Hormonal Control of Urine
Production
Long- Term
Regulation of
Blood Pressure
and body fluid
volume,
concentration, and
composition!
1
How can we alter osmolality?
• How can you make a
fluid more
concentrated?
– Solute
– Solvent- this changes
volume
• How can you make a
fluid more dilute?
– Solute
– Solvent- this changes
volume
2
Hormonal regulation of Osmolarity
(And Blood Volume/Pressure)
• ADH-water control
• Angiotensin II- solute
and water control
• Aldosterone- solute
and water control
• Atrial Natriuretic
Peptide (ANP—a.k.a
atriopeptin)
3
ADH
• Made in hypothalamus
and released from
posterior pituitary
• Increases water
permeability of principal
cells and collecting ducts
• Increases activity of Na+K+-2Cl- transporter
• Increases urea
permeability of inner
medullary duct
4
Collecting Duct- tapping into the water reserve
How much water is left to reabsorb?
Tubular Cells
Tubular Lumen
H20 (depends
on ADH)
Aquaporin-3
H20
Aquaporins
ADH
cAMP
V2 receptor
Vesicle
Aquaporin-2
H20
More water reabsorbed=
concentrated, scant urine
Less water reabsorbed=
less concentrated,
5
copious urine
Copyright © 2006 by Elsevier, Inc.
Stimuli for ADH Secretion and Thirst
• Increased osmolarity
• Decreased blood volume
– (cardiopulmonary reflexes)
•
Decreased blood pressure
– (arterial baroreceptors)
• Other stimuli:
–
–
–
–
–
–
–
dryness of mouth
nausea
Fever
Burns
excessive sweating
vomiting, or diarrhea
severe blood loss
6
Factors that decrease
ADH and Thirst
•
•
Decreased osmolarity
Increased blood volume
(cardiopulmonary reflexes)
• Increased blood pressure
(arterial baroreceptors)
• Other factors:
– alcohol (inhibits ADH!!!)
– Gastric distention (inhibits
thirst)
A decrease in ADH means copious
amounts of urine of dilute
concentration
Urea
7
Regulation of Sodium and water
Balance: Angio II & Aldosterone
• The renin-angiotensin mechanism
triggers the release of aldosterone
• This is mediated by the
juxtaglomerular apparatus, which
releases renin in response to:
– Sympathetic nervous system
stimulation
– Decreased filtrate osmolality
– Decreased stretch (due to
decreased blood pressure)
• Renin catalyzes (ultimately) the Macula
production of angiotensin II, which
prompts aldosterone release
Sympathetic
nerve fiber
densa
Juxtaglomerular
cells
8
Renin-Angiotensin- System
Made by Liver
renin
ACE in lungs
9
Angiotensin II Increases Na+ and
Water Reabsorption
• Stimulates aldosterone release
• Directly increases Na+ reabsorption (proximal, loop, and in
principal cells of late distal convoluted tubules)
• Constricts efferent arterioles
– Helps to maintain GFR and decreases peritubular capillary
hydrostatic pressure
– more reabsorption
Ang II
Ang II
Na+
Na+
ATP
Interstitial
Fluid
K+
H+
Na+
HCO3-
Ang II
Tubular
Lumen
10
•
Regulation of Sodium/ Potassium Balance:
Aldosterone
Hyperkalemia and
hypokalemia can:
– Disrupt electrical
conduction in the heart
– Lead to sudden death
• Increased K+ in the ECF
(hyperkalemia) around the
adrenal cortex causes:
– Release of
aldosterone leads to
K+ secretion
• Potassium controls its
own ECF concentration
via feedback regulation of
aldosterone release
11
Late Distal Convoluted Tubule
Principal Cells
Na +
Na +
K+
Tubular Lumen
ATP
K+
Cl -
Aldosterone
When aldosterone levels are high, all
remaining Na+ is actively reabsorbed (last 8%)
Aldosterone stimulates potassium ion
secretion by principal cells
For each Na+ reabsorbed, a K+ is secreted
12
Copyright © 2006 by Elsevier, Inc.
Low K+ diet only
Alkalosis!
Normal or
high K+ diet
acidosis
13
Conn’s
• Hyperaldosteronism
• Hypernatremia
• Hypokalemia (low
potassium)
• Hypertension
Cushing’s
• Hyperadrenalism-too much
aldosterone and
glucocorticoids
• Hypernatremia
• hypokalemia
• Hypertension
• Increased glucocorticoid
production, resulting in excess
blood sugar levels (resembling
Diabetes Mellitus)
• Increased androgen
production, resulting in more
masculinizing signs
14
Addison’s Disease
• Primary adrenal
insufficiency –not enough
aldosterone and
glucocorticoids
• Hypoaldosteronism
• Low blood pressure
• Low sodium (hyponatremia)
• High potassium
(hyperkalemia)
• Mild acidosis
• Decreased glucocorticoid
hormones, low blood sugar
15
Inhibitors of Aldosterone
and Sodium Reabsorption
• Atrial natriuretic peptide (ANP)
• Increased Na+ concentration
•(osmolality)
ACE inhibitors (captopril, benazipril, etc)
• Ang II antagonists (losartan, etc.)
• decrease aldosterone
• directly inhibit Na+ reabsorption of “reserve”
• decrease efferent arteriolar resistance
Natriuresis and Diuresis +
Blood Pressure
16
Atrial Stretch Reflexes and ANP
• Located in the atria of the
heart.
• Released due to increased
ECF volume (stretch receptors
in atria detect increased
chronic venous return)
• ANP
– Vasodilation of afferent
arterioles
– Vasoconstriction of efferent
arterioles
– Increased GFR!
– directly inhibits Na+
reabsorption
– inhibits renin release (and
hence, angio II production) and
aldosterone formation
– Reduces ADH release
– helps to minimize blood
volume expansion through
potent diuretic and natriuretic
effects
17
We must separate solute from solvent! Where will
this occur in the nephron?
Formation of a
Concentrated Urineantidiuresis
• Continue electrolyte
reabsorption
• Increase water
reabsorption
• Maximal urine
concentration
= 1200 - 1400 mOsm / L
(specific gravity ~
1.030)
Formation of a Dilute
Urine-diuresis
• Continue electrolyte
reabsorption
• Decrease water
reabsorption
• Minimal urine
concentration
= 50 - 70 mOsm / L
(specific gravity ~
1.003)
18
Obligatory Water loss-Just how
concentrated can the urine get?
• The minimum urine volume in which the excreted solute
can be dissolved and excreted.
• Obligatory water loss reflects the fact that:
– Kidneys excrete 600-1400 mOsm of solutes to
maintain blood homeostasis
– Urine solutes must be flushed out of the body in
water Example:
If the max. urine osmolarity was 1200 mOsm/L,
and a minimum of 600 mOsm of solute must be
excreted each day to maintain electrolyte balance,
the obligatory urine volume is:
600 mOsm/d
1200 mOsm/L
= 0.5 L/day
19
Water, water everywhere
Nor any drop to drink
(Coleridge’s: The Rime of the ancient Mariner)
• Depending on the location, seawater
varies from 2000-2400mOsm (8x
that of plasma!)
• You are dehydrated from being at
sea-you drink 1L of seawater
(2400mOsmoles!)
• Your blood plasma now has a higher
osmolality.
• Maximum you can concentrate your
urine ~1200mOsm-don’t forget the
600mOsmoles you MUST excrete for
the day!
• 3000/1200= 2.5L (that’s 1. 5L more
than what you drank!)
• Hey, Bear, should you really be
drinking that urine?
• 1200 + 600= 1800/1200= 1.5L!
That’s 0.5 L more than what he
drank!
20
Steps in production of a
HYPER-osmotic urine
• How does the
kidney make a
urine more
concentrated
than blood?
• What determines
how
concentrated the
urine will be?
ADH!
21
Figure 28-8;
Guyton and Hall
thirst
Osmoreceptor–
antidiuretic hormone
(ADH)-Thirst feedback
mechanism for
regulating extracellular
fluid osmolarity
Osmolality
Plasma volume
/Scant urine and HIGH urine osmolarity
22
With ADH around we create a
scant, concentrated urine
TAL- more solute reabsorption
Principal cells of LDCT and collecting
duct insert AQP2
More urea reabsorption of medullary
duct
23
Syndrome of inappropriate ADH
(SIADH)
• Circulating levels of ADH
are inappropriately HIGH
• Head injury or tumors
(lung)
• Urine hyperosmotic
• Plasma osmolarity
decreased
• Demeclocycline inhibits
ADH activity in kidney
24
Production of a
Hypo-osmotic urine
Low levels of ADH
PCT not affected: 67%
of solute and water
reabsorbed
TAL- water not
reabsorbed anyway
EDT- solute reabsorption
continues (diluting)
LDT and collecting
ducts- DO NOT express
AQP2 gene (no water
permeability)
25
Diabetes Insipidus-”bland urine of high flow”
• Too little ADH
•
•
•
•
•
•
Polydypsia (high thirst)
Polyuria (high urine output)
Urine osmolality?
Plasma osmolality?
1) Central Diabetes Insipidus – head injury
– Results from decreased production of ADH by
the CNS
– CD, therefore, has poor permeability to water
and leads to diuresis
– dDAVP- 1-deamino-8-D-arginine vasopressin
2) Nephrogenic Diabetes Insipidus
– Deals with problem of nephron to sense ADH
and malfunctioning ADH receptors in the
Collecting Duct
– CD, therefore, has poor permeability to water
– Give thiazide diuretics
26
Let’s go through the hormones again, but
with respect to solute maintenance
• Sodium salts most abundant
in ECF:
– Account for 90-95% of all
solutes in the ECF
• Sodium is the only cation
exerting significant osmotic
pressure
• Changes in plasma sodium
levels affect:
– Plasma volume, blood
pressure
– ICF and interstitial fluid
volumes
• Renal acid-base control
mechanisms are coupled to
sodium ion transport—
review how!
27
REGULATION OF Na+
BALANCE
• Sympathetic nerve activity- more Na+
reabsorption by PCT
• R-A-A system: more sodium
reabsorption
• Atriopeptin (ANP: Atrial natriuretic
peptide)- increases GFR and
decreased Na+ reabsorption
• Starling forces in peritubular capillaries
28
29
30
SNS can
directly
stimulate Na+
reabsorption
in tubule cells,
too!
31
Figure 26.9
32
Protein UP
HCT N.C.
Protein down
HCT N.C.
33
TYPE
EXAMPLE
ECF
ICF
OSMOLARITY
HCT
PROTEIN
ISO
CONTRACTION
DIARRHEA; BURN
DOWN
N.C.
N.C.
UP
UP
HYPER
CONTRACTION
SWEATING; DIABETES
INSIPIDUS; dehydration
DOWN
DOWN
UP
N.C.
UP
HYPO
CONTRACTION
ADRENAL
INSUFFICIENCY
Abuse of diuretics
DOWN
UP
DOWN
UP
UP
ISO
EXPANSION
INFUSION OF
ISOOSMOTIC NACL
UP
N.C.
N.C.
DOWN
DOWN
HYPER
EXPANSION
HIGH NACL INTAKE
Conns ; Cushings
UP
DOWN
UP
DOWN
DOWN
HYPO
EXPANSION
SIADH
UP
UP
DOWN
N.C.
DOWN
Which rows are hypernatremia? Which rows show hyponatremia?
34
Hypertension
• Primary- unknown cause. Treat the
symptoms-diuretics, ace inhibitors,
calcium channel blockers
• Secondary- some other physiological
event triggers the hypertension
– Goldblatt: renin released
inappropriately. Leads to cascade
and ultimately increased blood
pressure and hypertrophied heart
muscle (CHF).
• Anything that leads to decreased
RBF/ low GFR will lead to renin
release.
• Anorexia, blockage in renal
artery, etc.
35
DIURESIS-more water flow
• Decreasing the amount of solutes
reabsorbed in the tubules
increases the water in the tubule
and thus more urine output
• diabetes mellitus (sweet urine of
high flow): unreabsorbed glucose
in tubules causes diuresis and
water loss
– Lack of insulin or failure of insulin
to work (hyperglycemia)
– High tubular loads and Tm for
glucose is maxed
– Polyuria
– Glucosuria and ketonuria
– Polydipsia (high thirst)
• Many types of diuretics to cause
changes in water reabsorption by
altering solute reabsorption
36
OSMOTIC DIURETIC•
•
•
•
•
•
Mannitol- simple sugar, derived
from mannose.
Is small and freely filtered into
kidney tubules and not harmful to
pt.
Given IV verses eaten
To make it osmotic diuretic, it must
not be reabsorbed. It must then
stay in tubule lumen.
(OBLIGATORY WATER LOSS!)
Water stays in tubule to keep
concentration at 300 mOsmolal.
Water and mannitol is then
excreted.
Mannitol makes pt excrete more
water.
37
Diuretics- thick ascending loop
of Henle
• Furosemide, aka “
Lasix”
• Inhibits the Na+K+CLtransporters so the
medullary interstitial
gradient no longer exists
• Water remains in the
lumen
• Very potent
• Affects K+ balance, so
risk of hypokalemia
(which can affect RMP of
excitable cells & cause
hyperpolarization.
38
Diuretics- Early Distal CT
• Thiazides
• Inhibit Na/Cl
transporters- no salt
reabsorption.
• Water stays in lumen
39
Diuretics- late DCT (aldosterone inhibitors)
• Spironolactone
• Decreases numbers of Na/K
pumps on basolateral
membranes so that NaCl
reabsorption is blocked.
• Results in more salt excreted
(& water follows salt out so
more water is also excreted)
• Pro’s: prevents loss of K+
(potassium sparing diuretic).
• Often used in conjunction
with Loop diuretic
• Con’s: can lead to
hyperkalemia and Antiandrogen effect!! Female
athletes use it to mask steroid
use! Men have gynecomastia.
40
Diuretics- late DCT (sodium inhibitors)
• Amiloride
• Blocks Na+ channels on
luminal membranes so
that less Na+ is able to
enter the tubule from the
lumen in the first place.
• Also potassium sparing—
used with loop diuretic
• Therefore, more is
excreted and water
follows
41