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Research ArticleCardiovascular

Pharmacological Characterization of 1-Nitrosocyclohexyl Acetate, a Long-Acting Nitroxyl Donor That Shows Vasorelaxant and Antiaggregatory Effects

Sonia Donzelli, Gerry Fischer, Bruce S. King, Christin Niemann, Jenna F. DuMond, Jörg Heeren, Hartwig Wieboldt, Stephan Baldus, Christian Gerloff, Thomas Eschenhagen, Lucie Carrier, Rainer H. Böger and Michael Graham Espey
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 339-347; DOI: https://doi.org/10.1124/jpet.112.199836
Sonia Donzelli
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Gerry Fischer
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Bruce S. King
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Christin Niemann
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Jenna F. DuMond
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Jörg Heeren
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Hartwig Wieboldt
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Stephan Baldus
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Christian Gerloff
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Thomas Eschenhagen
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Lucie Carrier
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Rainer H. Böger
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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Michael Graham Espey
Department of Experimental Pharmacology and Toxicology (S.D., T.E., L.C.), Department of Neurology (S.D., C.G.), Department of Clinical Pharmacology and Toxicology (G.F., C.N., R.H.B.), Department of Molecular Cell Biology (J.H.), and Cardiovascular Research Center (S.D., S.B., T.E., L.C., R.H.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Cardiology, Heart and Diabetes Centre North-Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (G.F.); Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina (B.S.K., J.F.D.); Department of Cardiology, University Heart Center, Hamburg, Germany (H.W., S.B.); INSERM, Institut de Myologie, University Pierre et Marie Curie-Paris, Paris, France (L.C.); and Office of the Scientific Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.G.E.)
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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 (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.

Footnotes

  • This work was supported by the Marie Curie Intra European Fellowship within the 7th European Community Framework Programme [PIEF-GA-2008-221666]; the sixth Framework Program of the European Union [Marie Curie EXT-014051]; and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant HL62198]. This research was also supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases.

  • dx.doi.org/10.1124/jpet.112.199836.

  • Received September 17, 2012.
  • Accepted November 19, 2012.
  • U.S. government work not protected by U.S. copyright.
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleCardiovascular

HNO Donor in Cardiovascular Disease

Sonia Donzelli, Gerry Fischer, Bruce S. King, Christin Niemann, Jenna F. DuMond, Jörg Heeren, Hartwig Wieboldt, Stephan Baldus, Christian Gerloff, Thomas Eschenhagen, Lucie Carrier, Rainer H. Böger and Michael Graham Espey
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 339-347; DOI: https://doi.org/10.1124/jpet.112.199836

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Research ArticleCardiovascular

HNO Donor in Cardiovascular Disease

Sonia Donzelli, Gerry Fischer, Bruce S. King, Christin Niemann, Jenna F. DuMond, Jörg Heeren, Hartwig Wieboldt, Stephan Baldus, Christian Gerloff, Thomas Eschenhagen, Lucie Carrier, Rainer H. Böger and Michael Graham Espey
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 339-347; DOI: https://doi.org/10.1124/jpet.112.199836
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