title: Mechanism of vascular relaxation induced by the nitric oxide (NO)/nucleophile complexes, a new class of NO-based vasodilators.
abstract: Compounds formed by reacting nitric oxide (NO) with various nucleophiles have been shown to dilate aortic segments with a potency that correlates strongly with the amount of NO they release spontaneously in aqueous buffers. We performed experiments aimed at confirming their mechanism of action and using the data to design improvements in their pharmacologic properties. That the vasorelaxant action these agents induce is endothelium-independent was demonstrated by exposure of denuded versus intact aortic segments to the diethylamine/NO complex (DEA/NO); denudation had no significant effect on potency. Similarly, NG-monomethyl-L-arginine, an NO synthase inhibitor, did not affect the action of DEA/NO. However, both the vasorelaxant potency of DEA/NO and the amount of cyclic guanosine monophosphate it induced were significantly diminished by the guanylate cyclase inhibitor, methylene blue. The results support the view that the NO/nucleophile adducts induce vasodilation by spontaneously releasing NO, which then activates guanylate cyclase. This mechanistic conclusion suggests that not only potency but also duration of action, a clinically relevant parameter not studied in the previous investigation, might also be controllable by structural modification. We tested this hypothesis by comparing DEA/NO and the spermine/NO adduct (SPER/NO), whose half-lives (t1/2) are 2.1 and 39 min, respectively, for persistence of their dilatory effects. The response to DEA/NO rapidly peaked (maximum at 5 min) and receded during the 60-min observation period; SPER/NO required 15 min to reach peak relaxation but maintained this level throughout the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: D
authors.initials: D
authors.lastname: Morley
authors.forename: C M
authors.initials: CM
authors.lastname: Maragos
authors.forename: X Y
authors.initials: XY
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Boignon
authors.forename: D A
authors.initials: DA
authors.lastname: Wink
authors.forename: L K
authors.initials: LK
authors.lastname: Keefer
mesh_terms: D000818:Animals; D004048:Diethylamines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009566:Nitrates / Q000378:metabolism; D017942:Nitric Acid; D005996:Nitroglycerin / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D004048:Diethylamines; D009566:Nitrates; D014665:Vasodilator Agents; D009599:Nitroprusside; D017942:Nitric Acid; C031406:N-nitrodiethylamine; D005996:Nitroglycerin