We aimed to determine the relaxant pathway of seventeen synthetic compounds derived from coumarin-3-carboxamide. An isolated rat aorta assay was used. To determine the vasorelaxant mode of action, receptor blockers and specific enzyme inhibitors involved in endothelial and smooth muscle signaling pathways were used. The compounds 2, 4, and 5 showed higher activity than the other compounds. N-nitro-L-arginine methyl ester (10 µM) and methylene blue (10 µM) significantly inhibited the relaxant effect of the compounds 2, 4, and 5 (p ≤ 0.05), but not tetraethylammonium (5 mM), indomethacin (10 µM), or atropine (1 µM). The compounds 2, 4, and 5 abated the contraction induced by CaCl