Shock and Lethality with Anthrax Edema Toxin in Rats Are Associated with Reduced Arterial Responsiveness to Phenylephrine and Are Reversed with Adefovir

Although edema toxin (ETx) and lethal toxin (LTx) contribute to shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h ( ≤ 0.0003) and increased plasma cAMP at 4, 24, and 48 h ( < 0.0001) and nitric oxide (NO) at 24 and 48 h ( ≤ 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP ( < 0.0001 and = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality ( = 0.01), increased MAP ( ≤ 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively ( ≤ 0.03), and plasma NO at both times ( ≤ 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h ( = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality. The most important aspects of the present study are the findings that ) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and ) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge.