Peroxynitrite and myocardial contractility: In vivo versus in vitro effects

Tatsuo Katori, Sonia Donzelli, Carlo G. Tocchetti, Katrina M. Miranda, Gianfrancesco Cormaci, Douglas D. Thomas, Elizabeth A. Ketner, Myung Jae Lee, Daniele Mancardi, David A. Wink, David A. Kass, Nazareno Paolocci

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Generation of peroxynitrite (ONOO-) as a result of altered redox balance has been shown to affect cardiac function; however, inconsistencies in the data exist, particularly for myocardial contractility. The hypothesis that the cardiac impact of ONOO- formation depends on its site of generation, intravascular or intramyocardial, was examined. Cardiac contractility was assessed by pressure-volume analysis to delineate vascular versus cardiac changes on direct infusion of ONOO- into the right atria of conscious dogs both with normal cardiac function and in heart failure. Additionally, ONOO- was administered to isolated murine cardiomyocytes to mimic in situ cardiac generation. When infused in vivo, ONOO- had little impact on inotropy but led to systemic arterial dilation, likely as a result of rapid decomposition to NO2- and NO3-. In contrast, infused ONOO- was long lived enough to abolish β-adrenergic (dobutamine)-stimulated contractility/relaxation, most likely through catecholamine oxidation to aminochrome. When administered to isolated murine cardiomyocytes, ONOO- induced a rapid reduction in sarcomere shortening and whole cell calcium transients, although neither decomposed ONOO- or NaNO2 had any effect. Thus, systemic generation of ONOO- is unlikely to have primary cardiac effects, but may modulate cardiac contractile reserve, via blunted β-adrenergic stimulation, and vascular tone, as a result of generation of NO2- and NO3-. However, myocyte generation of ONOO- may impair contractile function by directly altering Ca2+ handling. These data demonstrate that the site of generation within the cardiovascular system largely dictates the ability of ONOO- to directly or indirectly modulate cardiac pump function.

Original languageEnglish (US)
Pages (from-to)1606-1618
Number of pages13
JournalFree Radical Biology and Medicine
Volume41
Issue number10
DOIs
StatePublished - Nov 15 2006

Keywords

  • Adrenergic (ant)agonists
  • Angeli's salt
  • Contractile function
  • Heart failure
  • Isolated myocytes
  • Nitric oxide
  • Nitroxyl (HNO)
  • Peroxynitrite

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Katori, T., Donzelli, S., Tocchetti, C. G., Miranda, K. M., Cormaci, G., Thomas, D. D., Ketner, E. A., Lee, M. J., Mancardi, D., Wink, D. A., Kass, D. A., & Paolocci, N. (2006). Peroxynitrite and myocardial contractility: In vivo versus in vitro effects. Free Radical Biology and Medicine, 41(10), 1606-1618. https://doi.org/10.1016/j.freeradbiomed.2006.08.023