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

Background-Flow-dependent, endothelium-mediated vasodilation (FDD) and acti vity of extracellular superoxide dismutase (EC-SOD), the major antioxidativ e enzyme of the arterial wall, are severely impaired in patients with coron ary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) an d angiotensin II type 1 receptor antagonist (AT(1)-A) increase bioavailabil ity of nitric oxide (NO) by reducing oxidative stress in the vessel wall, p ossibly by increasing EC-SOD activity. Methods and Results-Thirty-five patients with CAD were randomized to 4 week s of ACEI (ramipril 10 mg/d) or AT(1)-A (losartan 100 mg/d). FDD of the rad ial artery was determined by high-resolution ultrasound before and after in tra-arterial N-monomethyl-L-arginine (L-NMMA) to inhibit NO synthase and be fore and after intra-arterial vitamin C to determine the portion of FDD inh ibited by oxygen free radicals. EC-SOD activity was determined after releas e from endothelium by heparin bolus injection. FDD was improved after ramip ril 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 r amipril 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 AT(1)-A, 13.5+/-1.0 v ersus 3.9+/-0.9 U . mL(-1) . min(-1); each P<0.01). Conclusions-Four weeks of therapy with ramipril or losartan improves endoth elial function to similar extents in patients with CAD by increasing the bi oavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reducti on of oxidative stress within the arterial wall, mediated in part by increa sed EC-SOD activity.