The effect of angiotensin-converting enzyme inhibition on endothelial function and oxidant stress

Abstract

Angiotensin-converting enzyme (ACE) inhibitors effectively interfere with the renin–angiotensin system and exert various beneficial actions on vascular structure and function beyond their blood pressure-lowering effects. Data from experimental studies showed that angiotensin-converting enzyme inhibitors can attenuate the development of atherosclerosis in a wide range of species. The postulated mechanisms of this atheroprotective effect are the antioxidant actions of angiotensin-converting enzyme inhibitors and their enhancement of the endothelial elaboration of bioactive nitric oxide. The aim of this study was to assess the comparative effects of three angiotensin-converting enzyme inhibitors on endothelial nitric oxide production and action, and on endothelial oxidative stress. Using bovine aortic endothelial cells in culture grown to confluence, we examined the effects of 1, 10, 30 and 60 μM of each of captopril, zofenopril and enalapril on nitrite/nitrate accumulation in the media, cyclic GMP accumulation in the cell lysate, and F₂-isoprostanes in lipid extracts from the cells. Results showed that the sulfhydryl angiotensin-converting enzyme inhibitor zofenopril has unique properties compared with captopril and enalapril. This compound improves nitric oxide production and bioactivity, and does so in conjunction with decreased endothelial cell oxidant stress. The biochemical basis for this protective mechanism is not entirely clear; however, these actions suggest that zofenopril may reduce endothelial effects of risk factors for atherothrombotic disease.

Introduction

Angiotensin-converting enzyme (ACE) inhibitors interfere with the renin–angiotensin system and reduce the risk of myocardial infarction, stroke and cardiovascular death exerting various beneficial actions on cardiac and vascular structures beyond their blood pressure-lowering effects (Lonn, 2002). Indeed, controlled clinical trials have shown that angiotensin-converting enzyme inhibitors improve endothelial function, and cardiac and vascular remodeling. Angiotensin-converting enzyme inhibitors may reduce atherogenesis in experimental models through various protective mechanisms Hayek et al., 1998, Hayek et al., 1999, Napoli et al., 1999, Keidar et al., 2000, de Nigris et al., 2001, Chobanian et al., 1990, Aberg and Ferrer, 1990, Rolland et al., 1991, Charpiot et al., 1993, Kowala et al., 1994, including antiproliferative effects on vascular smooth muscle cells Daemen et al., 1991, Li et al., 1999, reduction of blood pressure Chobanian et al., 1990, Aberg and Ferrer, 1990 and low-density lipoprotein (LDL) oxidation Hayek et al., 1995, Hayek et al., 1998, Hayek et al., 1999, Napoli et al., 1999, Keidar et al., 2000, de Nigris et al., 2001, inhibitory effects on platelet activation Napoli et al., 1999, de Nigris et al., 2001, Keidar et al., 1996, modulation of proinflammatory signals in the vasculature (Gonzalez et al., 2000), reduction of macrophage accumulation Napoli et al., 1999, Keidar et al., 2000, de Nigris et al., 2001, Kowala et al., 1994, and improvement of endothelial dysfunction Rolland et al., 1991, Buikema et al., 2000.

Endothelial nitric oxide production is one manifestation of normal endothelial function. Angiotensin-converting enzyme inhibitors, in part, promote endothelial function by their antioxidant effects and by enhancing bradykinin-mediated endothelial nitric oxide synthesis. Thus, the goal of the present study was to assess in vitro the comparative effects of three different angiotensin-converting enzyme inhibitors on endothelial nitric oxide production and action, and on endothelial oxidative stress.