title: Nitric oxide production contributes to Bacillus anthracis edema toxin-associated arterial hypotension and lethality: ex vivo and in vivo studies in the rat.
abstract: We showed previously that Bacillus 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 ET's arterial effects. Compared with 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 with placebo, l-nitro-arginine methyl-ester (l-NAME), an NO synthase (NOS) inhibitor, reduced ET's effects on MCF and EC50 in patterns that approached or were significant (P = 0.06 and 0.03, respectively). In animals challenged with 24-h ET infusions, l-NAME (0.5 or 1.0 mg·kg(-1)·h(-1)) coadministration increased survival to 17 of 28 animals (60.7%) compared with 4 of 27 (14.8%) given placebo (P = 0.01). Animals receiving l-NAME but no ET all survived. Compared with 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. NO production contributes to ET's arterial relaxant, hypotensive, and lethal effects in the rat.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Xizhong
authors.initials: X
authors.lastname: Cui
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Wanying
authors.initials: W
authors.lastname: Xu
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Lernik
authors.initials: L
authors.lastname: Ohanjanian
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Hanish
authors.initials: H
authors.lastname: Sampath-Kumar
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Dante
authors.initials: D
authors.lastname: Suffredini
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Leppla
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fitz
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and peichacker@mail.cc.nih.gov.
authors.forename: Peter Q
authors.initials: PQ
authors.lastname: Eichacker
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology* / Q000633:toxicity; D001011:Aorta / Q000187:drug effects*; D001427:Bacterial Toxins / Q000494:pharmacology* / Q000633:toxicity; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D066298:In Vitro Techniques; D008297:Male; D009026:Mortality; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; C030325:anthrax toxin; D010656:Phenylephrine; D002956:Citrulline; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013890:Thiourea; C086717:S-methylthiocitrulline; D019331:NG-Nitroarginine Methyl Ester
keywords: NOS inhibitor; anthrax; arterial contraction; edema toxin; hypotension; nitric oxide