97cascade renin-angiotensinogen-angiotensin I-angiotensin II-aldosterone. The mere
understanding of these molecules of the location for their initial (and prevalent)
synthesis and knowledge of currently used drug classes (recommended by guide-
lines) in the therapeutic targeting of the RAAS does not provide any more a com-
plete grasp on the multifaceted aspects of its deficient functioning in RH.
Thus, studies have shown that, once treatment with one of RAAS modulators is
initiated, various escape mechanisms are triggered, which are far less known and
investigated and which will represent the center of our discussion onward.
Firstly, pathological changes involving aldosterone extend far beyond dysregula-
tions in the sodium and potassium balance, inflammation, cardiovascular remodel-
ing, and renal injury [ 38 ]. Vascular smooth muscle cell hypertrophy and hyperplasia,
vascular matrix impairment, endothelial dysfunction, decreased vascular compli-
ance, increased peripheral vascular resistance, impaired autonomic vascular con-
trol, myocardial norepinephrine release, and decreased serum high-density
lipoprotein cholesterol represent all consequences of aldosterone-impaired function
[ 39 ]. These actions occur through both mineralocorticoid-dependent and
mineralocorticoid- independent pathways, and they are either delayed (genomic)
mechanisms or rapid (nongenomic) [ 40 ]. While some of these effects may be com-
pensated by chronic treatment with angiotensin-converting enzyme inhibitors
(ACE-I) and angiotensin receptor blockers (ARB), research has shown that there
exists an escape mechanism which brings aldosterone concentrations back to base-
line value, possibly reversing the beneficial effects of the treatment on left ventricu-
lar hypertrophy [ 41 ] and increasing renal damage for patients with type 2 diabetes
mellitus [ 42 ].
There appears to be a secondary synthesis site besides the adrenal cortex at the
vascular level.
Studies have recorded the angiotensin II reactivation and aldosterone escape dur-
ing treatment with ACE-I or ARB [ 42 ], possibly due to accumulation of renin and
angiotensin I and to the recently discovered renin-dependent but ACE-independent
pathways, which account for 30 to 40% of angiotensin II formation in the normal
status. However, experimental studies have shown that the direct renin-prorenin
interaction has no direct contribution to the increasing aldosterone levels, which
indicates that there exists also and angiotensin II escape pathway involved [ 43 ].
Furthermore, it appears that ACE gene polymorphisms [ 44 ] intervene in the ade-
quate regulation of the neurohormonal response to long-term treatment, involving
the angiotensin II type 2 receptor (AT2R) [ 45 ], which, although its functional effects
are still unclear, influences hemodynamic function and circulating RAS mediators.
Moreover, for chronic heart failure patients, a higher prevalence of the DD pheno-
type for ACE has been described [ 46 ].
The same receptor is the main character in the escape pathway for ARB treat-
ment, which is related to an AT2R-dependent mechanism correlated with target-
organ damage in animal models. Recent studies investigate the involvement of
proteins expressed by the extracellular matrix in the adrenal cortex, such as bone
morphogenetic protein (BMP) [ 47 ] and endothelin-1 (ET-1) in the design and func-
tion of the aldosterone escape pathway.
7 Pathophysiological Insights in Resistant Hypertension