Aldosterone receptor antagonists - how cardiovascular actions may explain their beneficial effects in heart failure

Abstract

Ovaert, P., Elliott, J., Bernay, F., Guillot, E., Bardon, T. Aldosterone receptor antagonists – how cardiovascular actions may explain their beneficial effects in heart failure. J. vet. Pharmacol. Therap.33, 109–117. Historically, aldosterone receptor antagonists (ARA) have been classified as ‘potassium sparing diuretics’. However, the positive effect of spironolactone, the most extensively studied ARA, on morbidity and mortality observed in humans suffering cardiac insufficiency could not be explained by the renal effect of the drug alone, and a pivotal clinical study has led to extensive research. Many experimental studies have demonstrated that ARA have previously unexpected beneficial effects on the cardiovascular system including reduction in remodelling of the vascular smooth muscle cells and myocytes and improvement of endothelial cell dysfunction in heart failure. These effects improve vascular compliance and slow down the progression of left ventricular dysfunction and end‐organ damage. Furthermore, aldosterone receptor blockade also restores the baroreceptor reflex, improving heart rate variability in heart failure in humans. Some of these effects have been demonstrated in dog models of cardiac disease and so justified further investigation of the potential benefit of ARA in dogs with congestive heart failure (CHF). Positive effects of spironolactone on morbidity and mortality appear to have been seen in studies conducted in dogs suffering from naturally occurring CHF. In addition, eplerenone has been shown to have benefits in canine models of heart failure. The precise mechanisms by which ARA produce these beneficial effects in dogs remain to be determined but this group of drugs clearly provide therapeutic actions out‐with their diuretic effects.

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

“…MR overexpression in embryonic stem cell-derived cardiomyocytes increased the frequency of contractions coincident with increased expression of the hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 pacemaker channel [129]. Conversely, a reduction in heart rate has cardioprotective effects and MR blockade by spironolactone decreases both the heart rate and heart rate variability, demonstrating parasympathetic nerve activity is, in part, MR-dependent [130][131][132], although MR-mediated heart rate change is not invariably observed [133]. These extensive data demonstrate an important involvement of MR activation by corticosteroids and mineralocorticoids in the regulation of myocardial rhythmicity at the level of the myocyte and intact heart.…”

Target-based biomarker selection – Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression

“…A recent meta-analysis has demonstrated an association between increasing depression severity and lower HRV (Kemp et al, 2010;Licht et al, 2008). HRV is also associated with the activity of the renin-angiotensin-aldosterone system (RAAS) (Ovaert et al, 2010;Schmidt et al, 1999) and MR-activation (MacFadyen et al, 1997). 4.…”

Letter to the Editor

“…We would like to end this response by pointing out that this study was only 1 piece of extensive documentation submitted to the EMA to support market authorization. Some other pieces of this documentation have already been published 4,5 . Furthermore, we would like to point out that this and the other published studies of spironolactone should be regarded as the first in a line of future postlicensing studies.…”