Recent studies have suggested that coronary endothelial cells produce and release nitric oxide (NO), prostaglandin I2, and epoxyeicosatrienoic acids (EETs). These endothelium-derived vasodilators play an important role in the control of coronary vascular tone. However, the mechanism by which these endothelium-derived vasodilators cause relaxation of coronary arterial smooth muscle has yet to be determined. This study characterized and compared the effects of NO, prostaglandin I (2), and 11,12-EET on the two main types of potassium channels in small bovine coronary arterial smooth muscle: the large conductance Ca2+-activated K+channels (KCa) and 4-aminopyridine-sensitive delayed rectifier K+channels (Kdrf). In cell-attached patches, nonoate, an NO donor, activated both KCaand Kdrfchannels. The open probability of both KCaand Kdrfchannels increased 10- to 25-fold when nonoate was added to the bath at concentrations of 10-6to 10-4mol/L. 11,12-EET (10-8to 10-4mol/L) also increased the activity of the KCachannels in a concentration-dependent manner, but it had no effect on the activity of the Kdrfchannels, even in the highest concentration studied (10-4mol/L). In contrast to the effect of 11,12-EET, iloprost, a prostaglandin I2analogue (10-6to 10-4mol/L), produced a concentration-dependent increase in the activity of Kdrfchannels without affecting the KCachannels. In conclusion, all three endothelium-derived vasodilators act to open potassium channels; however, the channel types that they affect are different. NO activates both KCaand Kdrfchannels; 11,12-EET activates only the KCachannels; and prostaglandin I2activates only the Kdrfchannels. (Hypertension. 1997;29[part 2]:262-267.)