Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure

Proinflammatory cytokines depress myocardial contractile function by enhanc ing the expression of inducible NO synthase (iNOS), yet the mechanism of iN OS-mediated myocardial injury is not clear. As the reaction of NO with supe roxide to form peroxynitrite markedly enhances the toxicity of NO, we hypot hesized that peroxynitrite itself is responsible for cytokine-induced cardi ac depression. Isolated working rat hearts were perfused for 120 minutes wi th buffer containing interleukin-1 beta, interferon-gamma, and tumor necros is factor-alpha. Cardiac mechanical function and myocardial iNOS, xanthine oxidoreductase (XOR), and NAD(P)H oxidase activities (sources of superoxide ) were measured during the perfusion. Cytokines induced a marked decline in myocardial contractile function accompanied by enhanced activity of myocar dial XOR, NADH oxidase, and iNOS. Cardiac NO content, myocardial superoxide production, and perfusate nitrotyrosine and dityrosine levels, markers of peroxynitrite, were increased in cytokine-treated hearts. The peroxynitrite decomposition catalyst FeTPPS (5,10,15,20-tetrakis-[4-sulfonatophenyl]-por phyrinato-iron[III]), the NO synthase inhibitor N-G-nitro-L-arginine, and t he superoxide scavenger tiron each inhibited the decline in myocardial func tion and decreased perfusate nitrotyrosine levels. Proinflammatory cytokine s stimulate the concerted enhancement in superoxide and NO-generating activ ities in the heart, thereby enhancing peroxynitrite generation, which cause s myocardial contractile failure.