ROLE OF NITRIC-OXIDE AND PEROXYNITRITE IN THE CYTOKINE-INDUCED SUSTAINED MYOCARDIAL DYSFUNCTION IN DOGS IN-VIVO

Studies in vitro suggested that inflammatory cytokines could cause myo cardial dysfunction. However, the detailed mechanism for the cytokine- induced myocardial dysfunction in vivo remains to be examined. We thus examined this point in our new canine model in vivo, in which microsp heres with and without IL-1 beta were injected into the left main coro nary artery. Left ventricular ejection fraction (LVEF) was evaluated b y echocardiography for 1 wk, Immediately after the microsphere injecti on, LVEF decreased to similar to 30% in both groups. While LVEF rapidl y normalized in 2 d in the control group, it was markedly impaired in the IL-1 beta group even at day 7. Pretreatment with dexamethasone or with aminoguanidine, an inhibitor of inducible nitric oxide synthase, prevented the IL-1 beta-induced myocardial dysfunction. Nitrotyrosine concentration, an in vivo marker of the peroxynitrite production by ni tric oxide and superoxide anion, was significantly higher in the myoca rdium of the IL-1 beta group than in that of the control group or the group cotreated with dexamethasone or aminoguanidine. There was an inv erse linear relationship between myocardial nitrotyrosine concentratio ns and LVEF. These results indicate that IL-1 beta induces sustained m yocardial dysfunction in vivo and that nitric oxide produced by induci ble nitric oxide synthase and the resultant formation of peroxynitrite are substantially involved in the pathogenesis of the cytokine-induce d sustained myocardial dysfunction in vivo.