98
Hence, the presence of the BMP system, which has been shown to stimulate
angiotensin II-induced aldosterone production, appears to be an event pertaining to
the aldosterone cellular escape pathway, triggered under the influence of long-term
ARB treatment [ 48 ]. Additionally, the role of the endothelin system is being inves-
tigated within the framework of chronic heart failure. It has been shown that endo-
thelin- 1 (ET-1) system functions as a stimulating factor for aldosterone secretion via
both A and B receptors, while the ET peptide ET-1(1–31) seems to be a contributor
to adrenocortical growth [ 49 ].
Therapeutic correlation Given the important role played by the ET-1 system in
the aldosterone escape pathway and the connection with secondary organ damages
associated with RH, the potential use of endothelin antagonists in the prevention of
cardiovascular disease is being discussed [ 50 ].
The main initiator of the escape process appears to be an important decrease in
the levels of thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted
tube, while concurrently increasing in the apical Na/H exchanger of the proximal
tubule (NHE3), events which have shown to be nitric oxide dependent [ 51 ].
Also related to the aldosterone homeostasis is the expression of human prostasin
transgene, which regulates the RAAS and kallikrein-kinin systems, and the circula-
tory levels of the atrial natriuretic peptide [ 52 ], although further research is neces-
sary in order to enable their possible therapeutic targeting [ 53 ].
Finally, oxidative stress is a contributing factor which mediates the pathogenesis
of chronic cardiovascular and renal damage associated to the malfunctions in the
RAAS system and aldosterone homeostasis such as activation of the nuclear tran-
scription factor kappaB and stimulation of pathways and genes that promote vaso-
constriction, endothelial dysfunction, cell hypertrophy, fibroblast proliferation,
inflammation, excess extracellular matrix deposition, atherosclerosis, and thrombo-
sis [ 54 ].
Aldosterone/Renin Ratio
With respect to mineralocorticoid receptors, specialists differentiate two subtypes
of RH, associated with high and with normal plasma levels of aldosterone. The first
subtype is characterized by primary aldosteronism, obstructive sleep apnea, aldoste-
rone escape mechanism previously described, and increased aldosterone/renin ratio
[ 55 ], with increased plasma aldosterone levels, but without primary aldosteronism
features. The second subtype of hypertension is described by obesity, diabetes mel-
litus, chronic kidney disease, and polycystic ovary syndrome, and it is mediated by
mineralocorticoid receptor activation through individual MR pathways.
Primary aldosteronism holds a special position in the physiopathology of resis-
tant hypertension since it seems to be particularly characteristic for this subgroup of
patients, therefore providing potential grounds for designing a screening protocol.
Moreover, as advances in identifying confirmatory testing, subtype differentiation
A. Burlacu and A. Covic