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Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense, Denmark
THE RENIN-ANGIOTENSIN SYSTEM (RAS) has a central place
in this journal because it integrates cardiovascular and renal function in the control of blood pressure and salt and volume homeostasis. The
classical controllers of renin release from the kidney are the following.
First, the macula densa mechanism, which couples the tubular chloride
concentration inversely to the plasma renin concentration (PRC) in the
rat (13). Local changes in RAS help determine the sensitivity of the tubuloglomerular feedback mechanism and the set
point for autoregulation of renal blood flow (29).
Second, the sympathetic nervous system, which stimulates renin
secretion through Third, the pressure-sensitive mechanism for renin release, whose
activation in vivo is associated with activation of the sympathetic nervous system (35) and release of hormones, such as
oxytocin, which stimulate renin release in rats via a Mice maintain a constant arterial pressure during alterations in sodium
intake by changing the activity of the RAS, and when the RAS is
clamped, the blood pressure becomes salt sensitive (5).
Technically, it is important that in mice RAS activity is better
correlated to PRC than plasma renin activity (PRA). Increasing sodium
intake in conscious mice inhibits PRC, plasma ANG II, and aldosterone,
but has no effect on PRA (5). In humans, too, a reduction
in RAS activity after an oral salt load explains the adaptation of salt
excretion to salt intake (1). In addition to its role in
long-term salt homeostasis, the RAS defends cardiovascular function in
acute hypotension and hypovolemia. Fainting in healthy volunteers after
exposure to lower body negative pressure is associated with a sluggish
response of the RAS (8).
Nitric oxide (NO) promotes salt excretion. Inhibition of NO synthase
(NOS) in conscious dogs increases blood pressure and decreases salt and
volume excretion independently of renin (25), and NO helps
to prevent salt-sensitive hypertension in the Dahl salt-resistant rat
and decreases salt sensitivity of blood pressure in the Dahl
salt-sensitive rat (34). The importance of NO and RAS in
pregnancy was emphasized by the demonstration of increased blood
pressure in pregnant mice with deletion of the endothelial NOS gene or
with four copies of the angiotensinogen gene or combinations of these
(9). The effect of NO on salt excretion is
probably not mediated by inhibition of renin secretion, because
enhancing NO's second messenger cGMP by inhibition of
phosphodiesterase-5 stimulates renin secretion (27). The
RAS and NO also interact in growth control. Thus pretreatment with NOS
inhibitors prevents the ability of angiotensin-(1-7)
to inhibit angiogenesis in the mouse (17).
In addition to salt excretion, water and sodium intake are also
affected by the RAS: ANG II stimulates water intake, and thirst evoked
by arterial hypotension in rats depends on pressure-sensitive renin
release (30). Conversely, the ability of ANG II to
stimulate thirst is inhibited by increases in arterial pressure
(31). Administration of DOCA and
intracerebroventricular infusion of renin result in elevated sodium
intake (20).
Central administration of ANG II increased blood pressure in conscious
rats (2) and sheep, where inhibition of renal sympathetic nerve activity and PRA was also seen (19). In conscious
dogs with one kidney denervated, ANG II infusion caused sodium
retention. Sodium excretion from the innervated kidney was higher, but
after arterial baroreceptor denervation it was lower, suggesting that baroreflexes inhibit renal sympathetic nerve activity during ANG II-induced hypertension and that, in the absence of these reflexes, ANG
II had sustained renal sympathoexcitatory effects (14). The effects of ANG II on dog kidney function are not mediated by
endothelin (3). In conscious rats, the gain of
baroreceptor-mediated bradycardia is increased by blockade of brain
AT2 receptors (36).
The constituents of the RAS are highly active in the fetal kidney. At
embryonic day 14, the metanephros contains renin and ANG II
and both ANG II receptors (AT1 and AT2). Renin
is found in cells scattered within the mesenchyme (24). A
functioning fetal and early postnatal RAS is a prerequisite for normal
nephrogenesis in the rat. Insulin-like growth factor (IGF)-I
may be critically involved in this process, because
angiotensin-converting enzyme (ACE) inhibition suppresses renal
IGF-I expression and treatment with IGF-I normalizes renal function and
histology after early ACE inhibition (23). In fetal sheep,
infusion of IGF-I increased renin synthesis and secretion
(18). In the sheep fetus, the concentrations of ANG I and
renin are higher than in the ewe, whereas the ANG II concentration is
comparable (22). Similar to the situation in the ewe,
infusion of ANG II into the fetus increases blood pressure and lowers
PRC and renin gene expression (21). The sympathetic
control of renin secretion is functional in the sheep fetus, because
denervation reduces the PRC, but it does not affect renal renin content
or expression (7). Furthermore, denervation does not
interfere with pressure control of renin release and synthesis
(26). Asphyxia is another stimulator of renin secretion in
the adult and has the same effect in fetal sheep (16). In
hydronephrotic neonatal rats, ANG II stimulates renal
TGF- Renin has been suggested to be involved in the hypertrophic responses
in hypertension and heart failure, but renin is clearly not mandatory
for this, because ventricular hypertrophy develops in a rat
salt-overload model with a suppressed renin system and stimulation of
the renin system by a low-sodium diet did not cause ventricular
hypertrophy (12). In heart failure, the falling blood
pressure and increased sympathetic activity activate the RAS, which
contributes to the salt and water retention. In rats with heart failure
induced by an aortocaval shunt, the activation of the sympathetic
nervous system was blunted by injection of an AT1
antagonist into the nucleus of the solitary tract (NTS), suggesting
that ANG II in the NTS contributes to the sympathetic activation
(28). In dogs with pacing-induced heart failure, a fixed
normal-level ANG II concentration led to a higher peripheral resistance, filtration fraction, and norepinephrine concentration. A
further increase in ANG II led to antinatriuretic,
sympathoexcitatory, and dipsogenic responses, suggesting that ANG
II plays a critical role in the transition from compensated to
decompensated heart failure (15).
Components of the RAS are also present and functional in fish. The
angiotensinogen gene is expressed in kidney and liver of rainbow trout,
and ACE inhibition causes vasodilation, an increased glomerular
filtration rate, and decreased water reabsorption
(4). On the other hand, there are also differences between
fish and mammals: in seawater-adapted eels, infusion of an ACE
inhibitor depressed drinking and arterial blood pressure independently
of plasma ANG II (32). The response may be explained by
the formation of bradykinin-like peptides, which unlike in mammals
inhibit drinking and increase blood pressure in the eel
(33).
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-adrenergic receptors on the juxtaglomerular cells
(6).
-adrenergic
receptor-dependent mechanism (10, 11).
1 expression through AT1 receptors and
clusterin expression via AT2 receptors. The latter response
is opposite to that of the adult rat, suggesting preponderance of
AT2 receptors in the developing kidney
(37).
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FOOTNOTES |
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10.1152/ajpregu.00625.2001
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