Nω-hydroxy-l-arginine homologues and hydroxylamine as nitric oxide-dependent vasorelaxant agents

Endothelium-independent relaxant activities of Nω-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. Nω-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 P450 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.