This paper defines the properties of interaction of endothelin-1 (Et-1) with cloned bovine ETA receptors. The Kd value of Et-1/ETA receptor complexes was estimated in membrane preparations to 20 pM using kinetic experiments and saturation experiments performed under quasi equilibrium conditions. Competition experiments yield a wide range of apparent Kd(Et-1) values from 20 pM to 1 nM which were in fact measures of the receptor concentrations rather than of Kd values. This resulted from the fact that complex second-order rate kinetics rather than pseudo-first-order kinetics control the association of Et-1 to its receptor when the receptor concentration is larger than Kd(Et-1). Et-1 induced a production of inositol phosphates with an apparent affinity of 2.3 nM, 100 times higher than the Kd(Et-1) value determined previously. Numerical simulation suggested that under time-limited conditions, sub-nanomolar rather than picomolar concentrations of Et-1 are necessary to occupy an important fraction of picomolar sites. It is concluded that bovine ETA receptors have a single affinity state for Et-1 (Kd = 20 pM) and that this affinity state can account for nanomolar actions of Et-1 in intact cells. It is suggested that the sensitivity of a preparation to Et-1 is a cell property rather than a receptor property. It is also suggested that the main advantage of high-affinity Et-1 binding is to promote autocrine actions rather than a high potency of the peptide.