title: β1-Adrenergic blockers exert antioxidant effects, reduce matrix metalloproteinase activity, and improve renovascular hypertension-induced cardiac hypertrophy.
abstract: Hypertension induces left-ventricular hypertrophy (LVH) by mechanisms involving oxidative stress and unbalanced cardiac matrix metalloproteinase (MMP) activity. We hypothesized that β1-adrenergic receptor blockers with antioxidant properties (nebivolol) could reverse hypertension-induced LVH more effectively than conventional β1-blockers (metoprolol) when used at doses that exert similar antihypertensive effects. Two-kidney one-clip (2K1C) hypertension was induced in male Wistar rats. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10 mg kg(-1)day(-1)) or metoprolol (20 mg kg(-1)day(-1)) for 4 weeks. Systolic blood pressure was monitored weekly by tail-cuff plethysmography. LV structural changes and fibrosis were studied in hematoxylin/eosin- and picrosirius-stained sections, respectively. Cardiac MMP levels and activity were determined by in situ zymography, gel zymography, and immunofluorescence. Dihydroethidium and lucigenin-derived chemiluminescence assays were used to assess cardiac reactive oxygen species (ROS) production. Nitrotyrosine levels were determined in LV samples by immunohistochemistry and green fluorescence and were evaluated using the ImageJ software. Cardiac protein kinase B/Akt (AKT) phosphorylation state was assessed by Western blot. Both β-blockers exerted similar antihypertensive effects and attenuated hypertension-induced cardiac remodeling. Both drugs reduced myocyte hypertrophy and collagen deposition in 2K1C rats. These effects were associated with lower cardiac ROS and nitrotyrosine levels and attenuation of hypertension-induced increases in cardiac MMP-2 levels and in situ gelatinolytic activity after treatment with both β-blockers. Whereas hypertension increased AKT phosphorylation, no effects were found with β-blockers. In conclusion, we found evidence that two β1-blockers with different properties attenuate hypertension-induced LV hypertrophy and cardiac collagen deposition in association with significant cardiac antioxidant effects and MMP-2 downregulation, thus suggesting a critical role for β1-adrenergic receptors in mediating those effects. Nebivolol is not superior to metoprolol, at least with respect to their capacity to reverse hypertension-induced LVH.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Elen
authors.initials: E
authors.lastname: Rizzi
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Guimaraes
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Ceron
authors.affiliation: Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, 14049-900 Ribeirao Preto, SP, Brazil.
authors.forename: Cibele M
authors.initials: CM
authors.lastname: Prado
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Lucas C
authors.initials: LC
authors.lastname: Pinheiro
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Alisson
authors.initials: A
authors.lastname: Martins-Oliveira
authors.affiliation: Department of Morphology, Estomatology, and Physiology, Ribeirao Preto Dental School, University of Sao Paulo, 14049-900 Ribeirao Preto, SP, Brazil.
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Gerlach
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil. Electronic address: tanus@fmrp.usp.br.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D001578:Benzopyrans / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D015536:Down-Regulation; D004983:Ethanolamines / Q000627:therapeutic use*; D006978:Hypertension, Renovascular / Q000188:drug therapy*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy*; D007668:Kidney / Q000098:blood supply / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use; D008790:Metoprolol / Q000627:therapeutic use*; D000068577:Nebivolol; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000959:Antihypertensive Agents; D000975:Antioxidants; D001578:Benzopyrans; D004983:Ethanolamines; D061965:Matrix Metalloproteinase Inhibitors; D017382:Reactive Oxygen Species; D000068577:Nebivolol; C002744:3-nitrotyrosine; D014443:Tyrosine; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D008790:Metoprolol
keywords: Cardiac remodeling; Free radicals; Hypertension; MMP-2; Oxidative stress; β-Blockers