Renin – Angiotensin –
Aldosterone System
Activation of the renin – angiotensin –
aldosterone system is an important mechanism in the pathophysiology of heart
failure as part of the counter-regulatory neurohormonal response to impaired
cardiac output. In conjunction with sympathetic drive, there is an increase in
peripheral vasoconstriction mediated by increased sympathetic tone and
angiotensin II coupled with the salt and water retention induced by elevated
aldosterone concentrations. Together, these increase preload and afterload on
the heart, further compromising impaired ventricular function and setting up a
vicious circle of heart failure.
Angiotensin – converting enzyme
inhibitor drugs (ACE inhibitors) block this increase in aldosterone production
and are effective drugs in the clinical management of chronic heart failure. In
randomized controlled trials, ACE inhibitors have been shown to improve
symptoms and reduce the incidence of further cardiac events including hospital
readmission for heart failure, myocardial infarction and death.
Renin
Renin is synthesized and stored in the
juxtaglomerular cells of the kidney. These are located in the walls of
the afferent arterioles which supply the glomeruli (Fig. 36a). These
arterioles also contain baroreceptors, which fire off in response to
changes in flow rate and pressure. The cells of the macula densa are
sensitive to changes in urinary cations such as Ca2+, Na2+
and Cl−. The afferent arterioles, the juxtaglomerular cells and the
macula densa are together termed the juxtaglomerular apparatus.
Release. Renin is an enzyme with a molecular weight of
about 40 kDa which is released in response to a rise in blood osmolarity or to
hypovolaemia, although there are different theories as to what the
physiological stimuli to release are. The theories are that:
1. the macula
densa cells monitor changes in cations and pass this information to the
adjacent juxtaglomerular cells;
2. the
baroreceptors in the afferent arterioles fire off in response to changes in the
mean renal perfusion pressure (the baroreceptors may be part of the
juxtaglomerular cells themselves);
3. there is
autonomic innervation of juxtaglomerular cells (sympathetic stimulation
releases renin).
It is possible that all three theories
are significant in the regula- tion of renin release.
Action. Renin cleaves angiotensinogen to angiotensin I in
the plasma and kidney (Fig. 36b). Angiotensinogen is a globulin with a
molecular weight of about 60 kDa, which is synthesized continuously in the
liver and released in the circulation. Angiotensin I is converted into the
biologically active form, the octapeptide angiotensin II, by a
converting enzyme which occurs in plasma, vascular endothelial cells, kidney,
lung and many other tissues. Angiotensin-converting enzyme (ACE) has another
function in the inactivation of a potent vasodilator called bradykinin.
Angiotensin II
Angiotensin II is the most potent
natural vasoconstrictor so far discovered. The hormone is rapidly inactivated
by angiotensinase enzymes in the peripheral capillaries. One of the break-down
metabolites, called angiotensin III, occurs in large amounts in the
adrenal gland, and has been found to stimulate aldosterone release without
significant vasopressor effect. Angiotensin III is a heptapeptide, resulting
from the removal of the N-terminal aspartic acid from angiotensin II.
Actions of angiotensin II
1 Vascular
smooth muscle and heart. Angiotensin
II has a potent and direct vasoconstrictor effect on vascular muscle, and plays
a critical role in the regulation of arterial blood pressure. There are marked
regional differences in constrictor responses to angiotensin II in different
vascular beds. Blood vessels in the kidney, mesenteric plexus and the skin are
highly responsive to angiotensin II, while those in the brain, lungs and
skeletal muscle respond less to administered peptide. In the heart,
angi-otensin II acts on atrial and ventricular myocytes during the plateau
phase of the action potential, to increase Ca2+ entry through
voltage-gated channels, thereby prolonging the action potential, which
increases the force of contraction of the heart.
2 Kidney.
Angiotensin II regulates
glomerular permeability, tubular Na+ and water reabsorption and
renal haemodynamics. Angiotensin II has three important renal actions:
(a) It constricts
the renal arterioles, especially the efferent arterioles, which lowers the
glomerular filtration rate proportionately more than renal blood flow. This
causes an increase in the osmolarity of blood feeding into the peritubular
capillaries, which drives solutes and water back into the tubular cell and
thence to the bloodstream.
(b) Angiotensin II has been shown to constrict
glomerular mesangial cells, which also contributes to the fall in glomerular
filtration rate.
(c)
Angiotensin
II has a direct action on the tubule cells to stimulate Na+ reabsorption.
3 Adrenal cortex. Angiotensin II alone, or through conversion to angiotensin III, acts on the
glomerulosa cells to increase aldosterone synthesis.
4 Nervous system. Angiotensin II binds to specific presynaptic receptors on sympathetic nerve
terminals to enhance norepinephrine release. It has been shown to depolarize
adrenal medullary chromaffin cells, causing release of epinephrine, and, when
injected directly into the brain, causes an increase in salt and thirst
appetite. Angiotensin stimulates vasopressin release from the posterior
pituitary gland, an
effect potentiated by dehydration.
5 Water absorption. Angiotensin II stimulates Na+ and water
absorption from the lumen of the gastrointestinal tract (GIT) at low doses.
During dehydration, haemorrhage or salt loss, angiotensin II acts on the small
intestine to limit loss, while aldosterone acts predominantly upon the large
intestine to limit loss.
6 Cell proliferation. Angiotensin II has been shown to have trophic
effects on smooth muscle vascular cells, fibroblasts, adrenocortical cells and
human fetal kidney mesangial cells. The peptide appears to stimulate the
production of specific proteins such as α-actin, and may play a role in repair
following vascular injury.
Receptor subtypes. Angiotensin II receptor subtypes have been
discovered using different analogues of angiotensin II. The AT1 receptor,
acting through G proteins and the IP3 second messenger system, mediates the
increase in blood pressure in extracellular volume and cell proliferation. The
AT2 receptor may mediate cell proliferation.
Tissue distribution of receptor
subtypes. Aortic smooth muscle
cells, GIT, kidney, liver, lung, placenta and urinary bladder express
exclusively AT1 receptors. Both AT1 and AT2 receptors are expressed in the
brain, where AT1 receptors may mediate the central actions of angiotensin II on
blood pressure, water and electrolyte balance, the renal arterioles, adrenal
cells, heart and uterus. There is evidence for the existence of even more
subtypes of angiotensin II receptors.
More recent studies have identified
the presence of angiotensin II receptors on the nuclear membrane of
cardiomyocytes, which activate NFk ß expression. This suggests a role for angiotensin
directly on cardiac function.
