Peroxynitrite and myocardial contractility: in vivo versus in vitro effects.
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 beta-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 beta-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.
Katori
Tatsuo
T
935 Ross, Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Donzelli
Sonia
S
Tocchetti
Carlo G
CG
Miranda
Katrina M
KM
Cormaci
Gianfrancesco
G
Thomas
Douglas D
DD
Ketner
Elizabeth A
EA
Lee
Myung Jae
MJ
Mancardi
Daniele
D
Wink
David A
DA
Kass
David A
DA
Paolocci
Nazareno
N
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003971:Diastole / Q000187:drug effects; D004280:Dobutamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004285:Dogs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology*; D013318:Stroke Volume / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D030421:Peroxynitrous Acid; D004280:Dobutamine; D002118:Calcium