Heme Oxygenase-1 Induction and Organic Nitrate Therapy: Beneficial Effects on Endothelial Dysfunction, Nitrate Tolerance, and Vascular Oxidative Stress
Effects of the HO-1 inducer hemin on GTN-induced tolerance and effects of the HO-1 suppressor apigenin on PETN side effects. Hemin (25 mg/kg) was administrated by single i.p. injection on day 3 of GTN treatment (6.6 μg/kg/min for 4 days via s.c. infusion) and markedly improved vascular GTN responsiveness (see area between curves) as demonstrated by isometric tension studies (a), a significant decrease in mitochondrial ROS formation (b), and improvement of mitochondrial ALDH-2 activity (c). Effects of bolus bilirubin on ROS formation in isolated heart mitochondria from GTN in vivo treated rats were determined by L-012 (100 μM) ECL in the presence of 2.5 mM succinate and bilirubin (0–25 μM) (d). Apigenin (10 mg/kg/d) was coinfused over 4d together with PETN (10.5 μg/kg/min for 4 days via s.c. infusion). Apigenin cotreatment decreased PETN vasodilator potency (see area between curves) and induced a tolerance-like right shift in the PETN concentration-relaxation-curve (E). This observation was accompanied by increased mitochondrial ROS formation (F). Data are mean ± SEM of (a), 40 (b), 6–18 (c), 4–6 (d), 9–11 (e), and 28–43 (f) independent experiments. versus GTN or PETN treatment. Modified from .
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