papa-nonoate and Heart-Diseases

Whereas previous studies suggest that tumor necrosis factor-alpha (TNF-alpha) 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-alpha-related changes in cardiac contractile function (Langendorff), cellular injury, and intracellular myocyte Ca(2+) concentration ([Ca(2+)](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 challenge. Supernatant creatine kinase (CK), cell viability (Trypan blue dye exclusion), and myocyte [Ca(2+)](i) (fura 2-acetoxymethyl ester) were measured. In parallel experiments, cardiac function (Langendorff) was examined after TNF-alpha challenge in the presence or absence of SNAP or PAPA/NO (0.1 and 1.5 mM). TNF-alpha 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-alpha-mediated cardiac injury and improved contractile dysfunction, whereas high concentrations of NO donor exacerbated TNF-alpha-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.

Topics: Animals; Azetidines; Dose-Response Relationship, Drug; Heart Diseases; Hydrazines; In Vitro Techniques; Myocardial Contraction; Myocardium; Nitric Oxide; Nitric Oxide Donors; Osmolar Concentration; Penicillamine; Rats; Rats, Sprague-Dawley; S-Nitroso-N-Acetylpenicillamine; Tumor Necrosis Factor-alpha