The relaxant effect of 4-hydroxynonenal (4-HNE), a lipid peroxidation product, on human cerebral arteries was studied. Addition of 4-HNE to artery rings promoted no contraction, and after stimulation with prostaglandin F2 alpha (PFG2 alpha; 10(-7)-3 x 10(-6) M), 100% relaxation was obtained with 3 x 10(-5) M 4-HNE. Inhibition of nitric oxide formation with NG-nitro-L-arginine methyl ester hydrochloride (L-NAME; (10(-4) M), as well as prostaglandin synthesis with indomethacin (3 x 10(-6) M), partially prevented 4-HNE-induced relaxation, but each of these substances separately failed to inhibit complete relaxation. Addition of both inhibitors together reduced 4-HNE-induced relaxation to approximately 50%, but relaxation could not be abolished. When the endothelium was removed, 4-HNE did not promote relaxation after PGF2 alpha stimulation. The possible roles of different intracellular signaling systems in the vascular effect of 4-HNE are discussed.