Urocortin is a recently characterized mammalian peptide which appears to be an endogenous ligand for corticotropin-releasing factor (CRF) receptors, in particular CRF receptor type 2. The effect of rat urocortin on protein extravasation and edema, produced by immersion of the paws of anesthetized rats in 58 degrees C water for 5 min, was compared to that of rat/human CRF. Urocortin administered i.v. dose-dependently inhibited the leakage of Evans blue dye into the skin of the footpad and the increase in paw weight, with a potency 6.6-6.7 times greater than CRF. alpha-Helical CRF-(9-41), a more potent antagonist of type 2 than type 1 CRF receptors, completely reversed the inhibition of edema produced by either CRF or urocortin, at a dose (200 nmol/kg) that did not affect adrenocorticotropin secretion induced by either peptide. These data indicate that urocortin is a potent inhibitor of heat-induced edema, and that this action is mediated by CRF receptors, most likely CRF receptor type 2.