Nω-hydroxy-L-arginine hornologues and hydroxylarnine as nitric oxide-dependent vasorelaxant agents

Endothelium-independent relaxant activities of A N-omega-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 a-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-omega-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 fort-nation 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 guanylyt cyclase, through a 7-ethoxyresorufin-inhibited mechanism. (c) 2005 Elsevier B.V. All rights reserved.