title: Redox variants of NO (NO{middle dot} and HNO) elicit vasorelaxation of resistance arteries via distinct mechanisms.
abstract: The free radical form of nitric oxide (NO(.)) is a well-known mediator of vascular tone. What is not so well recognized is that NO(.) exists in several different redox forms. There is considerable evidence that NO(.) and its one-electron reduction product, nitroxyl (HNO), have pharmacologically distinct actions that extend into the regulation of the vasculature. The aim of this study was to compare the vasorelaxation mechanisms of HNO and NO(.), including an examination of the ability of these redox variants to hyperpolarize and repolarize vascular smooth muscle cells from rat mesenteric arteries. The HNO donor Angeli's salt (0.1 nM-10 microM) caused a concentration-dependent hyperpolarization of vessels at resting tone and a simultaneous, concentration-dependent vasorelaxation and repolarization of vessels precontracted and depolarized with methoxamine. Both vasorelaxation and repolarization responses to Angeli's salt were significantly attenuated by both the HNO scavenger l-cysteine (3 mM) and the voltage-dependent K(+) (K(v)) channel inhibitor 4-aminopyridine (4-AP; 1 mM) and virtually abolished by the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM) or 30 mM K(+). In contrast, NO(.) (0.01-1 microM) repolarized arteries to a lesser extent than HNO, and these responses were resistant to inhibition by ODQ (10 microM) and 4-AP (1 mM). Blockade of K(v) channels (1 mM 4-AP) also significantly inhibited the repolarization response to YC-1 (0.1-10 microM), confirming a role for sGC/cGMP in the activation of K(v) channels in this preparation. We conclude that HNO causes vasorelaxation via a cGMP-dependent activation of K(v) channels and that there are different profiles of vasorelaxant activity for the redox siblings HNO and NO(.).
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Medical Sciences, Royal Melbourne Institute of Technology, Univ., PO Box 71, Bundoora West, Victoria 3083, Australia. Joanne.Favaloro@rmit.edu.au
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Favaloro
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D017538:Mesenteric Artery, Superior / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009573:Nitrites; D009589:Nitrogen Oxides; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; C021229:oxyhyponitrite; D009569:Nitric Oxide; D015761:4-Aminopyridine; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C039900:nitroxyl; D006152:Cyclic GMP; D003545:Cysteine