The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and -adrenergically desensitized ventricular myocytes.

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Erscheinungsjahr:
2010
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Beschreibung:
  • 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.
  • 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.
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  • info:eu-repo/semantics/restrictedAccess
Quellsystem:
Forschungsinformationssystem des UKE

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oai:pure.atira.dk:publications/0032f2f0-b3aa-4795-a3b5-e6640b3ce421