title: Cerebral Microvascular Dysfunction and Inflammation Are Improved by Centrally Acting Antihypertensive Drugs in Metabolic Syndrome.
abstract: We aimed to investigate the effects of chronic oral treatment with centrally acting antihypertensive drugs, such as clonidine (CLO), an α2-adrenoceptor agonist, or LNP599, a selective I1imidazoline receptor agonist, on brain microvascular function in rats with high-fat diet (HFD)-induced metabolic syndrome.
  
  
  
  Male Wistar Kyoto rats were maintained on a normal diet (CON) or a HFD for 20 weeks. After this period, the HFD group received oral CLO (0.1 mg/kg), LNP599 (20 mg/kg), or vehicle daily for 4 weeks. Systolic blood pressure and heart rate (HR) were evaluated by photoplethysmography. Functional capillary density, endothelial function, and endothelial-leukocyte interactions in the brain were investigated by intravital video microscopy. Cerebral microcirculatory flow was evaluated by laser speckle contrast imaging. Brain tissue endothelial nitric oxide synthase, oxidative enzyme, and inflammatory marker expression levels were analyzed.
  
  
  
  Metabolic syndrome decreased brain functional capillary density and microvascular blood perfusion, changes accompanied by deficient brain microcirculation vasodilatory responses to acetylcholine. Significant numbers of rolling and adherent leukocytes were also observed in the brain venules. Chronic sympathetic inhibition with clonidine and LNP599 reduced blood pressure and HR. These effects were accompanied by reversals of cerebral capillary rarefaction, improvements in cerebral microvascular blood flow and endothelial function, and decreases in endothelial-leukocyte interactions in the cerebral venules.
  
  
  
  Our results suggest that central sympathetic inhibition exerts beneficial effects by increasing perfusion and reducing inflammatory marker expression and oxidative stress in the brains of rats with metabolic syndrome. Centrally acting antihypertensive drugs may be helpful in regulating cerebral microcirculatory function and vascular inflammation in metabolic syndrome.
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .|2 Institute of Drug Technology , Owaldo Cruz Foundation, Rio de Janeiro, Brazil .
authors.forename: Vanessa
authors.initials: V
authors.lastname: Estato
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nascimento
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .
authors.forename: Barbara
authors.initials: B
authors.lastname: Antunes
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .
authors.forename: Fabiana
authors.initials: F
authors.lastname: Gomes
authors.affiliation: 3 Laboratory for Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .
authors.forename: Laura
authors.initials: L
authors.lastname: Coelho
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .
authors.forename: Raquel
authors.initials: R
authors.lastname: Rangel
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .|3 Laboratory for Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .
authors.forename: Luciana
authors.initials: L
authors.lastname: Garzoni
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .
authors.forename: Anissa
authors.initials: A
authors.lastname: Daliry
authors.affiliation: 4 Laboratory of Neurobiology and Cardiovascular Pharmacology, Faculty of Medicine, University of Strasbourg , Strasbourg, France .
authors.forename: Pascal
authors.initials: P
authors.lastname: Bousquet
authors.affiliation: 1 Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation , Rio de Janeiro, Brazil .|5 National Institute of Cardiology , Rio de Janeiro, Brazil .
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tibiriçá
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008833:Microcirculation / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D013565:Sympatholytics / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C584078:(3-chloro-2-methylphenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)amine; D000814:Aniline Compounds; D000959:Antihypertensive Agents; C000609942:ICAM1 protein, rat; D018836:Inflammation Mediators; D011758:Pyrroles; D013565:Sympatholytics; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; D003000:Clonidine
keywords: brain microcirculation; centrally acting antihypertensive drugs; high-fat diet consumption; laser speckle contrast imaging