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Abstract: Endothelium-independent relaxant activities of N ω-hydroxy-l-arginine (l-NOHA) homologues and hydroxylamine, a possible intermediate in nitric oxide (NO) formation, were examined in rat aortic rings. Addition of one –CH2– group to the –(CH2) x – chain between the α-amino acid and the hydroxyguanidine group (x =4) almost abolished–while deletion of one or two –CH2– (x =1 or 2) enhanced–the relaxant activity of l-NOHA homologues. N ω-hydroxy-nor-l-arginine- (x =2) and hydroxylamine-induced relaxations were blunted by a NO scavenger and by inhibitors of the guanylyl cyclase pathway, but not by NO synthase or cytochrome P 450 inhibitors (except 7-ethoxyresorufin). However, aortic NO formation was detected (using electron paramagnetic resonance) in the presence of concentrations of these compounds higher than those producing relaxation. These findings support the view that endothelium-independent vasorelaxations induced by both l-NOHA homologues with a required chain length x ≤3 and hydroxylamine are mediated by NO-dependent activation of guanylyl cyclase, through a 7-ethoxyresorufin-inhibited mechanism. [Copyright &y& Elsevier]