title: Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects.
abstract: Nitroxyl (HNO) donors have potential benefit in the treatment of heart failure and other cardiovascular diseases. 1-Nitrosocyclohexyl acetate (NCA), a new HNO donor, in contrast to the classic HNO donors Angeli's salt and isopropylamine NONOate, predominantly releases HNO and has a longer half-life. This study investigated the vasodilatative properties of NCA in isolated aortic rings and human platelets and its mechanism of action. NCA was applied on aortic rings isolated from wild-type mice and apolipoprotein E-deficient mice and in endothelial-denuded aortae. The mechanism of action of HNO was examined by applying NCA in the absence and presence of the HNO scavenger glutathione (GSH) and inhibitors of soluble guanylyl cyclase (sGC), adenylyl cyclase (AC), calcitonin gene-related peptide receptor (CGRP), and K(+) channels. NCA induced a concentration-dependent relaxation (EC(50), 4.4 µM). This response did not differ between all groups, indicating an endothelium-independent relaxation effect. The concentration-response was markedly decreased in the presence of excess GSH; the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide had no effect. Inhibitors of sGC, CGRP, and voltage-dependent K(+) channels each significantly impaired the vasodilator response to NCA. In contrast, inhibitors of AC, ATP-sensitive K(+) channels, or high-conductance Ca(2+)-activated K(+) channels did not change the effects of NCA. NCA significantly reduced contractile response and platelet aggregation mediated by the thromboxane A(2) mimetic 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F(2)(α) in a cGMP-dependent manner. In summary, NCA shows vasoprotective effects and may have a promising profile as a therapeutic agent in vascular dysfunction, warranting further evaluation.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf., Martinistr. 52, D-20246 Hamburg, Germany. s.donzelli@uke.de
authors.forename: Sonia
authors.initials: S
authors.lastname: Donzelli
authors.forename: Gerry
authors.initials: G
authors.lastname: Fischer
authors.forename: Bruce S
authors.initials: BS
authors.lastname: King
authors.forename: Christin
authors.initials: C
authors.lastname: Niemann
authors.forename: Jenna F
authors.initials: JF
authors.lastname: DuMond
authors.forename: Jörg
authors.initials: J
authors.lastname: Heeren
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wieboldt
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Christian
authors.initials: C
authors.lastname: Gerloff
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Michael Graham
authors.initials: MG
authors.lastname: Espey
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism*; D009603:Nitroso Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C554428:1-nitrosocyclohexyl acetate; D000085:Acetates; D001057:Apolipoproteins E; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; C039900:nitroxyl