Among three endothelin (ET) isopeptides, ET-3 shows the most potent initial depressor response through the endothelium-dependent mechanism. We studied the presence of specific binding sites for ET-3 in cultured bovine endothelial cells (EC) and its cellular mechanism of action. Binding studies revealed the presence of two distinct subclasses of ET-3 receptors with high and low affinities. ET-3 dose-dependently (10−10−10−7 M) increased both intracellular Ca2+ levels ([Ca−2]) and inositol trisphosphate (IP3) formation. The ET-3-induced increase in [Ca2+]i was not affected by either removal of extracellular Ca2+ or Ca2+-channel blockers. These data suggest that ET-3 induces phosphoinositide breakdown and increase in [Ca2+]i in ECs, possibly resulting from intracellular Ca2+ mobilization, thereby leading to vasodilatation.
