Ganong's Review of Medical Physiology, 23rd Edition

672
SECTION VIII
Renal Physiology

sodium is approximately 1 ng of angiotensin I generated per
milliliter per hour. The plasma angiotensin II concentration in
such subjects is about 25 pg/mL (approximately 25 pmol/L).

ACTIONS OF ANGIOTENSINS

Angiotensin I appears to function solely as the precursor of
angiotensin II and does not have any other established action.
Angiotensin II—previously called hypertensin or angioto-
nin—produces arteriolar constriction and a rise in systolic and
diastolic blood pressure. It is one of the most potent vasocon-
strictors known, being four to eight times as active as norepi-
nephrine on a weight basis in normal individuals. However, its
pressor activity is decreased in Na

• -depleted individuals and in
  patients with cirrhosis and some other diseases. In these condi-
  tions, circulating angiotensin II is increased, and this down-
  regulates the angiotensin receptors in vascular smooth muscle.
  Consequently, there is less response to injected angiotensin II.
  Angiotensin II also acts directly on the adrenal cortex to
  increase the secretion of aldosterone, and the renin–angiotensin
  system is a major regulator of aldosterone secretion. Addi-
  tional actions of angiotensin II include facilitation of the
  release of norepinephrine by a direct action on postganglionic
  sympathetic neurons, contraction of mesangial cells with a
  resultant decrease in glomerular filtration rate (see Chapter
  38), and a direct effect on the renal tubules to increase Na


• 
  

reabsorption.
Angiotensin II also acts on the brain to decrease the sensi-
tivity of the baroreflex, and this potentiates the pressor effect
of angiotensin II. In addition, it acts on the brain to increase

water intake and increase the secretion of vasopressin and

ACTH. It does not penetrate the blood–brain barrier, but it

triggers these responses by acting on the circumventricular

organs, four small structures in the brain that are outside the

blood–brain barrier (see Chapter 34). One of these structures,

the area postrema, is primarily responsible for the pressor

potentiation, whereas two of the others, the subfornical organ

(SFO) and the organum vasculosum of the lamina terminalis

(OVLT), are responsible for the increase in water intake (dip-

sogenic effect). It is not certain which of the circumventricu-

lar organs are responsible for the increases in vasopressin and

ACTH secretion.

Angiotensin III [(des-Asp

1

) angiotensin II] has about 40%

of the pressor activity of angiotensin II, but 100% of the aldos-

terone-stimulating activity. It has been suggested that angio-

tensin III is the natural aldosterone-stimulating peptide,

whereas angiotensin II is the blood-pressure-regulating pep-

tide. However, this appears not to be the case, and instead

angiotensin III is simply a breakdown product with some bio-

logic activity. The same is probably true of angiotensin IV,

though some researchers have argued that it has unique

effects in the brain.

TISSUE RENIN–ANGIOTENSIN SYSTEMS

In addition to the system that generates circulating angioten-

sin II, many different tissues contain independent renin–

angiotensin systems that generate angiotensin II, apparently

for local use. Components of the renin–angiotensin system are

found in the walls of blood vessels and in the uterus, the pla-

centa, and the fetal membranes. Amniotic fluid has a high con-

centration of prorenin. In addition, tissue renin–angiotensin

systems, or at least several components of the renin–angiotensin

system, are present in the eyes, exocrine portion of the pancre-

as, heart, fat, adrenal cortex, testis, ovary, anterior and inter-

mediate lobes of the pituitary, pineal, and brain. Tissue renin

contributes very little to the circulating renin pool, because plas-

ma renin activity falls to undetectable levels after the kidneys are

removed. The functions of these tissue renin–angiotensin

systems are unsettled, though evidence is accumulating that

angiotensin II is a significant growth factor in the heart and

blood vessels. ACE inhibitors or AT

1

receptor blockers are

now the treatment of choice for congestive heart failure, and

part of their value may be due to inhibition of the growth ef-

fects of angiotensin II.

ANGIOTENSIN II RECEPTORS

There are at least two classes of angiotensin II receptors. AT

1

receptors are serpentine receptors coupled by a G protein (G

q

)

to phospholipase C, and angiotensin II increases the cytosolic

free Ca

2+

level. It also activates numerous tyrosine kinases. In

vascular smooth muscle, AT

1

receptors are associated with ca-

veolae (see Chapter 2), and AII increases production of cave-

olin-1, one of the three isoforms of the protein that is

FIGURE 39–8
Diagrammatic representation of the structure
of the somatic form of angiotensin-converting enzyme.
Note the
short cytoplasmic tail of the molecule and the two extracellular cata-
lytic sites, each of which binds a zinc ion (Zn
2+
).
(Reproduced with
permission from Johnston CI: Tissue angiotensin-converting enzyme in cardiac and
vascular hypertrophy, repair, and remodeling. Hypertension 1994;23:258. Copyright
© 1994 by The American Heart Association.)

Extracellular

extension

Carboxyl terminal

catalytic site

Amino terminal

catalytic site

Trans-

membrane

domain

Intracellular

extension

COOH

Zn2+ Zn2+

NH 2