Cardiac Synthesis of Aldosterone: Going, Going, Gone… ?

Funder, John W.

doi:10.1210/en.2004-1057

Cited by 36 publications

(20 citation statements)

References 24 publications

(22 reference statements)

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“…One formal possibility is that, under such conditions, the damage from ischemia-reperfusion is elevated by ectopic production of aldosterone by the heart, so that ischemia-reperfusion alone does not represent a truly basal state. Although cardiac synthesis of aldosterone has had a relatively long and disputed 40 history, the most recent reports from vigorously controlled studies on levels of steroidogenic enzyme mRNA are widely regarded as providing a definitive negative answer to the question of cardiac aldosterone synthesis. 41,42 This is strong evidence that the protective inverse agonist effect of spironolactone is via MRs, for which spironolactone has much higher affinity than for androgen, progesterone, or GRs.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

et al. 2009

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“…Low levels of 11b-HSD1 and 11b-HSD2 have also been reported in rat and human heart (67,(71)(72)(73)(74)(75) and 11b-HSD1 is expressed in differentiated macrophages (76,77). On the balance of the evidence, with reference to the model in There have also been sporadic reports that vascular tissue and myocardium express the enzymes necessary for de novo steroidogenesis from cholesterol (72,78,79), although the magnitude, if any, of this contribution appears to be very small. The effects of glucocorticoids on cardiovascular tissues are summarised in Table 2, which shows diverse effects on vascular development, remodelling, tone and inflammation.…”

Section: Glucocorticoid Signalling In Cardiovascular Organsmentioning

confidence: 99%

Glucocorticoids and Cardiovascular Disease

Walker¹

2007

European Journal of Endocrinology

454

369

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Chronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, glucose intolerance, dyslipidaemia and hypertension. Subtle abnormalities of the hypothalamic-pituitaryadrenal axis and/or of tissue sensitivity to glucocorticoids are also associated with these cardiovascular risk factors in patients with the metabolic syndrome. Furthermore, glucocorticoids have direct effects on the heart and blood vessels, mediated by both glucocorticoid and mineralocorticoid receptors and modified by local metabolism of glucocorticoids by the 11b-hydroxysteroid dehydrogenase enzymes. These effects influence vascular function, atherogenesis and vascular remodelling following intravascular injury or ischaemia. This article reviews the systemic and cardiovascular effects of glucocorticoids, and the evidence that glucocorticoids not only promote the incidence and progression of atherogenesis but also modify the recovery from occlusive vascular events and intravascular injury. The conclusion is that manipulation of glucocorticoid action within metabolic and cardiovascular tissues may provide novel therapeutic avenues to combat cardiovascular disease.European Journal of Endocrinology 157 545-559

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“…27,28 Silvestre et al 29 found increased aldosterone concentrations after Ang II or adrenocorticotropic hormone administration in isolated perfused hearts of Wistar rats. Aldosterone production by the failing heart has been suggested on the basis of catheterobtained aldosterone concentrations across the heart.…”

Section: Fiebeler Et Almentioning

confidence: 99%

Aldosterone Synthase Inhibitor Ameliorates Angiotensin II–Induced Organ Damage

et al. 2005

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Background-Aldosterone and angiotensin (Ang) II both may cause organ damage. Circulating aldosterone is produced in the adrenals; however, local cardiac synthesis has been reported. Aldosterone concentrations depend on the activity of aldosterone synthase (CYP11B2). We tested the hypothesis that reducing aldosterone by inhibiting CYP11B2 or by adrenalectomy (ADX) may ameliorate organ damage. Furthermore, we investigated how much local cardiac aldosterone originates from the adrenal gland. Methods and Results-We investigated the effect of the CYP11B2 inhibitor FAD286, losartan, and the consequences of ADX in transgenic rats overexpressing both the human renin and angiotensinogen genes (dTGR). dTGR-ADX received dexamethasone and 1% salt. Dexamethasone-treated dTGR-salt served as a control group in the ADX protocol. Untreated dTGR developed hypertension and cardiac and renal damage and had a 40% mortality rate (5/13) at 7 weeks. FAD286 reduced mortality to 10% (1/10) and ameliorated cardiac hypertrophy, albuminuria, cell infiltration, and matrix deposition in the heart and kidney. FAD286 had no effect on blood pressure at weeks 5 and 6 but slightly reduced blood pressure at week7 (177Ϯ6 mm Hg in dTGRϩFAD286 and 200Ϯ5 mm Hg in dTGR). Losartan normalized blood pressure during the entire study. Circulating and cardiac aldosterone levels were reduced in FAD286 or losartan-treated dTGR. ADX combined with dexamethasone and salt treatment decreased circulating and cardiac aldosterone to barely detectable levels. At week 7, ADX-dTGR-dexamethasone-salt had a 22% mortality rate compared with 73% in dTGR-dexamethasone-salt. Both groups were similarly hypertensive (190Ϯ9 and 187Ϯ4 mm Hg). In contrast, cardiac hypertrophy index, albuminuria, cell infiltration, and matrix deposition were significantly reduced after ADX (PϽ0.05). Conclusions-Aldosterone

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Cardiac Synthesis of Aldosterone: Going, Going, Gone… ?

Cited by 36 publications

References 24 publications

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

Glucocorticoids and Cardiovascular Disease

Aldosterone Synthase Inhibitor Ameliorates Angiotensin II–Induced Organ Damage

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