While controversial, several studies have suggested that nitric oxide (NO) alters cardiac contractility via cGMP, peroxynitrite or PARS activation. This study determined whether burn related upregulation of myocardial iNOS and NO generation contributes to burn-mediated cardiac contractile dysfunction. Methods: Mice homozygous null for the iNOS gene (iNOS knockouts) were obtained from Jackson Laboratory. iNOS knockouts as well as wildtype mice were given a cutaneous burn over 40% TBSA by applying brass probes (1x2x0.3 cm) heated to 100°C to the animals' sides/back for 5 sec (iNOS/KO burn and Wildtype burn). Additional groups of iNOS knockout and wildtype mice served as appropriate sham burn groups (iNOS/KO sham and Wildtype sham). Cardiac function was assessed 24 hrs postburn by perfusing hearts (N=7-10 mice/group). Results: Burn trauma in wildtype mice impaired cardiac function as indicated by the lower left ventricular pressure (LVP, 67±2 mmHg) compared to that measured in wildtype shams (94±2 mmHg, p<0.001), a lower rate of LVP rise (+dP/dt max, 1620±94 vs 2240±58 mmHg/sec, p<0.001) and a lower rate of LVP fall (-dP/dt max, 1200±84 vs 1800±42 mmHg/sec, p<0.001). Ventricular function curves confirmed significant contractile dysfunction after burn trauma in wildtype mice. Burn trauma in iNOS knockout mice produced less cardiac derangements compared to those observed in wildtype burns (LVP, 78±5; +dP/dt, 1889±160; -dP/dt,1480±154). Use of a pharmacologic approach to inhibit iNOS (aminoguanidine, given IP) in additional wildtype shams and burns confirmed the iNOS KO data. While the absence of iNOS attenuated burn mediated cardiac contractile dysfunction, these experiments did not determine the contribution of cardiac derived NO versus NO generated by immune cells. However, our data indicate a role for NO in cardiac dysfunction after major trauma.