Purpose: We showed previously that B. anthracis edema toxin (ET), comprised of protective antigen (PA) and edema factor (EF), inhibits phenylephrine (PE)-induced contraction in rat aortic rings and these effects are diminished in endothelial-denuded rings. Therefore, employing rat aortic ring and in vivo models, we tested the hypothesis that nitric oxide (NO) contributes to ETs arterial effects. Method and Results: Compared to rings challenged with PA alone, ET (PA+EF) reduced PE-stimulated maximal contractile force (MCF) and increased the PE concentration producing 50% MCF (EC50) (p<0.0001). Compared to placebo, L-nitro-arginine methyl-ester (L-NAME), an NO synthase (NOS) inhibitor, reduced ETs effects on MCF and EC50 in patterns that approached or were significant (p=0.06 and 0.03 respectively). In animals challenged with 24h ET infusions, L-NAME (0.5 or 1.0 mg/kg/h) co-administration increased survival to 17 of 28 animals (60.7%) compared to 4 of 27 (14.8%) given placebo (p=0.01). Animals receiving L-NAME but no ET all survived. Compared to PBS challenge, ET increased NO levels at 24 h and L-NAME decreased these increases (p<0.0001). ET infusion decreased mean arterial blood pressure (MAP) in placebo and L-NAME-treated animals (p<0.0001) but L-NAME reduced decreases in MAP with ET from 9 to 24 h (p=0.03 for the time interaction). S-methyl-L-thiocitrulline, a selective neuronal NOS inhibitor, had effects in rings and, at a high dose in vivo models, comparable to L-NAME, whereas N'-[3-(aminomethyl)benzyl]-acetimidamide, a selective inducible NOS inhibitor, did not. Conclusion: NO production contributes to ETs arterial relaxant, hypotensive and lethal effects in the rat.
- edema toxin
- nitric oxide
- NOS inhibitor
- arterial contraction
- Copyright © 2016, American Journal of Physiology - Heart and Circulatory Physiology