Affiliation:
1. Critical Care Medicine Department, Clinical Center, National Institutes of Health (NIH), Bethesda, Maryland;
2. Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio;
3. Howard Hughes Medical Institute-NIH Research Scholar;
4. National Institute of Allergy and Infectious Diseases, NIH, Bethesda; and
5. Human Genome Sciences, Rockville, Maryland
Abstract
While anthrax edema toxin produces pronounced tachycardia and lethal toxin depresses left ventricular (LV) ejection fraction in in vivo models, whether these changes reflect direct cardiac effects as opposed to indirect ones related to preload or afterload alterations is unclear. In the present study, the effects of edema toxin and lethal toxin were investigated in a constant pressure isolated perfused rat heart model. Compared with control hearts, edema toxin at doses comparable to or less than a dose that produced an 80% lethality rate (LD80) in vivo in rats (200, 100, and 50 ng/ml) produced rapid increases in heart rate (HR), coronary flow (CF), LV developed pressure (LVDP), dP/d tmax, and rate-pressure product (RPP) that were most pronounced and persisted with the lowest dose ( P ≤ 0.003). Edema toxin (50 ng/ml) increased effluent and myocardial cAMP levels ( P ≤ 0.002). Compared with dobutamine, edema toxin produced similar myocardial changes, but these occurred more slowly and persisted longer. Increases in HR, CF, and cAMP with edema toxin were inhibited by a monoclonal antibody blocking toxin uptake and by adefovir, which inhibits the toxin's intracellular adenyl cyclase activity ( P ≤ 0.05). Lethal toxin at an LD80 dose (50 ng/ml) had no significant effect on heart function but a much higher dose (500 ng/ml) reduced all parameters ( P ≤ 0.05). In conclusion, edema toxin produced cAMP-mediated myocardial chronotropic, inotropic, and vasodilatory effects. Vasodilation systemically with edema toxin could contribute to shock during anthrax while masking potential inotropic effects. Although lethal toxin produced myocardial depression, this only occurred at high doses, and its relevance to in vivo findings is unclear.
Publisher
American Physiological Society
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
23 articles.
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