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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, Vol. 344, No. 2, 01.02.2013, p. 339-47.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Donzelli, S, Fischer, G, King, BS, Niemann, C, DuMond, JF, Heeren, J, Wieboldt, H, Baldus, S, Gerloff, C, Eschenhagen, T, Carrier, L, Böger, RH & Espey, MG 2013, 'Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects', J PHARMACOL EXP THER, vol. 344, no. 2, pp. 339-47. https://doi.org/10.1124/jpet.112.199836

APA

Donzelli, S., Fischer, G., King, B. S., Niemann, C., DuMond, J. F., Heeren, J., Wieboldt, H., Baldus, S., Gerloff, C., Eschenhagen, T., Carrier, L., Böger, R. H., & Espey, M. G. (2013). Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects. J PHARMACOL EXP THER, 344(2), 339-47. https://doi.org/10.1124/jpet.112.199836

Vancouver

Donzelli S, Fischer G, King BS, Niemann C, DuMond JF, Heeren J et al. Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects. J PHARMACOL EXP THER. 2013 Feb 1;344(2):339-47. https://doi.org/10.1124/jpet.112.199836

Bibtex

@article{2eb85ebbcbf344df9b7d66f1f58a7e85,
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.",
keywords = "Acetates, Animals, Aorta, Thoracic, Apolipoproteins E, Atherosclerosis, Blood Platelets, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelium, Vascular, Half-Life, Humans, Mice, Mice, Inbred C57BL, Nitric Oxide Donors, Nitrogen Oxides, Nitroso Compounds, Platelet Aggregation, Platelet Aggregation Inhibitors, Vasodilation, Vasodilator Agents",
author = "Sonia Donzelli and Gerryansjah Fischer and King, {Bruce S} and Christin Niemann and DuMond, {Jenna F} and J{\"o}rg Heeren and Hartwig Wieboldt and Stephan Baldus and Christian Gerloff and Thomas Eschenhagen and Lucie Carrier and B{\"o}ger, {Rainer H} and Espey, {Michael Graham}",
year = "2013",
month = feb,
day = "1",
doi = "10.1124/jpet.112.199836",
language = "English",
volume = "344",
pages = "339--47",
journal = "J PHARMACOL EXP THER",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

RIS

TY - JOUR

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 -