The new HNO donor, 1-nitrosocyclohexyl acetate, increases contractile force in normal and β-adrenergically desensitized ventricular myocytes.
Contractile dysfunction and diminished response to β-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 μg/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 μM). 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 β-adrenergic stimulation with ISO (1 μM). NCA (60 μM) 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 μM) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and β-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.
Department of Pharmacology, University Medical Center Göttingen, Georg August University, Göttingen, Germany. ali.el-amouche@med.uni-goettingen.de
Ali
A
El-Armouche
Azadeh
A
Wahab
Katrin
K
Wittköpper
Thomas
T
Schulze
Felix
F
Böttcher
Lutz
L
Pohlmann
S Bruce
SB
King
Jenna F
JF
DuMond
Christian
C
Gerloff
Rainer H
RH
Böger
Thomas
T
Eschenhagen
Lucie
L
Carrier
Sonia
S
Donzelli
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology*
C554428:1-nitrosocyclohexyl acetate; D000085:Acetates; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; C039900:nitroxyl