title: Macrophage depletion lowers blood pressure and restores sympathetic nerve α2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats.
abstract: We tested the hypothesis that vascular macrophage infiltration and O2 (-) release impairs sympathetic nerve α2-adrenergic autoreceptor (α2AR) function in mesenteric arteries (MAs) of DOCA-salt hypertensive rats. Male rats were uninephrectomized or sham operated (sham). DOCA pellets were implanted subcutaneously in uninephrectomized rats who were provided high-salt drinking water or high-salt water with apocynin. Sham rats received tap water. Blood pressure was measured using radiotelemetry. Treatment of sham and DOCA-salt rats with liposome-encapsulated clodronate was used to deplete macrophages. After 3-5, 10-13, and 18-21 days of DOCA-salt treatment, MAs and peritoneal fluid were harvested from euthanized rats. Norepinephrine (NE) release from periarterial sympathetic nerves was measured in vitro using amperometry with microelectrodes. Macrophage infiltration into MAs as well as TNF-α and p22(phox) were measured using immunohistochemistry. Peritoneal macrophage activation was measured by flow cytometry. O2 (-) was measured using dihydroethidium staining. Hypertension developed over 28 days, and apocynin reduced blood pressure on days 18-21. O2 (-) and macrophage infiltration were greater in DOCA-salt MAs compared with sham MAs after day 10. Peritoneal macrophage activation occurred after day 10 in DOCA-salt rats. Macrophages expressing TNF-α and p22(phox) were localized near sympathetic nerves. Impaired α2AR function and increased NE release from sympathetic nerves occurred in MAs from DOCA-salt rats after day 18. Macrophage depletion reduced blood pressure and vascular O2 (-) while restoring α2AR function in DOCA-salt rats. Macrophage infiltration into the vascular adventitia contributes to increased blood pressure in DOCA-salt rats by releasing O2 (-), which disrupts α2AR function, causing enhanced NE release from sympathetic nerves.
authors: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan;
authors: Loc V
authors: LV
authors: Thang
authors: Neuroscience Program, Michigan State University, East Lansing, Michigan;
authors: Stacie L
authors: SL
authors: Demel
authors: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan; Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan;
authors: Robert
authors: R
authors: Crawford
authors: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan; Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan;
authors: Norbert E
authors: NE
authors: Kaminski
authors: Neuroscience Program, Michigan State University, East Lansing, Michigan; Department of Chemistry, Michigan State University, East Lansing, Michigan; and.
authors: Greg M
authors: GM
authors: Swain
authors: Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors: Nico
authors: N
authors: Van Rooijen
authors: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan; Neuroscience Program, Michigan State University, East Lansing, Michigan; galliga1@msu.edu.
authors: James J
authors: JJ
authors: Galligan
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000276:immunology*; D004002:Clodronic Acid / Q000494:pharmacology; D064791:Desoxycorticosterone Acetate; D006973:Hypertension / Q000209:etiology / Q000276:immunology* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000276:immunology / Q000294:innervation*; D008901:Mineralocorticoids; D019255:NADPH Oxidases / Q000276:immunology / Q000378:metabolism; D009392:Nephrectomy; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000276:immunology* / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D013481:Superoxides; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D008901:Mineralocorticoids; D018341:Receptors, Adrenergic, alpha-2; D017673:Sodium Chloride, Dietary; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D013481:Superoxides; D064791:Desoxycorticosterone Acetate; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D009638:Norepinephrine
keywords: amperometry; immune activation; salt-sensitive hypertension; sympathetic nervous system; α2-adrenergic autoreceptors