Abstract 5522: Improvement of Angiotensin-II-Induced Vascular Dysfunction and Oxidative Stress by the Organic Nitrate Pentaerithrityl Tetranitrate Depends on Heme Oxygenase-1-Induction
Objective: Pentaerithrityl tetranitrate (PETN)-treatment is devoid of nitrate tolerance which has been attributed to the induction of the antioxidant enzyme heme oxygenase-1 (HO-1). With the present study we tested, whether chronic treatment with PETN can improve angiotensin-II (AT-II)-induced vascular oxidative stress and dysfunction.
Methods and Results: In contrast to isosorbide mononitrate (ISMN, 75mg/kg/d/7d), co-treatment with PETN (15mg/kg/d/7d) improved impaired endothelial and smooth muscle function and normalized vascular and cardiac ROS production (mitochondria, NADPH oxidase activity and uncoupled endothelial nitric oxide synthase [eNOS]) as assessed by dihydroethidine (DHE)-staining, lucigenin-enhanced chemiluminescence and quantitative HPLC of DHE-oxidation products in AT-II (1mg/kg/d/7d) treated rats. The antioxidant features of PETN were recapulated in spontaneously hypertensive rats. In addition to increase in HO-1 protein expression, PETN but not ISMN augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase-I and dihydrofolate reductase in AT-II-treated rats, thereby preventing eNOS uncoupling. In AT-II-treated (0.1mg/kg/d/7d) HO-1+/− mice, PETN failed to be antioxidant, whereas HO-1 induction by hemin (25mg/kg) mimicked the PETN effect in AT-II-treated HO-1+/+ mice.
Conclusions: PETN improves AT-II-induced vascular oxidative stress and dysfunction via induction of HO-1. Thus, PETN is the first organic nitrate to be beneficial in an experimental model of arterial hypertension.