Comparative effect of ACE inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: Role of superoxide dismutase

Abstract

Background - Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT1-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity. Methods and Results - Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT1-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial N-monomethyl-L-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection, FDD was improved after ramipril and losartan (each group P<0.01), and in particular, the portion of FDD mediated by NO, ie, inhibited by L-NMMA, was increased by >75% (each group P<0.01). Vitamin C improved FDD initially, an effect that was lost after ramipril or losartan. After therapy, EC-SOD activity was increased by >200% in both groups (ACEI, 14.4 ± 1.1 versus 3.8 ± 0.9 and AT1-A, 13.5 ± 1.0 versus 3.9 ± 0.9 U · mL-1 · min-1; each P<0.01). Conclusions - Four weeks of therapy with ramipril or losartan improves endothelial function to similar extents in patients with CAD by increasing the bioavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reduction of oxidative stress within the arterial wall, mediated in part by increased EC-SOD activity.