We aimed to investigate the effects of epoxygenases on electrical field stimulation (EFS)-mediated nitric oxide (NO)-dependent and NO-independent nonadrenergic noncholinergic (NANC) relaxations in isolated rabbit corpus cavernosum. The tissues of 20 male adult albino rabbits (2.5-3 kg) were suspended in organ baths containing aerated Krebs solution, and isometric contractions were recorded. EFS-mediated NANC relaxations were obtained on phenylephrin (3 x 10(-5) M)-contracted tissues in the presence of guanethidine (10(-6) M) and atropine (10(-6) M). Miconazole (10(-9)-10(-4) M), 17-octadecynoic acid (ODYA) (10(-10)-10(-5) M), 14,15-epoxyeicosatrienoic acid (EET) (10(-11)-10(-8) M), 11,12-EET (10(-12)-3 x 10(-8) M) and 20-hydroxyeicosatetraenoic acid (HETE) (10(-11)-3 x 10(-8) M) were added cumulatively (n = 5-7 for each set of experiments). For NO-independent relaxations, N-omega-nitro-l-arginine methyl ester (l-NAME) (10(-4) M) was added before a group of experiments. Depending on the concentration, miconazole, 17-ODYA, 14,15-EET, 11,12-EET, and 20-HETE significantly enhanced both NO-dependent and NO-independent EFS-mediated relaxations (p < 0.05). Epoxygenases showed similar effect on NO-dependent and NO-independent relaxant responses except 20-HETE which caused significantly more enhanced relaxation on NO-dependent responses (p < 0.05). No drug caused a significant relaxation response on tissues contracted with phenylephrine. Epoxygenases contribute to EFS-mediated NO-dependent and NO-independent NANC relaxations by presynaptic mechanisms, offering a new treatment alternative for erectile dysfunction which needs to be explored in further in vivo, molecular and clinical studies.