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.
El-Armouche
Ali
A
Department of Pharmacology, University Medical Center Göttingen, Georg August University, Göttingen, Germany. ali.el-amouche@med.uni-goettingen.de
Wahab
Azadeh
A
Wittköpper
Katrin
K
Schulze
Thomas
T
Böttcher
Felix
F
Pohlmann
Lutz
L
King
S Bruce
SB
DuMond
Jenna F
JF
Gerloff
Christian
C
Böger
Rainer H
RH
Eschenhagen
Thomas
T
Carrier
Lucie
L
Donzelli
Sonia
S
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