- Overview:
Biosynthesis
- Renin catalyzed
conversion of angiotensinogen to
angiotensin I
- Conversion of
angiotensin I to angiotensin II by
converting enzyme
- Degradation of
angiotensin II by peptidases
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- Renin/Regulation of renin secretion:
- Renin:
- aspartyl protease
(catalyzes the conversion of angiotensinogen
 angiotensin
I (decapeptide)
- preprohormone prohormone Renin {glycoprotein}
- Most circulatory
renin is synthesized in the
kidneys
- Nephron
synthetic and storage
site: juxtaglomerular
apparatus
- afferent
and efferent arterioles } contain
granular cells
(juxtaglomerular cells --
synthetic, storage, and
renin release site)
- macula densa-- specialized
tubular segment:
associated with
juxtaglomerular vascular
elements
- Afferent
and efferent arterioles
and macula densa are
innervated by the
adrenergic system
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- Primary determinants
of renin-angiotensin system
activity:
- Renin secretion
rate.
- controlled
by:
- macula
densa
- influenced
by changes in rate of
sodium or chloride
delivery to the distal
tubule: decreased
delivery, increased renin
secretion; increased
delivery, decreased renin
secretion
- Mechanism
of Action:
Na/K/2Cl co-transporter
-- sensitive to luminal
chloride concentration
changes.
- renal
vascular receptor-- afferent
arteriole
- stretch
receptor: less stretch,
increased renin release;
more stretch, decreased
renin release
- angiotensin
II:
- Inhibits
renin secretion:
- Mechanism
of Action: direct peptide
effect on juxtaglomerular
cells {negative feedback}
- Interference
with this negative
feedback system results
in increased renin
secretion
- sympathetic
nervous system
- Increased
renal nerve activity:
increased renin secretion
- Norepinephrine
(direct
action on juxtaglomerular
cells) increases renin
release.
- usually b 1
adrenergic
receptor mediated
- Norepinephrine
may increase renin
release indirectly
through a receptor
activation -- {
norepinephrine-mediated
afferent arteriolar
vasoconstriction
activates the renal
vascular receptor and
decreases sodium chloride
delivery to the macula densa.}
- Rate
of renin secretion:
affected by circulating
catecholamines
- Drug
Effects:
- Stimulation:
- vasodilators
(hydralazine
(Apresoline),minoxidil
(Loniten), nitroprusside
sodium (Nipride))
- beta
adrenergic receptor
agonists (isoproterenol
(Isuprel))
- alpha
adrenergic antagonists
- diuretics
- anesthetics
- Inhibition:
- Sympatholytics
(blockade of renin
secretion)
- Renin
Inhibitors (competitive
blockade)
- Converting
Enzyme Inhibitors
- Angiotensin
Antagonists (e.g.,
losartin -- AT1
receptor blocker)
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- Angiotensinogen
- Renin
acts on angiotensinogen protein
substrate to form angiotensin I
- Angiotensinogen:
- synthesized
in liver
- important
factor in angiotensin
formation rate
- Angiotensinogen
production enhanced by:
- corticosteroids
- estrogens
- thyroid
hormones
- angiotensin
II
- Pregnancy,
estrogen-containing oral
contraceptives, glucocorticoid
use, and Cushing's syndrome
produce both an increase in
angiotensinogen concentration and
hypertensive states. There may be
a cause-effect relationship.
- Angiotensin I
- Very
limited biological activity:
- May
be converted to angiotensin II by
converting enzyme
OR
- May
be converted to
[des-ASP]-angiotensin I by plasma
or tissue aminopeptidases;
- [des-ASP]-angiotensin
I may be converted to angiotensin
III
by converting enzyme
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- Converting
Enzyme (peptidyl
dipeptidase [PDP], Kininase II)
- Catalyzes
dipeptide cleavage from carboxyl
terminal of some peptides.
- Important
substrates
(angiotensin II is not a
substrate):
- angiotensin I
angiotensin II
- bradykinininactivation
- Tissue
Localization: vascular
endothelial cell luminal surfaces
- Angiotensinase:
- Catabolizes
angiotensin II
- Enzyme
localization: -- vascular beds
(except pulmonary)
- Most
angiotensin II metabolites: in
active -- exception:[des-ASP]-angiotensin
II
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