enalaprilat-anhydrous and Necrosis

Angiotensin-converting enzyme (ACE) inhibitors were shown to improve endothelial dysfunction in various human diseases and some of these inhibitors have been proposed as enhancers of antioxidant defences. We measured glutathione peroxidase (GPX), superoxide dismutase (SOD) and malondialdehyde (MDA) in human endothelial cells treated with captopril or enalaprilat, two ACE inhibitors, and we showed that both inhibitors decreased GPX and SOD activities but not MDA, the end-product of lipoperoxidation. Captopril and enalaprilat were also unable to protect against etoposide-induced apoptosis in endothelial cells, indicating that they cannot be considered as protective drugs for the endothelium, in particular in clinical situations involving oxidative stress or apoptosis. Moreover, when used at high concentration captopril, but not enalaprilat, was toxic for endothelial cells with both necrotic and apoptotic effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Apoptosis; Captopril; Cells, Cultured; Dose-Response Relationship, Drug; Enalaprilat; Endothelium, Vascular; Etoposide; Glutathione Peroxidase; Humans; Lipid Peroxidation; Malondialdehyde; Necrosis; Oxidative Stress; Superoxide Dismutase; Umbilical Veins

Angiotensin-converting enzyme (ACE) inhibitors differ in their ability to inhibit tissue ACE. This study was, therefore, undertaken to determine whether high tissue affinity ACE inhibitors would improve endothelial function and thereby decrease tissue necrosis during ischemia.. In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion. During the period of coronary occlusion, 10 pigs received enalaprilat (low affinity tissue ACE inhibitor), 0.05 mg/kg intravenously, 10 received quinaprilat (high affinity tissue ACE inhibitor), 10 mg intravenously, and 10 others received no ACE inhibitor.. Wall motion scores (4, normal, to -1, dyskinesia) were higher in animals treated with ACE inhibitors (3.20+/-0.15 SE enalaprilat versus 3.08+/-0.23 quinaprilat versus 1.52+/-0.07 no ACE; both p < 0.0001 from no ACE). Endothelial-dependent relaxation to bradykinin was best preserved in the quinaprilat-treated hearts (32.1%+/-7.6% enalaprilat versus 65.8%+/-12.6% quinaprilat versus 30.6%+/-10.7% no ACE; p < 0.0001 from no ACE; p < 0.005 from enalaprilat). This was associated with a greater reduction in infarct size: area necrosis/area risk 24.3%+/-0.8% enalaprilat (p < 0.0001 from no ACE) versus 14.3%+/-3.2% quinaprilat (p < 0.0001 from no ACE; p < 0.005 from enalaprilat) versus 40.0%+/-1.7% no ACE.. ACE inhibitors with higher affinity to tissue ACE result in better preservation of endothelial function and less tissue necrosis during coronary revascularization.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalaprilat; Endothelium, Vascular; Infusions, Intravenous; Isoquinolines; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Swine; Tetrahydroisoquinolines