In the present study, a canine model was developed to study the effects of ETx and LeTx alone and together on cardiopulmonary and other organ dysfunction. This model utilized continuously sedated and mechanically ventilated animals that had both systemic and pulmonary arterial catheters in place. Intravascular hemodynamic studies were complemented by serial echocardiographic measures. In an initial set of studies, the effects of individual toxins administered as 24 h infusions were tested. In these studies, ETx and LeTx, produced very different patterns of cardiovascular injury. ETx produced marked decreases in central venous pressure, systemic blood pressure, and systemic vascular resistance and increases in heart rate that occurred early and persisted for up to 96 h. LeTx on the other hand produced gradual hypotension and progressive decreases in left ventricular function. Notably, in subsequent analysis of these studies, it became apparent that ETx produced polyuria and precipitously low serum sodium levels. While both toxins produced increases in creatinine reflecting renal dysfunction, this appeared pre-renal in origin for ETx but not for LeTx. Thus, the hemodynamic effects of ETx appear to result both from both vasodilation and renal loss of fluid and sodium, while LeTx may have directly depressed myocardial function. Notably, the effects of ETx are rapid and persistent while those of LeTx require time to develop. These patterns are consistent with the recognized actions of ETx (i.e. an adenyl cyclase producing rapid increases in cellular camp levels) and LeTx (i.e. a protease which inhibits stress kinase pathways and downstream signaling events). In subsequent studies the effect of the toxins were studied together. In contrast to smaller animal models, in this large model, ETx and LeTx had synergistic effects on survival. A dose of ETx that alone was nonlethal, significantly increased the lethality of an LeTx challenge. In both studies, daily fluid loading was found to increase blood pressure and cardiac output suggesting that this conventional treatment may be beneficial in patients with shock related to toxin production during anthrax infection. The following abstracts were presented at the 2008 Annual Meeting of the Infectious Diseases Society of America: Sweeney D, et al. Hypotension is associated with the development of renal and hepatic dysfunction with anthrax edema but not lethal toxin. Sweeney D, et al. Anthrax edema and lethal toxins have synergistic effects on mortality and cardiac dysfunction in a large animal model. At this time a study is now being designed to further compare the effects of conventional hemodynamic support and toxin directed agents either alone or together.