The question you raise has numerous complexities: 1) Although aldosterone does not bind to non-MR sites (membrane- and cytosolic), MR receptors are widely expressed at  non-classical sites, encompassing better studied tissues such as the cardiovascular tree, but many other tissues in which their role is much more vaguely defined, such as adipose tissue and certain brain areas. Some of these tissues/systems may be able to synthesize aldosterone locally, although this is under debate. 2) Aldosterone can transactivate angiotensin II receptors (AT1R) action and increase their expression. 3) The dose of spironolactone is critical. Spironolactone can affect steroidogenesis in the zona glomerulosa: ther is some evidence for inhibitory effect on aldo synthesis and also evidence for the formation of spirinolactone bodies withinn aldosterone-producing -adenomas which are enriched with steroidogenic activities. 4) The spironolactone dose does matter. In animal studies, large doses are often used to show some effects. In humans, stimulation of RAS takes place depending on the spironolactone dose selected for treatment and the type of disease (congestive heart failure, resistant hypertension, primary hyperaldosteronism). The dose that effectively modidies RAS may or may not be effective in blocking MR receptor in various tissues. Also, local activation of RAS components may be unrelated to systemic RAS activation (eg, fat tissue RAS).

The clearest response can be provided to your last question: Yes, eplerenone has ben shown to lower blood pressure in humans under a variety of clinical conditions, both in itself and in combination with other drugs.

I hope these references can help you:

Prognostic value of aldosterone and cortisol in patients hospitalized for acutely decompensated chronic heart failure with and without mineralocorticoid receptor antagonism      DOI:10.1016/j.cardfail.2014.12.011

Mineralocorticoid Receptor Antagonists Modulate Galectin-3 and Interleukin-33/ST2 Signaling in Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction      DOI:10.1016/j.jchf.2014.07.015

Biomarkers, Mineralocorticoid Receptor Antagonism, and Cardiorenal Remodeling     DOI:10.1016/j.jchf.2014.10.003

Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment     DOI:10.1016/j.ejim.2013.11.007

Renin-Angiotensin-Aldosterone System Inhibition : Overview of the Therapeutic Use of Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, Mineralocorticoid Receptor Antagonists, and Direct Renin Inhibitors     DOI:10.1016/j.pop.2014.08.002

Thank you so much for your answers and comments gentlemen!

In our experiments, blocking MR with eplerenone increases a lot plasmatic aldosterone levels and downstream targets of aldo (eg SGK1) are still high in these conditions!

I will indeed  have a closer look at AT1R, since the interplay between angiotensin and aldo is a well described phenomenon. It seems blocking MR alone is not sufficient in my setting so I will try to block both AT1R and MR.

Also, I do not know what is the influence of cortisol on the cardiac MR in mice, as it seems to be present at very low plasmatic levels in this species.

You are right about cortisol in rodents. However, corticosterone is abundant in rodents and binds very effectively to MR. In epithelial tissues, the MR is protected by the activity of 11beta dehydrogenase type 2. In humans, the myocardial expression of this enzyme appears to be minimal (JCEM 99:915-22, 2014) but levels may be upregulated, depending on the biological setting (Endocrinology. 2009;150:4270-7, 2009). You may want to examine these issues in your studies.