DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Renin and Angiotensin
Randa Hilal-Dandan
The renin–angiotensin system (RAS) participates significantly
in the pathophysiology of hypertension, congestive
heart failure, myocardial infarction, and diabetic
nephropathy. This realization has led to a thorough
exploration of the RAS and the development of new
approaches for inhibiting its actions. This chapter discusses
the biochemistry, molecular and cellular biology,
and physiology of the RAS; the pharmacology of
drugs that interrupt the RAS; and the clinical utility of
inhibitors of the RAS. Therapeutic applications of
drugs covered in this chapter are also discussed in
Chapters 27 and 28.
THE RENIN–ANGIOTENSIN SYSTEM
History. In 1898, Tiegerstedt and Bergman found that crude saline
extracts of the kidney contained a pressor substance that they named
renin. In 1934, Goldblatt and his colleagues demonstrated that constriction
of the renal arteries produced persistent hypertension in
dogs. In 1940, Braun- Menéndez and his colleagues in Argentina and
Page and Helmer in the U.S. reported that renin was an enzyme that
acted on a plasma protein substrate to catalyze the formation of the
actual pressor material, a peptide, that was named hypertensin by
the former group and angiotonin by the latter. These two terms persisted
for nearly 20 years until it was agreed to rename the pressor
substance angiotensin and to call the plasma substrate angiotensinogen.
In the mid-1950s, two forms of angiotensin were recognized, a
decapeptide (angiotensin I [AngI]) and an octapeptide (angiotensin II
[AngII]) formed by proteolytic cleavage of AngI by an enzyme
termed angiotensin-converting enzyme (ACE). The octapeptide was
shown to be the more active form, and its synthesis in 1957 by
Schwyzer and by Bumpus made the material available for intensive
study.
It was later shown that the kidneys are important for aldosterone
regulation and that angiotensin potently stimulates the production
of aldosterone in humans. Moreover, renin secretion
increased with depletion of Na + . Thus, the RAS came to be recognized
as a mechanism to stimulate aldosterone synthesis and secretion
and an important homeostatic mechanism in the regulation of
blood pressure and electrolyte composition.
In the early 1970s, polypeptides were discovered that either
inhibited the formation of AngII or blocked AngII receptors. These
inhibitors revealed important physiological and pathophysiological
roles for the RAS and inspired the development of a new and broadly
efficacious class of antihypertensive drugs: the orally active ACE
inhibitors. Studies with ACE inhibitors uncovered roles for the RAS
in the pathophysiology of hypertension, heart failure, vascular disease,
and renal failure. Selective and competitive antagonists of
AngII receptors were developed that yielded losartan, the first orally
active, highly selective, and potent nonpeptide AngII receptor antagonist.
Subsequently, many other AngII receptor antagonists have
been developed. Recently aliskiren, a direct renin inhibitor, was
approved for antihypertensive therapy (see Chapter 27).
Components of the Renin–
Angiotensin System
Overview. AngII, the most active angiotensin peptide, is
derived from angiotensinogen in two proteolytic steps.
First, renin, an enzyme released from the kidneys,
cleaves the decapeptide AngI from the amino terminus of
angiotensinogen (renin substrate). Then, ACE removes
the carboxy- terminal dipeptide of AngI to produce the
octapeptide AngII. These enzymatic steps are summarized
in Figure 26–1. AngII acts by binding to two heptahelical
GPCRs, AT 1
and AT 2
.
The understanding of the RAS has expanded in
recent years. The current view of the RAS also includes
a local (tissue) RAS, alternative pathways for AngII
synthesis (ACE independent), formation of other biologically
active angiotensin peptides (AngIII, AngIV,
Ang[1–7]), and additional angiotensin binding receptors
(angiotensin subtypes 1, 2, and 4 [AT 1
, AT 2
, AT 4
];
Mas) that participate in cell growth differentiation,
hypertrophy, inflammation, fibrosis, and apoptosis. All
components of the RAS are described in detail in a later
section.
Renin. Renin is the major determinant of the rate of AngII production.
It is synthesized, stored, and secreted by exocytosis into the