Appraisal of the Role of Angiotensin II and Aldosterone in Ventricular Myocyte Apoptosis in Adult Normotensive Rat

Angelis, Noeleen De; Fiordaliso, Fabio; Latini, Roberto; Calvillo, Laura; Funicello, Marcella; Gobbi, Marco; Mennini, Tiziana; Masson, Serge

doi:10.1006/jmcc.2002.2115

Cited by 65 publications

(52 citation statements)

References 29 publications

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“…Our study is in contrast to Chai et al, 22 who found no significant effect of aldosterone on extent of infarct area, and in agreement with several previous studies, which have shown that aldosterone promotes apoptosis. 19,27,28 The effect of aldosterone was mimicked by cortisol to aggravate myocardial infarct size and apoptosis, again with an EC 50 between 1 and 10 nM. This in itself is evidence for a cortisol effect via MR, for which cortisol has considerably higher affinity than for GRs; effects of physiological steroids via GRs are commonly seen over a dose range of 10 nM to 1 mol/L.…”

Section: Discussionmentioning

confidence: 90%

“…The doses of steroids were selected to range from physiological levels to supraphysiological levels used in previous studies. 19,20 Although corticosterone is the physiological steroid in rats, we used cortisol because it has affinity equal to that of aldosterone for MRs in the rat but substantially lower affinity for glucocorticoid receptors (GRs) than in cortisol-secreting species. We used cortisol (10 and 100 nM), aldosterone (1, 10, and 100 nM), dexamethasone (10 and 100 nM), the MR antagonist spironolactone (10 nM and 1 mol/L), or the GR/progesterone receptor antagonist mifepristone (RU486; 100 nM and 1 mol/L) added to the perfusate either alone or in combination before inducing ischemia and throughout the reperfusion period.…”

Section: Experimental Protocolsmentioning

confidence: 99%

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Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

et al. 2009

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Abstract-Myocardial ischemia-reperfusion leads to significant changes in redox state, decreased postischemic functional recovery, and cardiomyocyte apoptosis, with development and progression of heart failure. Ischemia-reperfusion in the isolated perfused rat heart has been used as a model of heart failure. Clinically, mineralocorticoid receptor blockade in heart failure decreases morbidity and mortality versus standard care alone. The effects of corticosteroids on infarct area and apoptosis were determined in rat hearts subjected to 30 minutes of ischemia and 2.5 hours of reperfusion. Both aldosterone and cortisol increased infarct area and apoptotic index, an effect half-maximal between 1 and 10 nM and reversed by spironolactone. Dexamethasone and mifepristone aggravated infarct area and apoptotic index, similarly reversed by spironolactone. Spironolactone alone reduced infarct area and apoptotic index below ischemia-reperfusion alone, in hearts from both intact and adrenalectomized rats. The present study shows that cardiac damage is aggravated by activation of mineralocorticoid receptors by aldosterone or cortisol or of glucocorticoid receptors by dexamethasone.Mifepristone unexpectedly acted as a glucocorticoid receptor agonist, for which there are several precedents. Spironolactone protected cardiomyocytes via inverse agonist activity at mineralocorticoid receptors, an effect near maximal at a relatively low dose (10 nM

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Section: Discussionmentioning

confidence: 90%

Section: Experimental Protocolsmentioning

confidence: 99%

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

et al. 2009

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“…The mechanism by which EPL prevented apoptosis is not known. However, in vitro studies have shown that aldosterone can cause apoptosis in cardiomyocytes, 20 thymocytes, and neuronal cells. 40,41 Likewise, we found that chronic aldosterone infusion in mice is associated with myocyte apoptosis.…”

Section: Mineralocorticoid Receptors Mediate Myocyte Apoptosismentioning

confidence: 99%

“…17,18 Pressure overload leads to increased myocyte apoptosis 17 that may contribute to myocardial failure. Recently, we 19 and others 20 have shown that aldosterone, probably acting via mineralocorticoid receptors, can induce apoptosis both in vitro and in vivo. In addition, it has been shown that activation of matrix metalloproteinases (MMP), which degrade most components of the interstitial matrix, precedes LV dilation in high-salt hypertension.…”

mentioning

confidence: 94%

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

et al. 2005

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Background-Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. Methods and Results-We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4Ϯ0.1 versus 3.7Ϯ0.1 mm) and end-systolic (2.0Ϯ0.1 versus 2.5Ϯ0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42Ϯ2% versus 34Ϯ4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. Conclusions-Mineralocorticoid

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“…8 Some of the cardiovascular effects of aldosterone that may contribute to the development and progression of post-AMI HF include myocardial and vascular fibrosis, catecholamine potentiation, potassium and magnesium loss, ventricular arrhythmias, cardiomyocyte apoptosis, sodium retention, ischemic injury, and endothelial dysfunction. [9][10][11][12] Animal and human models have demonstrated reversal of these harmful pathophysiologic effects with aldosterone blockade post AMI. [12][13][14][15] Based on the above, EPHESUS was designed to explore the Clin.…”

Section: The Burden Of Post-acute Myocardial Infarction Heart Failurementioning

confidence: 99%

Aldosterone blockade in post‐acute myocardial infarction heart failure

Pitt

Ferrari

Gheorghiade

et al. 2006

Clinical Cardiology

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Summary: Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setting. However, lack of practical experience with aldosterone blockade may make clinicians hesitant to use these therapies. This review is based on a consensus cardiology conference that occurred in May 2005 (New York City) concerning these topics. Potential barriers to the use of aldosterone blockade are discussed and an algorithm for appropriate in-hospital pharmacologic management of AMI with LVSD and/or HF is presented.

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Appraisal of the Role of Angiotensin II and Aldosterone in Ventricular Myocyte Apoptosis in Adult Normotensive Rat

Cited by 65 publications

References 29 publications

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

Aldosterone blockade in post‐acute myocardial infarction heart failure

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