Mineralocorticoid Receptor Blockade Improves Vasomotor Dysfunction and Vascular Oxidative Stress Early After Myocardial Infarction

Abstract

Abstract-Mineralocorticoid receptor blockade improves mortality early after myocardial infarction (MI). This study investigated the vascular effects of mineralocorticoid receptor blockade in the early phase postinfarction in rats. Starting immediately after coronary ligation, male Wistar rats were treated with placebo or eplerenone (100 mg/kg/d). After 7 days, hemodynamic assessment was performed and endothelial function was determined. Maximum acetylcholineinduced relaxation was significantly attenuated in aortic rings from rats with heart failure after MI, and ameliorated by eplerenone treatment. Endothelium-independent relaxation by DEA-NONOate was similar among the groups. Endothelial NO synthase phosphorylation was reduced in the aorta of MI rats and restored by eplerenone therapy. Angiotensin I-induced vasoconstriction as well as angiotensin-converting enzyme protein levels were enhanced in aortas from MI placebo rats, and reduced by mineralocorticoid receptor inhibition. Aortic reactive oxygen species formation as well as the expression of the NAD(P)H oxidase subunit p22 phox were increased after MI and normalized in eplerenone treated rats. In conclusion, mineralocorticoid receptor antagonism improved endothelial dysfunction in the early phase post-MI. Underlying mechanisms involve inhibition of vascular angiotensin-converting enzyme upregulation and improvement of endothelial NO synthase-derived NO bioavailability. Key Words: aldosterone Ⅲ acute myocardial infarction Ⅲ endothelial dysfunction Ⅲ oxidative stress C hronic heart failure is accompanied by endothelial dysfunction. 1 Increased production of vascular reactive oxygen species, especially superoxide anion (O 2 Ϫ ), as well as diminished antioxidant defense in heart failure contribute to a reduced bioavailability of NO. 2 The renin angiotensin aldosterone system (RAAS) is markedly activated and displays a central role in heart failure progression. 3,4 Aldosterone synthesis and mineralocorticoid receptors (MR) have been described in the vascular wall. 5,6 Aldosterone stimulates vascular ACE expression/activity and potentiates angiotensin II effects. 7-10 Angiotensin II and aldosterone stimulate vascular O 2 Ϫ production, promoting NO scavenging and reducing its bioavailability. [11][12][13] In healthy subjects, contradictory effects of aldosterone on endothelial function are reported. Farquharson et al 14 showed that intravenous infusion of aldosterone reduced the forearm blood flow response to acetylcholine but did not affect sodium nitroprusside-induced vasodilation, thus inducing acute endothelial dysfunction. Others reported that aldosterone increases forearm blood flow and induces vasodilatation by stimulating NO release through rapid nongenomic effects. 15 In a recent investigation, short-term and chronic aldosterone excess did not affect forearm blood flow, but enhanced the vasodilator response to exogenous NO and improved endothelium-dependent NO-mediated vasodilation in the forearm vasculature of healthy men. 16,17 However, in subjects wit...

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