Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects
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Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects. / Donzelli, Sonia; Fischer, Gerryansjah; King, Bruce S; Niemann, Christin; DuMond, Jenna F; Heeren, Jörg; Wieboldt, Hartwig; Baldus, Stephan; Gerloff, Christian; Eschenhagen, Thomas; Carrier, Lucie; Böger, Rainer H; Espey, Michael Graham.
in: J PHARMACOL EXP THER, Jahrgang 344, Nr. 2, 01.02.2013, S. 339-47.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects
AU - Donzelli, Sonia
AU - Fischer, Gerryansjah
AU - King, Bruce S
AU - Niemann, Christin
AU - DuMond, Jenna F
AU - Heeren, Jörg
AU - Wieboldt, Hartwig
AU - Baldus, Stephan
AU - Gerloff, Christian
AU - Eschenhagen, Thomas
AU - Carrier, Lucie
AU - Böger, Rainer H
AU - Espey, Michael Graham
PY - 2013/2/1
Y1 - 2013/2/1
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 (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.
AB - 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.
KW - Acetates
KW - Animals
KW - Aorta, Thoracic
KW - Apolipoproteins E
KW - Atherosclerosis
KW - Blood Platelets
KW - Disease Models, Animal
KW - Dose-Response Relationship, Drug
KW - Endothelium, Vascular
KW - Half-Life
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - Nitric Oxide Donors
KW - Nitrogen Oxides
KW - Nitroso Compounds
KW - Platelet Aggregation
KW - Platelet Aggregation Inhibitors
KW - Vasodilation
KW - Vasodilator Agents
U2 - 10.1124/jpet.112.199836
DO - 10.1124/jpet.112.199836
M3 - SCORING: Journal article
C2 - 23211362
VL - 344
SP - 339
EP - 347
JO - J PHARMACOL EXP THER
JF - J PHARMACOL EXP THER
SN - 0022-3565
IS - 2
ER -