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

those of the lung and skeletal muscle. Nevertheless,
high circulating concentrations of AngII may decrease
cerebral and coronary blood flow.
Enhancement of Peripheral Noradrenergic Neurotransmission.
AngII augments norepinephrine release from sympathetic
nerve terminals by inhibiting the reuptake of norepinephrine
into nerve terminals and by enhancing the
vascular response to NE (see Chapter 12). High concentrations
of the peptide stimulate ganglion cells directly.
Effects on the CNS. Small amounts of AngII infused
into the vertebral arteries cause an increase in arterial
blood pressure. This response— mediated by
increased sympathetic outflow— reflects effects of the
hormone on circumventricular nuclei that are not protected
by a blood-brain barrier (e.g., area postrema,
subfornical organ, organum vasculosum of the lamina
terminalis). Circulating AngII also attenuates
baroreceptor- mediated reductions in sympathetic discharge,
thereby increasing arterial pressure. The CNS
is affected both by bloodborne AngII and by AngII
formed within the brain, where it may serve as a neurotransmitter.
The brain contains all components of
the RAS. In addition to increasing sympathetic tone,
AngII also causes a centrally mediated dipsogenic
(thirst) effect and enhances the release of vasopressin
from the neurohypophysis.
Release of Catecholamines from the Adrenal Medulla.
AngII stimulates the release of catecholamines from the
adrenal medulla by depolarizing chromaffin cells.
Slow Pressor Response
Alteration of Renal Function. AngII has pronounced
effects on renal function, reducing the urinary excretion
of Na + and water while increasing the excretion of
K + . The overall effect of AngII on the kidneys is to
shift the renal pressure–natriuresis curve to the right
(Figure 26–7).
Direct Effects of Angiotensin II on Na + Reabsorption in the
Renal Tubules. Very low concentrations of AngII stimulate
Na + /H + exchange in the proximal tubule— an effect that
increases Na + , Cl – , and bicarbonate reabsorption.
Approximately 20-30% of the bicarbonate handled by the
nephron may be affected by this mechanism. AngII also
increases the expression of the Na + –glucose symporter in
the proximal tubule (Bautista et al., 2004). Paradoxically,
at high concentrations, AngII may inhibit Na + transport
in the proximal tubule. AngII also directly stimulates the
Na + –K + –2Cl – symporter in the thick ascending limb. The
proximal tubule secretes angiotensinogen, and the connecting
tubule releases renin, so a paracrine tubular RAS
may contribute to Na + reabsorption.
Urinary Na +
excretion
High salt
intake
Normal salt
intake
Low salt
intake
Renin
Renin
set
point
Mean arterial blood pressure
Figure 26–7. Pressure-natriuresis curve: effects of Na + intake on
renin release (AngII formation) and arterial blood pressure.
Inhibition of the renin-angiotensin system will cause a large drop
in blood pressure in Na + -depleted individuals. (Modified with
permission from Jackson EK, Branch RA, et al: Physiological
functions of the renal prostaglandin, renin, and kalikrein systems,
in Seldin DW, Giebisch GH, eds: The Kidney: Physiology
and Pathophysiology, Vol 1. Philadelphia: Lippincott Williams &
Wilkins, 1985, p 624. http://lww.com.)
Release of Aldosterone from the Adrenal Cortex. AngII stimulates
the zona glomerulosa of the adrenal cortex to
increase the synthesis and secretion of aldosterone, and
augments responses to other stimuli (e.g., ACTH, K + ).
Increased output of aldosterone is elicited by concentrations
of AngII that have little or no acute effect on blood
pressure. Aldosterone acts on the distal and collecting
tubules to cause retention of Na + and excretion of K + and
H + . The stimulant effect of AngII on aldosterone synthesis
and release is enhanced under conditions of hyponatremia
or hyperkalemia and is reduced when concentrations of
Na + and K + in plasma are altered in the opposite directions.
Altered Renal Hemodynamics. AngII reduces renal blood
flow and renal excretory function by directly constricting
the renal vascular smooth muscle, by enhancing
renal sympathetic tone (a CNS effect), and by facilitating
renal adrenergic transmission (an intrarenal effect).
AngII- induced vasoconstriction of preglomerular
microvessels is enhanced by endogenous adenosine
owing to signal- transduction systems activated by AT 1
and the adenosine A 1
receptor (Hansen et al., 2003).
AngII influences glomerular filtration rate (GFR)
by means of several mechanisms:
• constriction of the afferent arterioles, which reduces
intraglomerular pressure and tends to reduce GFR
• contraction of mesangial cells, which decreases the
capillary surface area within the glomerulus available
for filtration and also tends to decrease GFR
• constriction of efferent arterioles, which increases
intraglomerular pressure and tends to increase GFR
729
CHAPTER 26
RENIN AND ANGIOTENSIN