Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

Caitlin Hicks, Yan Li, Shu Okugawa, Steven B. Solomon, Mahtab Moayeri, Stephen H. Leppla, Ajana Mohanty, G. Mani Subramanian, Thi S. Mignone, Yvonne Fitz, Xizhong Cui, Peter Q. Eichacker

Research output: Contribution to journalArticle

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/dtmax, 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

Fingerprint

Edema
Heart Rate
Pressure
Anthrax
Dobutamine
anthrax toxin
Isolated Heart Preparation
Ventricular Pressure
Adenylyl Cyclases
Tachycardia
Vasodilation
Stroke Volume
Shock
Monoclonal Antibodies

Keywords

  • Heart function

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model. / Hicks, Caitlin; Li, Yan; Okugawa, Shu; Solomon, Steven B.; Moayeri, Mahtab; Leppla, Stephen H.; Mohanty, Ajana; Subramanian, G. Mani; Mignone, Thi S.; Fitz, Yvonne; Cui, Xizhong; Eichacker, Peter Q.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 300, No. 3, 03.2011.

Research output: Contribution to journalArticle

Hicks, Caitlin ; Li, Yan ; Okugawa, Shu ; Solomon, Steven B. ; Moayeri, Mahtab ; Leppla, Stephen H. ; Mohanty, Ajana ; Subramanian, G. Mani ; Mignone, Thi S. ; Fitz, Yvonne ; Cui, Xizhong ; Eichacker, Peter Q. / Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model. In: American Journal of Physiology - Heart and Circulatory Physiology. 2011 ; Vol. 300, No. 3.
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AU - Hicks, Caitlin

AU - Li, Yan

AU - Okugawa, Shu

AU - Solomon, Steven B.

AU - Moayeri, Mahtab

AU - Leppla, Stephen H.

AU - Mohanty, Ajana

AU - Subramanian, G. Mani

AU - Mignone, Thi S.

AU - Fitz, Yvonne

AU - Cui, Xizhong

AU - Eichacker, Peter Q.

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Y1 - 2011/3

N2 - 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/dtmax, 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.

AB - 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/dtmax, 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.

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