TY - JOUR T1 - Pharmacological Characterization of 1-Nitrosocyclohexyl Acetate, a Long-Acting Nitroxyl Donor That Shows Vasorelaxant and Antiaggregatory Effects JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 339 LP - 347 DO - 10.1124/jpet.112.199836 VL - 344 IS - 2 AU - Sonia Donzelli AU - Gerry Fischer AU - Bruce S. King AU - Christin Niemann AU - Jenna F. DuMond AU - Jörg Heeren AU - Hartwig Wieboldt AU - Stephan Baldus AU - Christian Gerloff AU - Thomas Eschenhagen AU - Lucie Carrier AU - Rainer H. Böger AU - Michael Graham Espey Y1 - 2013/02/01 UR - http://jpet.aspetjournals.org/content/344/2/339.abstract N2 - 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 (EC50, 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 Ca2+-activated K+ channels did not change the effects of NCA. NCA significantly reduced contractile response and platelet aggregation mediated by the thromboxane A2 mimetic 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α 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. ER -