of the b₁ subunit, whereas EET caused an iberiotoxin-sensitive depolarization in cells from wild-type, but not b₁^-/- mice. In pulmonary artery smooth muscle cells the BK channel is present in mitochondria and both EET and NS1619 reduced the mitochondrial membrane potential in wild-type, but not b₁^-/- cells. Moreover, stimulation with EET time-dependently induced the association of the BKa and b₁ subunit.

These data indicate that EETs enhance acute hypoxic pulmonary vasoconstriction by a mechanism that requires the b₁ subunit of the BK channel. Mechanistically, EETs reduce mitochondrial membrane polarization by inducing the association of the BKa with the b₁ subunit in mitochondria which leads to subsequent smooth muscle cell depolarization.