Abstract 301: Nebivolol Attenuates Prooxidant and Profibrotic Mechanisms and Decreases Vascular Remodeling in Renovascular Hypertension

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Abstract

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 vascular remodeling. 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 (Nebi 10 mg/kg/day), metoprolol (Meto 20 mg/kg/day) or vehicle for four weeks. Systolic blood pressure was monitored weekly. Morphologic changes in the aortic wall were studied in picrosirius red sections. Aortic NAD(P)H activity was evaluated by luminescence. Nitrotyrosine staining was evaluated to assess peroxynitrite formation by immunohistochemistry. TGF-β and matrix metalloproteinase-9 (MMP-9) levels were determined by immunofluorescence, and p-ERK 1/2 expression by western blotting. Both β1-receptor antagonists exerted very similar antihypertensive effects (156 ± 8 mmHg and 151 ± 9 mmHg, respectively, versus 206 ± 7 mmHg in hypertensive controls; both P<0.05). However, while metoprolol had no significant effects, nebivolol significantly (all P<0.05) attenuated vascular collagen surface (237944 ± 59567, 69784 ± 17686, 183215 ± 30338 μm2, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), attenuated hypertension-induced increases in aortic NAD(P)H oxidase activity (253887 ± 13712, 143765 ± 15642, and 232465 ± 14352 AU, respectively in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), in nitrotyrosine levels (166.3 ± 2.9, 145.3 ± 1.5, 172.1 ± 7.3 AU, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), in TGF-β upregulation (7.2 ± 0.12, 6.5 ± 0.03, 7.0 ± 0.3 AU, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups) and in MMP-9 levels (18.27 ± 0.8, 12.73 ± 0.4, 15.76 ± 1.4 AU, respectively in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups). No effects on p-ERK 1/2 expression were found with both drugs (P>0.05) (1.0 ± 0.16, 0.92 ± 0.15, 0.87 ± 0.37 AU, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups). These results show for the first time that nebivolol, but not metoprolol, attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMP-9, which promote vascular remodeling in hypertension.

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