Urocortin relaxes rat pulmonary arteries partly through a cyclic AMP-dependent but Ca(2+) channel-independent mechanism. However, other participating mechanisms are relatively unknown. The present study was designed to examine whether the forward mode of Na(+)-Ca(2+) exchangers play a role in the relaxant responses to urocortin in isolated rat small pulmonary arteries. Endothelium-denuded rings were mounted on small vessel myographs for measurement of changes in isometric tension. Urocortin inhibited 9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin F(2alpha) (U46619)-induced contraction in a concentration-dependent manner and this inhibition was reversed by astressin, a corticotropin-releasing factor receptor antagonist. Micromolar concentrations of nickel (Ni(2+)) chloride, a putative inhibitor of the Na(+)-Ca(2+) exchanger, reduced the relaxant responses to urocortin. Urocortin-induced relaxation was abolished in a Na(+)-free solution, a condition that eliminates influence of the forward mode of Na(+)-Ca(2+) exchanger. In contrast, the relaxant responses to atrial natriuretic peptide or forskolin were unaffected by Ni(2+) or with removal of extracellular Na(+). The present results provide indirect evidence suggesting that stimulation of Na(+)-Ca(2+) exchangers may contribute to urocortin-induced endothelium-independent pulmonary artery relaxation.