EPOXYEICOSATRIENOIC ACIDS RELAX AIRWAY SMOOTH MUSCLES AND DIRECTLY ACTIVATE RECONSTITUTED K-CA CHANNELS

Epoxyeicosatrienoic acids (EETs) relax various smooth muscles by incre asing outward K+ movement, but the molecular mode of action of EET reg ioisomers remains to be clarified. The effects of EETs were investigat ed on bovine airway smooth muscle tone and on reconstituted Ca2+-activ ated K+ (K-Ca) channels. 5,6-EET and 11,18-EET induced dose-dependent relaxations of precontracted bronchial spirals. These effects were par tly abolished by 10 nM iberiotoxin. Bilayer experiments have shown tha t 0.1-10 mu M 11,12-EET produced up to fourfold increases in the open probability of K-Ca channels from the cis (extracellular) side by enha ncing the mean open time constant and reducing the long closed time co nstant, without affecting the unitary conductance. EET-induced activat ions were blocked by 10 nM iberiotoxin. Addition of vehicles or other lipids as well as of GTP and guanosine 5'-O-(3-thiotriphosphate) in th e absence of EET had no effect on channel activity. Thus EETs directly activate K-Ca channels from airway smooth muscle through an interacti on with the extracellular face of the channel. We propose that EETs co uld represent candidate molecules as epithelium-derived hyperpolarizin g factors.