Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 402, Issue 2, Pages 340-344Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2010.10.030
Keywords
1-Nitrosocyclohexyl acetate; Cardiomyocytes; Contractile force; Ca(2+)-handling
Categories
Funding
- European Community [PIEF-GA-2008-221666]
- Forschungsforderungsfonds [NWF-08/04]
- Deutsche Forschungsgemeinschaft [FOR 604]
- European Union
- German Heart Foundation/German Foundation of Heart Research
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Contractile dysfunction and diminished response to p-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 mu g/g per day) or to vehicle (0.9% NaCl) for 5 days. Sarcomere shortening and Ca(2+) 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 (EC(50) similar to 55 mu 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 p-adrenergic stimulation with ISO (1 mu M). NCA (60 mu M) increased peak sarcomere shortening and Ca(2+) transient amplitude by similar to 200% and similar to 120%, respectively, suggesting effects on both myofilament Ca2+ sensitivity and sarcoplasmic reticulum (SR) Ca(2+) cycling. Importantly, NCA did not affect diastolic Ca(2+) or SR Ca(2+) content, as assessed by rapid caffeine application. NCA (45 mu M) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and beta-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. (C) 2010 Elsevier Inc. All rights reserved.
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