In the present study, a canine model has been developed to study the cardiopulmonary effects of ETx and LeTx alone and together. This model utilizes continuously sedated and mechanically ventilated animals that have both systemic and pulmonary arterial catheters in place. Intravascular hemodynamic studies are 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 preload, tachycardia and hypotension that occured early and persisted for up to 96 h. LeTx on the other hand produced gradual hypotension and progressive decreases in left ventricular function. Thus ETx appeard to have profound effects on the peripheral vasculature while LeTx may have been directly depressing myocardial function. 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 LeT challenge. Further analysis of this study is underway to determine the mechanisms for this synergistic effect. Findings to date emphasize how important adjunctive treatments may be that directly target the two toxins during anthrax associated shock.
