Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability.
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.
Imanishi
Toshio
T
Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama City, Wakayama 641-8510, Japan. t-imani@wakayama-med.ac.jp
Ikejima
Hideyuki
H
Tsujioka
Hiroto
H
Kuroi
Akio
A
Kobayashi
Katsunobu
K
Muragaki
Yasuteru
Y
Mochizuki
Seiichi
S
Goto
Masami
M
Yoshida
Kiyoshi
K
Akasaka
Takashi
T
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
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