The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and β-adrenergically desensitized ventricular myocytes
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The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and β-adrenergically desensitized ventricular myocytes. / El-Armouche, Ali; Wahab, Azadeh; Wittköpper, Katrin; Schulze, Thomas; Böttcher, Felix; Pohlmann, Lutz; King, S Bruce; DuMond, Jenna F; Gerloff, Christian; Böger, Rainer H; Eschenhagen, Thomas; Carrier, Lucie; Donzelli, Sonia.
in: BIOCHEM BIOPH RES CO, Jahrgang 402, Nr. 2, 2, 12.11.2010, S. 340-344.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and β-adrenergically desensitized ventricular myocytes
AU - El-Armouche, Ali
AU - Wahab, Azadeh
AU - Wittköpper, Katrin
AU - Schulze, Thomas
AU - Böttcher, Felix
AU - Pohlmann, Lutz
AU - King, S Bruce
AU - DuMond, Jenna F
AU - Gerloff, Christian
AU - Böger, Rainer H
AU - Eschenhagen, Thomas
AU - Carrier, Lucie
AU - Donzelli, Sonia
N1 - Copyright © 2010 Elsevier Inc. All rights reserved.
PY - 2010/11/12
Y1 - 2010/11/12
N2 - Contractile dysfunction and diminished response to -adrenergic agonists are characteristics for failing hearts. Chemically donated nitroxyl (HNO) improves contractility in failing hearts and thus may have therapeutic potential. Yet, there is a need for pharmacologically suitable donors. In this study we tested whether the pure and long acting HNO donor, 1-nitrosocyclohexyl acetate (NCA), affects contractile force in normal and pathological ventricular myocytes (VMs) as well as in isolated hearts. VMs were isolated from mice either subjected to isoprenaline-infusion (ISO; 30 g/g per day) or to vehicle (0.9% NaCl) for 5 days. Sarcomere shortening and Ca2+ transients were simultaneously measured using the IonOptix system. Force of contraction of isolated hearts was measured by a Langendorff-perfusion system. NCA increased peak sarcomere shortening by+40-200% in a concentration-dependent manner (EC50 55 M). Efficacy and potency did not differ between normal and chronic ISO VMs, despite the fact that the latter displayed a markedly diminished inotropic response to acute -adrenergic stimulation with ISO (1 M). NCA (60 M) increased peak sarcomere shortening and Ca2+ transient amplitude by 200% and 120%, respectively, suggesting effects on both myofilament Ca2+ sensitivity and sarcoplasmic reticulum (SR) Ca2+ cycling. Importantly, NCA did not affect diastolic Ca2+ or SR Ca2+ content, as assessed by rapid caffeine application. NCA (45 M) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and -adrenergically desensitized VMs as well as in isolated mouse hearts. This profile warrants further investigations of this HNO donor in the context of heart failure.
AB - Contractile dysfunction and diminished response to -adrenergic agonists are characteristics for failing hearts. Chemically donated nitroxyl (HNO) improves contractility in failing hearts and thus may have therapeutic potential. Yet, there is a need for pharmacologically suitable donors. In this study we tested whether the pure and long acting HNO donor, 1-nitrosocyclohexyl acetate (NCA), affects contractile force in normal and pathological ventricular myocytes (VMs) as well as in isolated hearts. VMs were isolated from mice either subjected to isoprenaline-infusion (ISO; 30 g/g per day) or to vehicle (0.9% NaCl) for 5 days. Sarcomere shortening and Ca2+ transients were simultaneously measured using the IonOptix system. Force of contraction of isolated hearts was measured by a Langendorff-perfusion system. NCA increased peak sarcomere shortening by+40-200% in a concentration-dependent manner (EC50 55 M). Efficacy and potency did not differ between normal and chronic ISO VMs, despite the fact that the latter displayed a markedly diminished inotropic response to acute -adrenergic stimulation with ISO (1 M). NCA (60 M) increased peak sarcomere shortening and Ca2+ transient amplitude by 200% and 120%, respectively, suggesting effects on both myofilament Ca2+ sensitivity and sarcoplasmic reticulum (SR) Ca2+ cycling. Importantly, NCA did not affect diastolic Ca2+ or SR Ca2+ content, as assessed by rapid caffeine application. NCA (45 M) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and -adrenergically desensitized VMs as well as in isolated mouse hearts. This profile warrants further investigations of this HNO donor in the context of heart failure.
KW - Acetates
KW - Animals
KW - Cells, Cultured
KW - Heart Ventricles
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Muscle Contraction
KW - Myocytes, Cardiac
KW - Nitric Oxide Donors
KW - Nitrogen Oxides
KW - Nitroso Compounds
U2 - 10.1016/j.bbrc.2010.10.030
DO - 10.1016/j.bbrc.2010.10.030
M3 - SCORING: Journal article
C2 - 20946877
VL - 402
SP - 340
EP - 344
JO - BIOCHEM BIOPH RES CO
JF - BIOCHEM BIOPH RES CO
SN - 0006-291X
IS - 2
M1 - 2
ER -