Endothelin-1 (ET-1) is a recently discovered 21 amino acid peptide with potent vasoconstrictor properties. So far, its expression has been found only in porcine aorta, whereas its putative role as the endothelium-derived constricting factor (EDCF) would require it to be expressed and active in most vascular beds. We have used quantitative receptor autoradiography on pig, rat, and some human tissues to determine the distribution and localization of specific binding sites for ET-1. In some cases where binding sites were found, studies were performed to determine whether these are likely to be functional receptors. Binding sites for ET-1 have been found in heart (nerves > atria > ventricle > coronary arteries), kidney (glomeruli > papilla), adrenal (zona glomerulosa > medulla), cerebellum, spinal cord, gut, spleen, and lung. The binding of [125I]ET-1 was displaced at all these sites by unlabeled ET-1 but not by nitrendipine, apamin, and other vasoconstrictor peptides. ET-1 contracted strips of human coronary artery at an EC50 of 15 nM, with a maximal contraction 130% that of K+. A positive inotropic effect was found in strips of human atria (EC50 = 1 nM), which was not blocked by α-or β-blockade. The widespread distribution of its binding sites suggests a more extensive role than control of vascular tone.