Abstract 265: Chronic Treatment with Nebivolol Attenuates the Vascular Changes in the 2-Kidney, 1-Clip Model of Renovascular Hypertension

Abstract

Nebivolol (Nebi) is a β-1 receptor antagonist with vasodilator and antioxidant properties. Matrix metalloproteinases (MMPs) are enzymes involved in cardiovascular remodeling, and MMP upregulation has been associated with increased reactive oxygen species (ROS). Because vascular remodeling is associated with increased ROS and MMPs, it is possible that Nebi reverses the increased MMP levels and vascular remodeling associated with 2K-1C hypertension through its antioxidant activity. Hypertension was induced in male Wistar rats by clipping the left renal artery. Six weeks after surgery, hypertensive and sham rats were treated with Nebi (10 mg/kg/day), metoprolol (Meto; 20 mg/kg/day) or vehicle for four weeks. Systolic blood pressure (SBP) was monitored weekly by tail-cuff plethysmography. Structural changes of the aortic wall were studied in hematoxylin/eosin sections. MMPs levels and activity were determined by zymography and in situ zymography. NADPH oxidase activity and ROS production were evaluated by luminescence and dihydroethidium. Similar reductions in SBP were found with both Meto or Nebi treatments (156 ± 8 mmHg and 151 ± 9 mmHg, respectively, versus 206 ± 7 mmHg in hypertensive controls; both P<0.05). However, only Nebi (all P<0.05) reversed aortic hypertrophy (aortic cross sectional area x 10 4 = 89±5, 68±3, and 80±8 μm 2 , respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), the increases in aortic MMP-2 levels (0.18±0.04, 0.07±0.02, and 0.12±0.06 arbitrary units; AU, respectively in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), in aortic MMP activity (21071±700, 16217±818, and 18848±1396, respectively in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), in aortic NADPH oxidase activity (253887±13712, 143765±15642, and 232465±14352 AU, respectively in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups) and in aortic ROS levels (8057±800, 4400±480, and 6230±1190 AU, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups). No significant differences were found in the Sham groups. Our results suggest that lower vascular NADPH oxidase may explain, at least in part, the attenuation of oxidative stress and vascular remodeling associated with Nebi.