title: Nitroxyl affords thiol-sensitive myocardial protective effects akin to early preconditioning.
abstract: Nitric oxide (NO) donors mimic the early phase of ischemic preconditioning (IPC). The effects of nitroxyl (HNO/NO(-)), the one-electron reduction product of NO, on ischemia/reperfusion (I/R) injury are unknown. Here we investigated whether HNO/NO(-), produced by decomposition of Angeli's salt (AS; Na(2)N(2)O(3)), has a cardioprotective effect in isolated perfused rat hearts. Effects were examined after intracoronary perfusion (19 min) of either AS (1 microM), the NO donor diethylamine/NO (DEA/NO, 0.5 microM), vehicle (100 nM NaOH) or buffer, followed by global ischemia (30 min) and reperfusion (30 min or 120 min in a subset of hearts). IPC was induced by three cycles of 3 min ischemia followed by 10 min reperfusion prior to I/R. The extent of I/R injury under each intervention was assessed by changes in myocardial contractility as well as lactate dehydrogenase (LDH) release and infarct size. Postischemic contractility, as indexed by developed pressure and dP/dt(max), was similarly improved with IPC and pre-exposure to AS, as opposed to control or DEA/NO-treated hearts. Infarct size and LDH release were also significantly reduced in IPC and AS groups, whereas DEA/NO was less effective in limiting necrosis. Co-infusion in the triggering phase of AS and the nitroxyl scavenger, N-acetyl-L-cysteine (4 mM) completely reversed the beneficial effects of AS, both at 30 and 120 min reperfusion. Our data show that HNO/NO(-) affords myocardial protection to a degree similar to IPC and greater than NO, suggesting that reactive nitrogen oxide species are not only necessary but also sufficient to trigger myocardial protection against reperfusion through species-dependent, pro-oxidative, and/or nitrosative stress-related mechanisms.
authors.affiliation: Dipartimento di Scienze Cliniche e Biologiche, Università degli Studi di Torino, Orbassano, Italy. pasquale.pagliaro@unito.it
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
authors.forename: Daniele
authors.initials: D
authors.lastname: Mancardi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rastaldo
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.forename: Donatella
authors.initials: D
authors.lastname: Gattullo
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Miranda
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
mesh_terms: D000818:Animals; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D009589:Nitrogen Oxides; D013438:Sulfhydryl Compounds; C039900:nitroxyl