title: Circulating neutrophils maintain physiological blood pressure by suppressing bacteria and IFNgamma-dependent iNOS expression in the vasculature of healthy mice.
abstract: Whether leukocytes exert an influence on vascular function in vivo is not known. Here, genetic and pharmacologic approaches show that the absence of neutrophils leads to acute blood pressure dysregulation. Following neutrophil depletion, systolic blood pressure falls significantly over 3 days (88.0 +/- 3.5 vs 104.0 +/- 2.8 mm Hg, day 3 vs day 0, mean +/- SEM, P < .001), and aortic rings from neutropenic mice do not constrict properly. The constriction defect is corrected using l-nitroarginine-methyl ester (L-NAME) or the specific inducible nitric oxide synthase (iNOS) inhibitor 1400W, while acetylcholine relaxation is normal. iNOS- or IFNgamma-deficient mice are protected from neutropenia-induced hypotension, indicating that iNOS-derived nitric oxide (NO) is responsible and that its induction involves IFNgamma. Oral enrofloxacin partially inhibited hypotension, implicating bacterial products. Roles for cyclooxygenase, complement C5, or endotoxin were excluded, although urinary prostacyclin metabolites were elevated. Neutrophil depletion required complement opsinization, with no evidence for intravascular degranulation. In summary, circulating neutrophils contribute to maintaining physiological tone in the vasculature, at least in part through suppressing early proinflammatory effects of infection. The speed with which hypotension developed provides insight into early changes that occur in the absence of neutrophils and illustrates the importance of constant surveillance of mucosal sites by granulocytes in healthy mice.
authors.affiliation: Department of Medical Biochemistry & Immunology, Cardiff University, Cardiff, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Morton
authors.forename: Barbara
authors.initials: B
authors.lastname: Coles
authors.forename: Kate
authors.initials: K
authors.lastname: Wright
authors.forename: Awen
authors.initials: A
authors.lastname: Gallimore
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Erin S
authors.initials: ES
authors.lastname: Terry
authors.forename: Peter B
authors.initials: PB
authors.lastname: Anning
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Vincent
authors.initials: V
authors.lastname: Dioszeghy
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kühn
authors.forename: Pavlos
authors.initials: P
authors.lastname: Chaitidis
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology; D001794:Blood Pressure; D001808:Blood Vessels / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007022:Hypotension / Q000209:etiology; D007249:Inflammation; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D014661:Vasoconstriction
chemical_list: D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II