title: The HNO donor Angeli's salt offers potential haemodynamic advantages over NO or dobutamine in ischaemia-reperfusion injury in the rat heart ex vivo.
abstract: Available inotropic pharmacotherapy for acute heart failure (HF) remains largely ineffective at ameliorating marked impairments in contractile function. Nitroxyl (HNO), the redox sibling of NO•, has recently attracted interest as a therapeutic approach for acute HF. We now compare the impact of ischaemia-reperfusion (I-R) injury on acute haemodynamic responsiveness of the HNO donor, Angeli's salt (AS), to that of NO and dobutamine. Dose-response curves to bolus doses of AS, diethylamine NONOate (DEA/NO, both 0.001-μmol) and dobutamine (0.1-100 nmol) were performed in rat isolated hearts, following I-R or normoxic perfusion. An additional 10μmol dose of Angeli's salt was included, to permit roughly equivalent inotropic responses to dobutamine. Changes in cardiac contraction, heart rate and coronary flow (CF) were determined. Although AS and DEA/NO elicited comparable dose-dependent increases in CF in normoxic hearts, only AS vasodilation was preserved after I-R. AS and dobutamine elicited dose-dependent inotropic responses in normoxic hearts and I-R blunted inotropic responses to both. Dobutamine however increased heart rate, which was exacerbated by I-R; this was not evident with AS. Further, AS infusion during reperfusion (1μM), in a separate cohort of rat hearts, improved recovery of cardiac contractility, with lower incidence of I-R-induced ventricular fibrillation. In conclusion, these observations suggest that HNO offers haemodynamic advantages over NO following I-R. Although I-R suppresses inotropy to both agents, residual contractile responses to AS following I-R is likely free of concomitant pro-arrhythmic events. HNO donors may thus offer haemodynamic advantages over existing pharmacotherapy in acute HF.
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; The School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
authors.forename: Kai Yee
authors.initials: KY
authors.lastname: Chin
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Michel
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia.
authors.forename: Cheng Xue
authors.initials: CX
authors.lastname: Qin
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia.
authors.forename: Nga
authors.initials: N
authors.lastname: Cao
authors.affiliation: The School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
authors.forename: Owen L
authors.initials: OL
authors.lastname: Woodman
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; Department of Medicine, Monash University, Clayton 3800 VIC, Australia. Electronic address: rebecca.ritchie@bakeridi.edu.au.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics; D008297:Male; D009200:Myocardial Contraction; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000494:pharmacology*; D009589:Nitrogen Oxides; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology*
chemical_list: D002316:Cardiotonic Agents; D020030:Nitric Oxide Donors; D009573:Nitrites; D009589:Nitrogen Oxides; C021229:oxyhyponitrite; D009569:Nitric Oxide; D004280:Dobutamine; C039900:nitroxyl
keywords: Cardioprotection; Diethylamine NONOate (DEA/NO; Dobutamine (PubChem CID36811); Nitric oxide; Nitroxyl; PubChem CID11963579); PubChem CID9571404); PubChem CIDCID 10129945); Sodium nitroferricyanide (III) dihydate/sodium nitroprusside dihydrate sodium nitroprusside (SNP; Sodium trioxodinitrate (Angeli’s salt; Vasodilation; Ventricular function