Nebivolol attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMPs, and decreases vascular remodeling in renovascular hypertension.
Nebivolol and metoprolol are β1-adrenergic receptor blockers with different properties. We hypothesized that nebivolol, but not metoprolol, could attenuate prooxidant and profibrotic mechanisms of hypertension and therefore protect against the vascular remodeling associated with hypertension. Hypertension was induced in male Wistar rats by clipping the left renal artery. 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. Morphologic changes in the aortic wall were studied in hematoxylin/eosin and picrosirius red sections. Aortic NAD(P)H activity and superoxide production were evaluated by luminescence and dihydroethidium, respectively, and TBARS levels were measured in plasma. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. TGF-β levels and p-ERK 1/2 expression were determined by immunofluorescence and Western blotting, respectively. Matrix metalloproteinase (MMP) activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence, and TIMP-1 was assessed by immunohistochemistry. Both β1-receptor antagonists exerted very similar antihypertensive effects. However, while metoprolol had no significant effects, nebivolol significantly attenuated vascular remodeling and collagen deposition associated with hypertension. Moreover, nebivolol, but not metoprolol, attenuated hypertension-induced increases in aortic NAD(P)H oxidase activity, superoxide production, TBARS concentrations, nitrotyrosine levels, TGF-β upregulation, and MMP-2 and -9 expression/activity. No effects on p-ERK 1/2 and TIMP-1 expression were found. These results show for the first time that nebivolol, but not metoprolol, attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMP-2 and MMP-9, which promote vascular remodeling in hypertension.
['Ceron|Carla S|CS|', 'Rizzi|Elen|E|', 'Guimarães|Danielle A|DA|', 'Martins-Oliveira|Alisson|A|', 'Gerlach|Raquel F|RF|', 'Tanus-Santos|Jose E|JE|']
D058671:Adrenergic beta-1 Receptor Antagonists D000818:Animals D000959:Antihypertensive Agents D000975:Antioxidants D001578:Benzopyrans D015153:Blotting, Western D004195:Disease Models, Animal D004983:Ethanolamines D005455:Fluorescent Antibody Technique D006978:Hypertension, Renovascular D008297:Male D020782:Matrix Metalloproteinases D000068577:Nebivolol D018384:Oxidative Stress D051381:Rats D017208:Rats, Wistar D016212:Transforming Growth Factor beta D066253:Vascular Remodeling
Nebivolol MMP Vascular remodeling Renovascular hypertension Metoprolol systolic blood pressure dihydroethidium TBARS Matrix metalloproteinases Matrix metalloproteinases 2 kidney, one clip 2K1C DHE ECM ERK 1/2 Oxidative stress SBP TGF extracellular matrix extracellular regulated kinase 1/2 matrix metalloproteinase thiobarbituric acid-reactive substances transforming grown factor