11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes the inactivation of cortisol (F) to cortisone (E) in aldosterone target tissues, thereby protects mineralocorticoid receptor from F. Failure of 11β-HSD2 function is the basis of apparent mineralocorticoid excess, and its mild disturbances are suggested to lead to hypertension.
Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA).
A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy.
Administration of low-dose mineralocorticoid receptor antagonists (spironolactone or eplerenone) effectively ameliorates abnormal EPR function in hypertension.
Angiotensin II (AngII) and the mineralocorticoid receptor (MR) ligand aldosterone both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling.
Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disease resulting from mutations within the hydroxysteroid (11β-dehydrogenase2 [HSD11B2]) gene causing a prominent mineralocorticoid receptor activation by cortisol and hypokalemic low renin hypertension as the main clinical feature.
Based on considerations of well-established clinical efficacy in hypertension and heart failure with reduced ejection fraction and the shortcomings of aforementioned clinical trials in HFpEF, we argue that RAAS blockers including MRAs (mineralocorticoid receptor antagonists; aldosterone antagonists) should be used in the treatment of patients with HFpEF.
Because the plasma concentration of cortisol in humans is about 30-fold higher than that of corticosterone, these findings strongly suggest that cortisone is one of the endogenous steroids responsible for early-onset hypertension in men and nonpregnant women carrying the MR(L810) mutation.
Blockade of MR signaling with MR antagonists (MRAs) has been used clinically to treat kidney and cardiac disease associated with hypertension and other chronic diseases, resulting in suppression of fibrosis in these organs.
Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension.
Cautious intensification of diuretics with the use of aldosterone receptor antagonists deserves attention when both high blood pressure and sleep apnea coexist.
Clinical studies have shown the benefit of MR blockade in patients with left ventricular dysfunction and heart failure after myocardial infarction (MI), hypertension or diabetic nephropathy.
CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) expression stimulates the sodium retentive actions of the mineralocorticoid receptor causative of hypertension, probably by means of its ability to substantially increase the level of 6β-hydroxylase activity.
Despite the lack of survival benefit current available data suggest the use of ACEis, aldosterone receptor blockers as first-line therapy for HTN in patients with heart failure with preserved ejection fraction.