Summary: Binding studies performed in dog kidney, lung, and spleen using [125I]endothelin (ET) 3 and a series of ETB-selective ligands indicated the presence of two subtypes of ETB receptors, an IRL-1620-sensitive (putative ETB1) and an IRL-1620-insensitive (putative ETB2) receptor. The IRL-1620-sensitive (but not IRL-1620-insensitive) ETB receptors displayed similar pharmacology to the cloned human ETB receptor and a high affinity for the ETB receptor antagonist RES-701. ETB1 receptors predominated in the dog kidney and lung and ETB2 receptors predominated in the dog spleen. Stimulation of ETB receptors in dogs in vivo inhibited sodium reabsorp-tion, as ET-1 infusion in the presence of the ETA antagonist BQ123, but not the mixed ETA/ETB receptor antagonist, (±)SB 209670, resulted in increased sodium excretion. Furthermore, infusion of the ETB-selective agonist Sarafotoxin S6c (S6c) resulted in an increase in sodium excretion, a response that was attenuated by infusion of RES-701. These data indicate that the putative ETB1 receptor may mediate ET-induced inhibition of tubule sodium reabsorption in the dog. In addition, we observed no putative ETB2 receptor-mediated renal vasoconstriction, consistent with the apparent low abundance of this subtype in the dog kidney.