Anthrax toxins induce shock in rats by depressed cardiac ventricular function

Linley E. Watson, Shu Ru Kuo, Khurshed Katki, Tongyun Dang, Seong Kyu Park, David E. Dostal, Wei Jen Tang, Stephen H. Leppla, Arthur E. Frankel

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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 μg/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 μg/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.

Original languageEnglish (US)
Article numbere466
JournalPLoS One
Volume2
Issue number5
DOIs
StatePublished - May 23 2007

Fingerprint

Ventricular Function
Rats
Shock
toxins
Edema
rats
Hypotension
Anthrax
Telemetry
edema
Telemetering
hypotension
anthrax
Serum
Echocardiography
Antigens
Bacillus anthracis
Poisons
Drug Design
Blood pressure

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Watson, L. E., Kuo, S. R., Katki, K., Dang, T., Park, S. K., Dostal, D. E., ... Frankel, A. E. (2007). Anthrax toxins induce shock in rats by depressed cardiac ventricular function. PLoS One, 2(5), [e466]. https://doi.org/10.1371/journal.pone.0000466

Anthrax toxins induce shock in rats by depressed cardiac ventricular function. / Watson, Linley E.; Kuo, Shu Ru; Katki, Khurshed; Dang, Tongyun; Park, Seong Kyu; Dostal, David E.; Tang, Wei Jen; Leppla, Stephen H.; Frankel, Arthur E.

In: PLoS One, Vol. 2, No. 5, e466, 23.05.2007.

Research output: Contribution to journalArticle

Watson, LE, Kuo, SR, Katki, K, Dang, T, Park, SK, Dostal, DE, Tang, WJ, Leppla, SH & Frankel, AE 2007, 'Anthrax toxins induce shock in rats by depressed cardiac ventricular function', PLoS One, vol. 2, no. 5, e466. https://doi.org/10.1371/journal.pone.0000466
Watson LE, Kuo SR, Katki K, Dang T, Park SK, Dostal DE et al. Anthrax toxins induce shock in rats by depressed cardiac ventricular function. PLoS One. 2007 May 23;2(5). e466. https://doi.org/10.1371/journal.pone.0000466
Watson, Linley E. ; Kuo, Shu Ru ; Katki, Khurshed ; Dang, Tongyun ; Park, Seong Kyu ; Dostal, David E. ; Tang, Wei Jen ; Leppla, Stephen H. ; Frankel, Arthur E. / Anthrax toxins induce shock in rats by depressed cardiac ventricular function. In: PLoS One. 2007 ; Vol. 2, No. 5.
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