title: Spironolactone Prevents Endothelial Nitric Oxide Synthase Uncoupling and Vascular Dysfunction Induced by β-Adrenergic Overstimulation: Role of Perivascular Adipose Tissue.
abstract: Sustained stimulation of β-adrenoceptors (β-ARs) and activation of renin-angiotensin-aldosterone system are common features of cardiovascular diseases with rising sympathetic activation, including essential hypertension, myocardial infarction, and heart failure. In this study, we investigated the role of AT1 receptor and mineralocorticoid receptor (MR) in the vascular alterations caused by β-AR overstimulation. β-AR overstimulation with associated cardiac hypertrophy and increased vasoconstrictor response to phenylephrine in aorta were modeled in rats by 7-day isoproterenol treatment. The increased vasoconstrictor response to phenylephrine in this model was blunted by the MR antagonist spironolactone, but not by the AT1 receptor antagonist losartan, despite the blunting of cardiac hypertrophy with both drugs. Spironolactone, but not losartan, restored NO bioavailability in association with lower endothelial nitric oxide synthase-derived superoxide production, increased endothelial nitric oxide synthase dimerization, and aortic HSP90 upregulation. MR genomic and nongenomic functions were activated in aortas from isoproterenol-treated rats. Isoproterenol did not modify plasma levels of MR ligands aldosterone and corticosterone but rather increased perivascular adipose tissue-derived corticosterone in association with increased expression of 11β-hydroxysteroid dehydrogenase type 1. The anticontractile effect of aortic perivascular adipose tissue was impaired by β-AR overstimulation and restored by MR blockade. These results suggest that activation of vascular MR signaling contributes to the vascular dysfunction induced by β-AR overstimulation associated with endothelial nitric oxide synthase uncoupling. These findings reveal an additional explanation for the protective effects of MR antagonists in cardiovascular disorders with sympathetic activation.
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
authors.forename: Jamaira A
authors.initials: JA
authors.lastname: Victorio
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
authors.forename: Stefano P
authors.initials: SP
authors.lastname: Clerici
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Palacios
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
authors.forename: María J
authors.initials: MJ
authors.lastname: Alonso
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
authors.forename: Dalton V
authors.initials: DV
authors.lastname: Vassallo
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
authors.forename: Luciana V
authors.initials: LV
authors.lastname: Rossoni
authors.affiliation: From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.). anadavel@unicamp.br.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Davel
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D007545:Isoproterenol / Q000494:pharmacology; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012380:Role; D013148:Spironolactone / Q000008:administration & dosage*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D052250:Nitric Oxide Synthase Type III; D019808:Losartan; D007545:Isoproterenol
keywords: adipose tissue; aorta; losartan; mineralocorticoid receptor