Transcript Blood Pressure Controls

Biology 319/519, Endocrinology
Fall 2008
Blood Pressure Controls:
Vasopressin,
Atrial Natriuretic Peptides
&
The Renin-Angiotensin- Aldosterone
Axis
Blood pressure is primarily maintained in
vertebrates by the balanced function of three
systems:
Vasopressin (VP, Anti-diuretic Hormone, ADH)
which controls water balance by regulating the
loss and elimination of water into urine,
The Renin-Angiotensin-Aldosterone (RAA)
cycle which regulates the amount of sodium
ion (Na+) lost and eliminated in urine,
And, the production of Atrial Natriuretic
Peptides (ANF, ANP) that counter the actions
of VP and the RAA system.
Physical Chemistry States that for a fluid-filled
rigid system there is a reciprocal relationship
between pressure and volume:
if the volume decreases, pressure increases
if volume increases, pressure decreases:
P1V1 = P2V2.
So, it should be possible to decrease blood
pressure by increasing the volume of the
circulatory system or by decreasing the volume
of fluid within a circulatory system of the same
size.
Note: In an elastic system like blood vessels, the
overall size of the system responds to the volume
of its contents somewhat like a balloon with a
minimal and maximal overall size. It also
responds to access to vessels that can be
controlled by muscles. In blood vessels, if
something decreases the volume of the blood in
the open vessels the pressure will decrease
because the size of the overall system decreases
only to its lower limit before the pressure exerted
by the fluid falls relative to what it would be if the
vessel were filled just to that lower limit.
Similarly, if something increases the volume of
blood in the open vessels the vessels will expand
to their limit and then the pressure will increase.
So what alters overall circulatory system size?
Overall system growth, selective growth of vessels
stimulated by angiogenic factors, e.g., in tumors or
expanding fat tissues.
Actions of nerves or adrenal medullary hormones
(epinephrine, norepinephrine): These may constrict
blood vessels like those at the body surface when
exposed to cold – thereby preserving blood flow to
central organs and restricting heat loss. And/or,
they may open capillary beds in internal organs like
the kidney to preserve perfusion. They may also
restrict venous outflow allowing local blood
accumulation, e.g., during penile erection, while
forcing systemic blood pressure decline.
What alters blood volume?
Removing H2O from the body decreases the volume
of blood; i.e., failing to retain H2O by failing to retrieve
it from urine when that is concentrated in the kidney
causes blood volume to decrease along with blood
pressure. VP/ADH stimulates the kidney distal
tubules to recapture the H2O in urine passing through
the tubules.
Increasing the osmotic or ionic content of blood will
increase blood volume by drawing H2O from body
tissues to dilute dissolved materials, e.g., glucose, or
ions, e.g., Na+. Sodium ion recovery from urine is
stimulated by the Renin-Angiotensin-Aldosterone
system which is stimulated by low blood pressure.
How are changes in blood pressure detected?
Brain, heart, & kidney respond to changes in
blood pressure via pressure receptors,
baroreceptors, & to changes in ionic
composition of blood via osmoreceptors.
Baroreceptors exist in large blood vessels, heart,
& the kidney glomerulus (maculodensa).
Osmoreceptors occur in hypothalamic &
glomerulus (juxtaglomerular) cells.
When osmolality is high or when
atrial pressure is low, VP release
is increased from the posterior
pituitary & VP stimulates
reuptake of water from urine in
the kidney. This is blocked by
ANF when osmolality falls or
artrial pressure rises.
Simultaneously, when the
kidney juxtaglomerular
apparatus detects a drop in
renal blood perfusion pressure
or a fall in blood sodium levels,
it increases production of the
enzyme renin. This acts to
elevate angiotensins I & II which
increases aldosterone which
stimulates sodium reuptake
from urine in the kidney distal
tubules. Renin & aldosterone
production is opposed by ANF
as blood volume & pressure
rise.
Left modified from Figure 47-4, p786, in Robert M. Berne & Matthew N. Levy, Physiology, 2nd Ed., C.V. Mosby Co.: St. Louis, MO, 1988;
right modified from Figure15.9, p373, in Mac E. Hadley, Endocrinology, 5th Ed., Prentice Hall: Upper Saddle River, NJ, 2000.
The specialized cells of the juxtaglomerular apparatus are found surrounding the
afferent arteriole (primarily) as well as in the portion of the ascending limb of the
distal convoluted tubule that most closely approaches the glomerulus. The
juxtaglomerular cells sense arteriole BP while the macula densa cells in the tubule
sense urinary Na+ & Cl-. These cells communicate with one another & produce
renin when arteriole BP falls, epinephrine is elevated, or when urinary ions fall.
The glomerulosa
layer of the adrenal
cortex responds to
Angiotensin II by
increasing
aldosterone
production. Other
controls include
direct ion effects,
inhibition by ANP, &
secondary control
by ACTH from the
corticotrope which
links the stress axis
including CRH to BP
control. More direct
links to stress are
neural via actions
on adrenal medulla
& cardiac rate.
Renin is an enzyme produced by the kidney glomerular apparatus that cuts
the protein angiotensogen from liver to produce a decapeptide angiotensin I.
This is cut by a second enzyme from lung & kidney, angiotensin converting
enzyme, ACE, to produce angiotensin II an octapeptide that is a powerful
vasoconstrictor & stimulator of aldosterone production. ACE inhibitors are
drugs that reduce BP. (How would that work?)
Angiotensin II can be inactivated by angiotensinases. While it is active
it stimulates aldosterone production by the adrenal cortical outer layer
& selectively alters blood flow through capillary beds by constricting
vascular smooth muscles. The latter actions complement those of
bradykinin & several other vasoconstrictor peptides.
Interestingly, the
same enzyme
(kallikrein) cleaves
the precursor forms
of renin & the
vasodilator kinin
while a second
enzyme (ACE)
processes both
angiotensin I and
kinin. Kallikrein
activates both
substrates while ACE
activates the
hormonally inactive
antiotensin I but
inactives kinin.
Note that locally
produced
prostaglandins may
be direct stimulators
of kallikrein actions.
The interconnected control loop for BP control by the RAA system is
depicted including the intervening roles of the enzymes kallikrein & renin,
the vasodilator bradykinin, the local hormones prostaglandins, the
vasoconstrictor angiotensin II, & the steroid aldosterone. The actions of
the vasoactive peptides are restricted to selected responsive vascular
elements, not all blood vessel respond to all agents.
Aldosterone is a
chemically labile steroid
with a short half life in
serum; it does not bind
to a carrier protein. It
acts via a nuclear,
mineralocorticoid (MCR),
receptor in the cuboidal
cells of the kidney distal
tubule. The receptor
binds equally well to
cortisol. Receptor
activation stimulates
synthesis of multiple
systems that synergize
with one another to
move Na+ from the
lumen of the kidney
tubule back into the
intracellular fluid &
blood at the serosal
surface of the cells.
But what about cortisol (normally very high in circulation
& required for glucose homeostasis) activating the MCR?
The paradox is resolved by aldosterone target cells expressing 11-steroid
oxoreductase which converts cortisol to cortisone a steroid that does not
bind to the MCR. Mutations in the oxoreductase enzyme may result in
persistent hypertension because cortisol now can activate the MCR.
The production & role of the ANPs (including
BNP) are shown here. These are made by
granular cells of the heart atria as a series of
peptides that counter the actions of VP/ADH &
the RAA system. Though natural BP reducers
they are not widely employed clinically.
Richard E. Klabunde
Cardiovascular Physiology Concepts: Atrial and Brain Natriuretic Peptides,
http://www.cvphysiology.com/Blood%20Pressure/BP017%20ANP%20new.gif
Such peptides are often chemically labile & may produce
actions besides those of primary interest. The complete
role of ANP and its relatives in BP control under
physiological conditions has not yet been fully defined.
In considering BP control, think about what
would happen in the short and long term,
minutes vs hours.
Consider the effect of rapid blood loss by
hemorrhage. What effect would burns have?
Would decreasing salt in the diet do anything
and how?
Might altering adrenal cortical steroid output do
anything?
How might adding a lot of fatty tissue to the
body alter BP via the systems mentioned?