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-induced cardiac contractile
dysfunction is concentration dependent
Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-9160
Whereas previous studies suggest that tumor necrosis
factor-
(TNF-) induces cardiac contraction-relaxation deficits,
the mechanisms remain unclear. Our recent studies have
implicated cardiac-derived nitric oxide (NO). This study examined the
detrimental and protective effects of NO donors
S-nitroso-N-acetyl-penicillamine (SNAP) or
(Z)-1- [N-(3-ammonio-propyl)-N-(n-propyl)amino]diazen-1-ium- 1,2diolate (PAPA/NO) on TNF--related changes in cardiac
contractile function (Langendorff), cellular injury, and intracellular
myocyte Ca2+ concentration
([Ca2+]i). Myocytes
were incubated in the presence/absence of TNF- (200-500
pg/ml × 105 cells) for 3 h; subsets of
myocytes were incubated with one of several concentrations of SNAP or
PAPA/NO (0.1, 0.3, 0.5, and 1.5 mM) for 15 min before TNF-
challenge. Supernatant creatine kinase (CK), cell viability (Trypan
blue dye exclusion), and myocyte [Ca2+]i (fura 2-acetoxymethyl
ester) were measured. In parallel experiments, cardiac function
(Langendorff) was examined after TNF- challenge in the presence or
absence of SNAP or PAPA/NO (0.1 and 1.5 mM). TNF- in
the absence of an NO donor impaired cardiac contraction and relaxation
and produced cardiomyocyte injury. Pretreating perfused hearts or
isolated cardiomyocytes with a low concentration of either SNAP or
PAPA/NO decreased TNF--mediated cardiac injury and improved
contractile dysfunction, whereas high concentrations of NO donor
exacerbated TNF--mediated cardiac effects. These data provide one
explanation for the conflicting reports of beneficial versus
detrimental effects of NO in the face of inflammation and suggest that
the effects of NO on organ function are concentration dependent; low
concentrations of NO are cardioprotective, whereas high
concentrations of NO are deleterious.
Sprague-Dawley rats; cardiac contraction and relaxation; Langendorff perfusion; cardiomyocytes in culture; tumor necrosis
factor--related cardiac depression
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