B. anthracis edema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model.

Abstract

B. anthracis edema toxin (ET) and lethal toxin (LT) are each composed of protective antigen (PA), necessary for toxin uptake by host cells, and their respective toxic moieties, edema factor (EF) and lethal factor (LF). Although both toxins likely contribute to shock during infection, their mechanisms are unclear. To test whether ET and LT produce arterial relaxation, their effects on phenylephrine (PE)-stimulated contraction in a Sprague-Dawley rat aortic ring model were measured. Rings were prepared and connected to pressure transducers. Their viability was confirmed, and peak contraction with 60 mM KCl was determined. Compared with PA pretreatment (control, 60 min), ET pretreatment at concentrations similar to those noted in vivo decreased the mean (±SE) maximum contractile force (MCF; percent peak contraction) in rings generated during stimulation with increasing PE concentrations (96.2 ± 7.0 vs. 57.3 ± 9.1) and increased the estimated PE concentration producing half the MCF (EC50; 10(-7) M, 1.1 ± 0.3 vs. 3.7 ± 0.8, P ≤ 0.002). ET inhibition with PA-directed monoclonal antibodies, selective EF inhibition with adefovir, or removal of the ring endothelium inhibited the effects of ET on MCF and EC50 (P ≤ 0.02). Consistent with its adenyl cyclase activity, ET increased tissue cAMP in endothelium-intact but not endothelium-denuded rings (P < 0.0001 and 0.25, respectively). LT pretreatment, even in high concentrations, did not significantly decrease MCF or increase EC50 (all P > 0.05). In rings precontracted with PE compared with posttreatment with PA (90 min), ET posttreatment produced progressive reductions in contractile force and increases in relaxation in endothelium-intact rings (P < 0.0001) but not endothelium-denuded rings (P = 0.51). Thus, ET may contribute to shock by producing arterial relaxation.

• Authors: Yan Li, Xizhong Cui, Steven B Solomon, Kenneth Remy, Yvonne Fitz, Peter Q Eichacker
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 305 Issue 2 Pg. H238-50 (Jul 15 2013) ISSN: 1522-1539 [Electronic] United States
• PMID: 23585140 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antigens, Bacterial
• Bacterial Toxins
• Organophosphonates
• Vasoconstrictor Agents
• Vasodilator Agents
• anthrax toxin
• Phenylephrine
• adefovir
• Cyclic AMP
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Antigens, Bacterial (pharmacology)
• Aorta (drug effects, metabolism)
• Bacterial Toxins (pharmacology)
• Cyclic AMP (metabolism)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects, metabolism)
• Organophosphonates (pharmacology)
• Phenylephrine (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Second Messenger Systems (drug effects)
• Up-Regulation
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology)