Download Pathophysiology and basic science in hyponatraemia

19/04/2013
Pathophysiology: Regulation of Water Intake and
Excretion, Ghent 03/2013
Université de
Montréal Groupe des Protéines
Membranaires; Service de
néphrologie, Hôpital du SacréCœur de Montréal
Daniel G. Bichet, M.D.
Outline: Regulation of water intake and excretion
• Cellular dehydration to perceive thirst and
release arginine-vasopressin (AVP), the
antidiuretic hormone
• Volume regulation including Angiotensin II
osmoregulatory gain
• Unregulated AVP release by tumors or
infections
• Concentration and dilution of the urine
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Increased blood-oxygen-level-dependent (BOLD) signal under conditions in which thirst
was stimulated in a healthy human by infusion of hypertonic saline anterior cingulate
cortex (ACC; left-hand arrow) and in the area of the lamina terminalis (right-hand arrow)
Mammals are Osmoregulators: They have
Evolved Mechanisms that Maintain Extracellular
fluid Osmolality near a Stable Value
• sagittal section of midline of
ventral brain around the 3rd
ventricle in mice
• subfornical organ (SFO)
• median preoptic nucleus (MnPO)
• lamina terminalis (OVLT)
Cellular dehydration ,that is, cell shrinking, is required for
thirst and Vasopressin release
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Deconstruction of a neural circuits for thirst and vasopressin
secretion…Osmoregulatory circuits in the mammalian brain and the periphery
ACC, anterior
cingulate
cortex
NTS, nucleus tractus
solitarius
INS,insula
PBN, parabrachial
nucleus
Charles Bourque, Nature Reviews, Neuroscience,July, 2008
Anterior Cingulate Cortex: involved in rational decision making
Virginia Hughes; Stress: The roots of resilience Nature 490, 165-167, 11 october 2012
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The act of drinking by the thirsty
person is pleasurable, Chapter
35 Thirst MICHAEL J. MCKINLEYT
Mammals Strive to Maintain a constant
Osmolality, yet Values Fluctuate around a
Set Point:
• 40 minutes of strenuous exercise in the heat , or
24 hours of water deprivation, causes plasma
osmolality to rise by more than 10 mosmol kg–1.
• In a dehydrated individual, drinking the
equivalent of two large glasses of water (~850 ml)
lowers osmolality by approximately 6 mosmol
kg–1 within 30 minutes .
• Ingestion of 13 g of salt increases plasma
osmolality by approximately 5 mosmol kg–1
within 30 minutes .
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Cationic channels inactivated by stretch, TRPVs (Transient Receptor Potential
Vanilloid channels), are the osmoreceptors of the anterior hypothalamus : thirst
and magnocellular neurons.
Hyperosmotic stimuli
depolarize these
cells via the activation
of nonselective cation
channels (NSCCs)
Hypoosmolality causes
hyperpolarization by
inhibiting NSCCs
Osmosensation in vasopressin neurons: Prager-Khoutorsky M,
Bourque CW.Trends Neurosci. 2010 Feb;33(2):76-83.
Angiotensin II is inducing an osmoregulatory gain.
This helps restoration of
volume and blood
pressure maintenance.
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Set-points and slopes of vasopressin secretion are changed by
effective arterial blood volume perceptions
a r
a r
osmolality
Arterial and venous blood volume perception
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Determinants of Vasopressin Secretion
B
5
1000
Increase in Plasma
Arginine-Vasopressin
(pg/mL)
Plasma
Arginine-Vasopressin
(pg/mL)
A
4
100
3
10
2
1
Detection Limit
120
125
130
1
0
135
140
Plasma Sodium (mEq/L)
145
10
20
30
40
50
60
% Fall in Mean Arterial
Blood Pressure
Hypertonicity sensing requires
cell shrinking
A, Time course of normalized
volume changes (nVol, relative to
baseline) observed in three isolated
mouse OVLT neurons exposed to a
60 min hyperosmotic stimulus (+40
mosmol/kg; excess mannitol)
B, Steady-state values of nVol
observed in different isolated OVLT
neurons exposed to various external
osmolalities (n = 19).
Sorana Ciura1, Wolfgang Liedtke2, and
Charles W. Bourque1The Journal of
Neuroscience, 12 October 2011, 31(41):
14669-14676;
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Hepatic Osmoreceptors Require
TRPV4 for Normal Function
The Molecular and Cellular Identity of Peripheral
Osmoreceptors:Lechner S.G. et al.Neuron: 69; 332-344, 2011.
Defective Osmoregulation of Trpv1-/and Trpv4-/- mice.
Neuron: 69; 332-344, 2011.
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Taste receptors in the mouth, more than just the basic five but no taste for water
Michael Eisenstein ; More than meets the mouth, Nature, 468, 23/30 dec
2010, Trivedi B.P.;The finer points of taste, Nature 21 june 2012
Model of urine concentration
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Separation
of salt and
water in the
thick
ascending
loop of
Henle
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Vasopressin makes the cortical and medullary collecting ducts
permeable to water
Bichet DG.Clin J Am Soc Nephrol. 2012 May;7(5):700-3
Molar mass of urea CO(NH2)2 = 60g/mol
Molecular weight calculation ; 12.0107 + 15.9994 + (14.0067
+ 1.00794x2)2
60g of urea = 1000 mmol
30g of urea = 500 mmol
“Medicinal urea” 30 g × 1 month will be less
than $1.00:
urea 10, NaHCO3 2g
Citric Acid 1.5g, sucrose 200 mg
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60g of urea=1000 mmol: forcing water excretion , however,
bitter taste and necessity to absorb with additional fluid
Daily Intake
(Solute + Water)
Urinary
Osmolality
(mOsm/kg)
Urine Volume
(Liter/day)
Water Balance
(Liter/day)
Normal
500 mmol of solute
+ 2 liters of water
250
2 liters
0
SIADH
500 mmol of solute
+ 2 liters of water
500
1 liter
(500/500)
+1
2.
500 mmol of solute
+ 500 mmol of urea
+ 2 liters of water
500
2 liters
(1000/500)
0
Editorial,What Is the Role of Vaptans in Routine Clinical
Nephrology? Daniel G. Bichet Clin J Am Soc Nephrol 7: 700–703, 2012.
What did we learn?
• Thirst and cellular dehydration
• Vasopressin secretion and cellular dehydration
• TRPV1 channels centrally and TRPV4 in the
periphery mediating the effects of cellular
dehydration
• Diluting segment of the nephron: thick
ascending loop of Henle
• Action of vasopressin on principal cells of the
collecting duct.
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