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 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.