101and endothelial cells in the human heart [ 81 ], as well as in cardiac interstitium [ 82 ].
Its activity results in continuing conversion of angiotensin I to angiotensin II despite
effective ACE-I treatment, with apparently higher specificity for angiotensin than
ACE. Chymase-dependent mechanisms may be involved in progression of chronic
kidney disease [ 83 ] as well as adverse atrial and ventricular remodeling.
On the other hand, the involvement of neutral endopeptidase 24.11 in cleavage of
atrial natriuretic peptide and angiotensin II has been investigated, establishing that
inhibition of the enzyme modulates circulating levels of angiotensin II when basal
levels are above normal [ 84 ].
Therapeutic correlation Therapeutic targeting of RAAS system is currently being
redesigned by the inclusion of the alternate pathways for the generation of angioten-
sin peptides. Additionally, to renin inhibitors, dual inhibitors of ACE and endopep-
tidase 24.11 are being considered, as well as gene therapy or antibody treatment.
Intracellular RAAS
The recent discovery of locally generated angiotensin products (angiotensin II, III,
and IV and Ang 1–7) in several tissue and organs such as the brain, bone marrow,
adipose tissue, epididymis, carotid body, liver, and pancreas [ 85 ], together with new
evidence that the prorenin/renin molecule is an intracrine enzyme, has led to the
introduction of the concept of intracellular RAAS [ 86 ], which describes indepen-
dent intracrine/autocrine/paracrine subsystems located in tissues throughout the
entire organism, opposing the endocrine system paradigm [ 87 ]. Thus, RAAS sys-
tem is proving out to be a continuous process involving both large and small struc-
tures, with independent control at several levels. Recent evidence establishes that in
its structure enter four main axes: (1) the classical renin-ACE-angiotensin II; (2) the
prorenin-PRR-MAP kinase; (3) the ACE2-Ang 1–7/Mas receptor, with seemingly
antagonistic effect; and (4) the angiotensin IV-insulin-regulated aminopeptidase
[ 88 ]. The locally generated angiotensin peptides apparently have multiple and new
functions such as cell growth, antiproliferation, apoptosis, reactive oxygen species
generation, hormonal secretion, promotion of inflammation and fibrosis, and vaso-
constriction and vasodilation.
Although the pathophysiological functions of these systems have yet to be
described in detail, evidence indicates the involvement of tissue intracrine systems
in etiopathogeny of cardiovascular disease and in cardiovascular structural remodel-
ing [ 89 ]. There appears to be also an angiotensin-regulated synthesis of aldosterone
in the cardiac tissue, which indicates the possible existence of an RAAS local car-
diovascular system [ 90 ]. Experimental studies show that in diabetic conditions, the
cardiac intracellular RAAS is activated, increasing oxidative stress and cardiac
fibrosis [ 91 ]. Moreover, local RAAS seems to be involved in control of cell com-
munication and inward Ca(2+) current [ 92 ].
7 Pathophysiological Insights in Resistant Hypertension