Abstract P3022: Pentoxifylline Exerts Antiinflammatory And Antioxidant Effects, Inhibits MMP-2 Activity And Attenuates Renovascular Hypertension-Induced Vascular Alterations

Abstract

Introduction: Angiotensin II promotes inflammation, oxidative stress and matrix metalloproteinases (MMP) activation leading to vascular remodeling in hypertension. Pentoxifylline (PTX) is a non-selective inhibitor of phosphodiesterases that has also shown antiinflamatory and antioxidant effects. Thus, the aim of the present study was to evaluate whether PTX treatment decreases morphological and functional vascular alterations in 2-kidney and 1-Clip (2K1C) rats through reduction of cytokines, oxidative stress and MMP-2 activity. Methods: Male 2K1C and Sham rats were treated with Vehicle or PTX. Systolic blood pressure (SBP) was measured weekly. Aortic rings were isolated to assess endothelium-dependent relaxations. The vascular hypertrohy were examined in the aorta sections stained with hematoxylin/eosin. Aortic MMP-2 levels and gelatinolytic activity were determined using gelatin and in situ zymography assays, respectively. Vascular oxidative stress was evaluated using dihydroethidium (DHE). Cytokines levels were analyzed using the enzyme-linked immunosorbent assay (ELISA). Results: 2K1C rats exhibited high SBP (195±4 mmHg vs Sham 123±2 mmHg ) and significant vascular hypertrophy when compared to Sham group (0.7±0.03 mm 2 vs 0.5±0.02 mm 2 ; p<0.05), which were attenuated with PTX treatment (174±4 mmHg and 0.6±0.02 mm 2 ;p<0.05). PTX treatment also ameliorated the endothelial dysfunction in aortas from 2K1C rats (from 78±5% to 98±6%; p<0.05). MMP-2 levels and activity were augmented in 2K1C rats when compared to sham group (p<0.05). The treatment with PTX reduced MMP-2 upregulation in 2K1C rats (p<0.05). Overproduction of ROS in aortas from 2K1C rats (136±1.8%) was reduced with PTX treatment (21±8%; p<0.05). Elevated tumor necrosis factor-alpha and interleukin-1 beta levels in 2K1C rats was diminished with PTX treatment (p<0.05). Conclusion: PTX ameliorates 2K1C-induced hypertension, vascular morphometric and functional alterations, oxidative stress, elevated MMP-2 activity and cytokines levels. PTX exerted antioxidant and immunomodulatory effects, and decreased renovascular hypertension-induced MMP-2 up-regulation, leading to improvement of vascular dysfunction and remodelling typically found in 2K1C hypertension.