title: Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability.
abstract: Angiotensin II and aldosterone both promote endothelial dysfunction and atherosclerosis. We investigated the effect of a combination of eplerenone, a selective aldosterone antagonist, and enalapril, an angiotensin-converting enzyme inhibitor, on NO bioavailability and spontaneous atherosclerotic changes. Twenty-four myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits were treated with vehicle (control), eplerenone (50 mg/kg per day), enalapril (3 mg/kg per day), or eplerenone plus enalapril for 8 weeks (n=6 in each group). After treatment, acetylcholine-induced NO production was measured as a surrogate for endothelium-protective function, and vascular peroxynitrite (a product of superoxide and NO) was measured to assess dysfunctional endothelial NO synthase activity. Plaque area was quantified by histology. Intra-aortic infusion of acetylcholine produced an increase in plasma NO concentration that was significantly higher with all of the drug treatments compared with the control. Eplerenone and enalapril, in combination, increased acetylcholine-induced NO by 7.9 nM, which was significantly higher than with either eplerenone or enalapril alone. Vascular peroxynitrite was significantly higher in the control group (1.3 pmol/mg of protein) and significantly lower with combination treatment (0.4 pmol/mg of protein) compared with the enalapril or eplerenone group. The highest tetrahydrobiopterin levels were observed after cotreatment with eplerenone and enalapril. Histology of the thoracic aorta showed a significantly decreased plaque area with combination therapy compared with monotherapy. Combined treatment with a selective aldosterone antagonist and an angiotensin-converting enzyme inhibitor has additive protective effects on endothelial function and on atherosclerotic changes via decreased nitrosative stress.
authors.affiliation: Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama City, Wakayama 641-8510, Japan. t-imani@wakayama-med.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Imanishi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ikejima
authors.forename: Hiroto
authors.initials: H
authors.lastname: Tsujioka
authors.forename: Akio
authors.initials: A
authors.lastname: Kuroi
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Muragaki
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Masami
authors.initials: M
authors.lastname: Goto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Akasaka
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000450:Aldosterone / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D004656:Enalapril / Q000494:pharmacology*; D000077545:Eplerenone; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000502:physiology; D030421:Peroxynitrous Acid / Q000378:metabolism; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D013148:Spironolactone; D009569:Nitric Oxide; D000450:Aldosterone; D000077545:Eplerenone; D004656:Enalapril; D002784:Cholesterol; D007703:Peptidyl-Dipeptidase A; D000109:Acetylcholine