Comparative Effect of ACE Inhibition and Angiotensin II Type 1 Receptor Antagonism on Bioavailability of Nitric Oxide in Patients With Coronary Artery Disease

Abstract

Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT(1)-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 AT(1)-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.

Olmesartan improves endothelial function in hypertensive patients: link with extracellular superoxide dismutase

“…8 Basic research has clearly demonstrated that the Ang II-mediated signal transduction pathway induces inflammation and oxidative stress. 9,10 In the clinical setting, ACEI and ARB reportedly improve endothelial function by increasing endothelium-bound (released by heparin injection) extracellular superoxide dismutase (EC-SOD) activity, 6 supporting the above observations. In addition, several pathological statuses have been reported to be associated with endothelial dysfunction, such as diabetes, 11 dyslipidemia 12 and chronic kidney diseases, 13 and RAS inhibitors improved endothelial dysfunction under these conditions.…”

“…Both angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II (Ang II) type 1 receptor antagonists (ARB) are essential drugs for such patients, 5 and have been reported to restore decreased endothelial function by improving NO availability. 6 However, it is still controversial whether improvement of endothelial function is an effect of the RAS inhibitor class because several investigators were unable to observe such an effect for ARB 7 in spite of beneficial effects seen for other classes of antihypertensives. 8 Basic research has clearly demonstrated that the Ang II-mediated signal transduction pathway induces inflammation and oxidative stress.…”

Pre-emptive gene therapy using recombinant adeno-associated virus delivery of extracellular superoxide dismutase protects heart against ischemic reperfusion injury, improves ventricular function and prolongs survival

“…6 Restoration of Ec-SOD availability is associated with improvement of endothelial function in patients with CAD and is related to reduction of oxidative stress in vessel wall. 5 Earlier studies carried out in rats have shown that infusion of recombinant Ec-SOD protein resulted in reduced levels of creatine kinase in the left ventricular free wall and SOD bound to endothelial surface was also associated with lower cardiac damage in Langendorffperfused rat hearts subject to 15 min of global ischemia followed by reperfusion. 36 Subsequent comparative study conducted on infusion of recombinant Ec-SOD protein, Ec-SOD plus catalase and catalase alone showed inverse relationship between infarct size and creatine kinase levels in a pig myocardium injury model.…”

“…4 A number of recent clinical studies have reported reduced levels of human extracellular superoxide dismutase (Ec-SOD) in patients with coronary artery disease and myocardial infarction. [5][6][7] Superoxide anion is product of oxygen metabolism and is produced by activated inflammatory cells. [8][9][10] SODs are family of metalloproteins that scavenges superoxide anion radicals and form oxygen and hydrogen peroxide.…”

Drug Treatment of Hypertension: Focus on Vascular Health

“…In patients with essential hypertension, treatment with cizalapril for 2 years and lisinopril for 3 years improved vascular responses to acetylcholine in the subcutaneous microcirculation 4,[116][117][118] . Furthermore, within the peripheral circulation, perindopril, ramipril, quinapril and the perindopril-indapamide combination improve flowmediated dilatation, which most likely relates to increased NO bioavailability and prevention of angiotensin-II induced oxidative stress 4,35,37,115,[119][120][121] . ACE inhibitors may also potentiate bradykinin activity, which stimulates release of NO, PGI 2 and EDHF from the endothelium 22 .…”