Anthrax infections are frequently associated with severe and often irreversible hypotensive
shock. The isolated toxic
proteins of Bacillus anthracis produce a non-
cytokine-mediated
hypotension in rats by unknown mechanisms. These observations suggest the
anthrax toxins have direct cardiovascular effects. Here, we characterize these effects. As a first step, we administered systemically
anthrax lethal toxin (LeTx) and
edema toxin (EdTx) to cohorts of three to twelve rats at different doses and determined the time of onset, degree of
hypotension and mortality. We measured serum concentrations of the protective
antigen (PA) toxin component at various time points after infusion. Peak serum levels of PA were in the microg/mL range with half-lives of 10-20 minutes. With doses that produced
hypotension with delayed lethality, we then gave bolus
intravenous infusions of toxins to groups of four to six instrumented rats and continuously monitored blood pressure by telemetry. Finally, the same doses used in the telemetry experiments were given to additional groups of four rats, and echocardiography was performed pretreatment and one, two, three and twenty-four hours post-treatment. LeTx and EdTx each produced
hypotension. We observed a doubling of the velocity of propagation and 20% increases in left ventricular diastolic and systolic areas in LeTx-treated rats, but not in EdTx-treated rats. EdTx-but not LeTx-treated rats showed a significant increase in heart rate. These results indicate that LeTx reduced left ventricular systolic function and EdTx reduced preload. Uptake of toxins occurs readily into tissues with
biological effects occurring within minutes to hours of serum toxin concentrations in the microg/mL range. LeTx and EdTx yield an irreversible
shock with subsequent death. These findings should provide a basis for the rational design of
drug interventions to reduce the dismal prognosis of systemic
anthrax infections.