Nitric oxide modulation of TNF-alpha-induced cardiac contractile dysfunction is concentration dependent

Whereas previous studies suggest that tumor necrosis factor-alpha (TNF-alph a) induces cardiac contraction-relaxation deficits, the mechanisms remain u nclear. 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-1,2-diolate (PAPA/NO) on TNF-alpha-related cha nges in cardiac contractile function (Langendorff), cellular injury, and in tracellular myocyte Ca2+ concentration ([Ca2+](i)). Myocytes were incubated in the presence/absence of TNF-alpha (200-500 pg/ml x 10(5) 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-alpha cha llenge. Supernatant creatine kinase (CK), cell viability (Trypan blue dye e xclusion), and myocyte [Ca2+](i) (fura 2-acetoxymethyl ester) were measured . In parallel experiments, cardiac function (Langendorff) was examined afte r TNF-alpha challenge in the presence or absence of SNAP or PAPA/NO (0.1 an d 1.5 mM). TNF-alpha in the absence of an NO donor impaired cardiac contrac tion and relaxation and produced cardiomyocyte injury. Pretreating perfused hearts or isolated cardiomyocytes with a low concentration of either SNAP or PAPA/NO decreased TNF-alpha-mediated cardiac injury and improved contrac tile dysfunction, whereas high concentrations of NO donor exacerbated TNF-a lpha-mediated cardiac effects. These data provide one explanation for the c onflicting reports of beneficial versus detrimental effects of NO in the fa ce of inflammation and suggest that the effects of NO on organ function are concentration dependent; low concentrations of NO are cardioprotective, wh ereas high concentrations of NO are deleterious.