Inhibitors of the RAA System

Inhibitors of the RAA System
Angiotensin-converting enzyme (ACE)
is a component of the antihypotensive
renin-angiotensin-aldosterone (RAA)
system. Renin is produced by specialized
cells in the wall of the afferent arteriole
of the renal glomerulus. These
cells belong to the juxtaglomerular apparatus
of the nephron, the site of contact
between afferent arteriole and distal
tubule, and play an important part in
controlling nephron function. Stimuli
eliciting release of renin are: a drop in
renal perfusion pressure, decreased rate
of delivery of Na+ or Cl– to the distal tubules,
as well as -adrenoceptor-mediated
sympathoactivation. The glycoprotein
renin enzymatically cleaves the
decapeptide angiotensin I from its circulating
precursor substrate angiotensinogen.
ACE, in turn, produces biologically
active angiotensin II (ANG II) from
angiotensin I (ANG I).
ACE is a rather nonspecific peptidase
that can cleave C-terminal dipeptides
from various peptides (dipeptidyl
carboxypeptidase). As “kininase II,” it
contributes to the inactivation of kinins,
such as bradykinin. ACE is also present in
blood plasma; however, enzyme localized
in the luminal side of vascular endothelium
is primarily responsible for the
formation of angiotensin II. The lung is
rich in ACE, but kidneys, heart, and other
organs also contain the enzyme.
Angiotensin II can raise blood pressure
in different ways, including (1)
vasoconstriction in both the arterial and
venous limbs of the circulation; (2)
stimulation of aldosterone secretion,
leading to increased renal reabsorption
of NaCl and water, hence an increased
blood volume; (3) a central increase in
sympathotonus and, peripherally, enhancement
of the release and effects of
norepinephrine.
ACE inhibitors, such as captopril
and enalaprilat, the active metabolite of
enalapril, occupy the enzyme as false
substrates. Affinity significantly influences
efficacy and rate of elimination.
Enalaprilat has a stronger and longerlasting
effect than does captopril. Indications
are hypertension and cardiac
failure.
Lowering of an elevated blood pressure
is predominantly brought about by
diminished production of angiotensin II.
Impaired degradation of kinins that exert
vasodilating actions may contribute
to the effect.
In heart failure, cardiac output rises
again because ventricular afterload diminishes
due to a fall in peripheral resistance.
Venous congestion abates as a
result of (1) increased cardiac output
and (2) reduction in venous return (decreased
aldosterone secretion, decreased
tonus of venous capacitance
vessels).
Undesired effects. The magnitude
of the antihypertensive effect of ACE inhibitors
depends on the functional state
of the RAA system. When the latter has
been activated by loss of electrolytes
and water (resulting from treatment
with diuretic drugs), cardiac failure, or
renal arterial stenosis, administration of
ACE inhibitors may initially cause an excessive
fall in blood pressure. In renal
arterial stenosis, the RAA system may be
needed for maintaining renal function
and ACE inhibitors may precipitate renal
failure. Dry cough is a fairly frequent
side effect, possibly caused by reduced
inactivation of kinins in the bronchial
mucosa. Rarely, disturbances of taste
sensation, exanthema, neutropenia,
proteinuria, and angioneurotic edema
may occur. In most cases, ACE inhibitors
are well tolerated and effective. Newer
analogues include lisinopril, perindopril,
ramipril, quinapril, fosinopril, benazepril,
cilazapril, and trandolapril.
Antagonists at angiotensin II receptors.
Two receptor subtypes can be
distinguished: AT1, which mediates the
above actions of AT II; and AT2, whose
physiological role is still unclear. The
sartans (candesartan, eprosartan, irbesartan,
losartan, and valsartan) are AT1
antagonists that reliably lower high
blood pressure. They do not inhibit
degradation of kinins and cough is not a
frequent side-effect.