Is aldosterone bad for the heart?

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Abstract

The recent clinical trials RALES and EPHESUS have shown that mineralocorticoid receptor (MR) antagonists added to standard of care substantially increase survival and decrease hospitalization in patients with heart failure. In both trials aldosterone levels and sodium status were unremarkable. Most epithelial and vascular smooth muscle cell MR are normally ‘protected’ by 11β-hydroxysteroid dehydrogenase, but are nonetheless normally largely occupied but not activated by glucocorticoids. When intracellular NADH rises in response to enzyme blockade or generation of reactive oxygen species MR are activated by glucocorticoids, mimicking the cardiovascular effects of inappropriate aldosterone for salt status. This may represent a novel face of MR activation in vascular inflammation and in ‘non-protected’ tissues, such as cardiomyocytes in heart failure.

Section snippets

Aldosterone can be bad for the heart

First, there is no question that inappropriate aldosterone for salt status can produce massive coronary vascular and cardiac damage. Among the most graphic and illuminating of studies showing this are those of Ricardo Rocha and colleagues [2] (Figure 1). In these studies, rats were maintained on 0.9% NaCl solution as drinking fluid for three weeks and infused with angiotensin II (Ang II). Over the course of the study, blood pressure rose progressively, whether the rats were intact,

MR and 11β-HSD2, the specificity-conferring enzyme in aldosterone target tissues

To support the contention that under such circumstances MR antagonists are blocking cortisol rather than aldosterone from activating MR we need to recapitulate the role of the specificity-conferring enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD2) in aldosterone action. Over 20 years ago, it was found that rat MR had similar affinity for aldosterone and physiological glucocorticoids, and were present at high levels in non-epithelial tissues such as hippocampus, in addition to classic

The limits of cortisol to cortisone conversion

Despite its high concentration (∼3.5×106 molecules per cell) and its low Km (high affinity) for glucocorticoids, it seemed inherently unlikely that 11β-HSD2 can totally inactivate intracellular cortisol, levels of which are ∼100-fold higher than those of aldosterone [12]. In an experiment to test this possibility, we found that 11β-HSD2 ‘debulked’ intracellular glucocorticoids, by converting ∼90% to receptor-inactive 11-keto congeners, which still leaves intracellular glucocorticoid levels

NAD, the forgotten cosubstrate for 11β-HSD2

What is often overlooked is that the cosubstrate for the enzyme is NAD (Figure 3). For every molecule of cortisol converted to cortisone a molecule of NADH is generated. Although 11β-HSD2 is expressed in a minority of kidney cells (perhaps ∼5%), its activity is such that renal venous levels of cortisol are lower, and those of cortisone higher, than in arterial blood. The kidneys account for 20–25% of cardiac output, so that within aldosterone target cells both cortisone and NADH are generated

Activation of MR by glucocorticoids: experimental studies

There are several studies that are best explained by such a hypothesis. In one of these [17], the classic coronary vascular and perivascular inflammatory response seen with mineralocorticoid/salt administration (Figure 5) was reproduced by administration of the 11β-HSD2 blocker carbenoxolone. That this proinflammatory effect was MR mediated is shown by the ability of the selective MR antagonist eplerenone to completely block the carbenoxolone effect. Our interpretation of these data are that

A role for redox activation of non-epithelial MR–glucocorticoid complexes?

If glucocorticoid MR activation is redox dependent, the implications might extend even beyond the role of normal levels of glucocorticoids – rather than raised levels of aldosterone – in vascular pathology. As noted earlier, 11β-HSD2 is not present in tissues such as cardiomyocytes, and the much higher affinity of physiological glucocorticoids for MR than for glucocorticoid receptors means that ‘unprotected’ MR are essentially always occupied by glucocorticoids across the range of diurnal

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