The renin–angiotensin system (RAS; ) is a multi-step peptidergic system by which circulating angiotensinogen, a liver-derived α-glycoprotein derived from liver and other sources such as the kidney, adipose tissue and the heart,1
is cleaved by renin, the rate limiting step in the biological cascade, to form the decapeptide angiotensin (Ang) I. In turn, AngI is transformed by angiotensin-converting enzyme (ACE), a membrane-bound metalloproteinase expressed in high concentrations on the surface of pulmonary endothelial cells,1
into the octapeptide AngII, the final effector of the RAS. The endocrine RAS, as above summarized, works in concert with local RASs, ie, self-contained, functionally autonomous AngII-generating systems in the heart, the nervous system, reproductive organs, and in interaction with other biological systems, eg, endothelins or nitric oxide.2
The renin–angiotensin system and cascade of bioactive angiotensins.
Most of the cardiovascular effects of AngII are mediated by G coupled type 1 receptors (AT1Rs) expressed in the vascular wall and organs such as liver, adrenals, brain, lung, kidney and the heart, that coexist with type 2 receptors mediating vasodilatation, inhibition of cell growth/proliferation and proapoptosis.3
(Pro)renin receptors, which accelerate renin catalytic properties, activate circulating prorenin and stimulate AngII-independent intracellular signaling pathways, have recently been identified4
whose more thorough understanding will likely unveil additional pathophysiologic facets of the RAS as a whole ().
Schematic representation of the classical renin–angiotensin system (RAS) and of the emerging concept integrating the (pro)renin receptor and the blocking of the system at different steps by pharmacological compounds.
Each step of the biological cascade leading to AngII, the biological effector of the system, can be pharmacologically inhibited by renin inhibitors such as aliskiren, ACE inhibitors (ACEIs) and All AT1R blockers (ARBs) (), these latter triggering a compensatory renin rise due to the disruption of the feedback inhibition of renin production.1
The increase in renin activity stimulates the conversion of Ang I and Ang II, which may limit the efficacy of RAS inhibition3
and the increased renin can also activate the prorenin/renin receptor causing renal and cardiovascular damages independent of Ang II4
(). ARBs constitute a heterogeneous pharmacological class () sharing AT1R antagonism5
as a common feature whose clinical profile has been clarified by several published randomized clinical trials7
() in hypertension, cardio-, cerebrovascular disease, diabetes, and others either completed30
or on their way to completion31
will further expand our knowledge on this topic.
Main pharmacokinetic characteristics of the available ARBs
Acronyms of completed and ongoing randomized controlled clinical trials with ARBs
Although primarily ascribable to AT1R antagonism of the vascular, neurohormonal and renal effects of blood-borne and locally produced AngII,1
the therapeutic effect of ARBs may be compounded by “pleiotropic” mechanisms related to modulation of the multiform effects of AngII on vascular cells () by which the peptide may accelerate the onset and progression of atherosclerotic vascular disease.33
Growing evidence, in fact, demonstrates the cytokine-like potential of locally-synthesized AngII to act in a paracrine, autocrine, and possibly intracrine manner to promote vascular inflammation, a main component of the atherogenic process (see below). That interesting possibility, generated by a consistent series of in-vitro
and animal studies, has stimulated a number of clinical studies focusing on the effect of ARBs on circulating inflammatory indices34
that this paper will discuss.
Effects of angiotensin II on vascular cellular biology.