Physiology of osmo- and volume regulation, LOs #78 & #79 · 2019.03.12. 1 Physiology of osmo- and...
Transcript of Physiology of osmo- and volume regulation, LOs #78 & #79 · 2019.03.12. 1 Physiology of osmo- and...
2019.03.12.
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Physiology of osmo- and volume regulation, LOs #78
& #79Gyöngyi Karcsúné Kis, MSc, PhD
1st March 2019
Characteristic Osmoregulation Volume regulation
What is being sensed Plasma osmolality Effective circulating volume
Sensors Hypothalamic
osmoreceptors
Carotid sinus
Afferent arteriole
Atria
Effectors ADH
Thirst
Renin-angiotensin-
aldosterone system
Sympathetic nervous
system
Natriuretic peptides (ANP,
urodilatin)
Pressure natriuresis
What is affected Water excretion
Water intake (via thirst)
Urinary sodium excretion
Share efferents, synergist reactions!
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Fluid contents
• Intracellular fluid accounts for about 67%.
• Extracellular fluid accounts for the rest.
• There are different types of extracellular fluid:
• Interstitial fluid (26%)
• Blood plasma (7%)
• Cerebrospinal fluid in the brain (approximately 1%)
Homeostasis• Plasma osmotic concentration (number of particles contained
in 1 liter of water)
• Clinical labs: glucose, urea and Na+ are measured
• Normal: 280-290 mosm/kg water
• Glucose & urea < 10 mosmol/kg water � sodium is the primary determinant of osmolality
• Sodium balance is the critical determinant of fluid compartment size (extracellular volume)
• Osmol(ality) gap
• Water balance alteration � manifests in plasma osmolality change � measured as plasma sodium concentration change (reflects ratio of solute and water)
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#Osmoregulation
• to maintain water balance; to compensate for water loss, avoid excess water gain, and maintain the proper osmotic concentration (osmolarity) of the body fluids
• 55-60 %, new-born: 75 %, elderly: 45 %
• Involves • multiple body-to-brain signalling mechanisms reporting the status of total body fluids
and of the distribution of fluids in the body
• a brain neural network (the visceral neuraxis) which receives and integrates body fluid-related input
• reflex (autonomic and endocrine) and behavioural (thirst- and sodium appetite-related behaviours) mechanisms that are controlled and activated by the visceral neuraxis
• Fluid balance – fast H2O change
• (NaCl-balance regulation is due to volume regulation)
Fluid balance
Water intake 2.2-3.5 l/day – excretion 2.2-3.5 l/day
food: 1l, drink: 1-2 l evaporation: 0.8-1 l, sweating: 0.2 l, (individuals!) faeces: 0.2 l, urine: 0.5 (min.)-2 l
Regulation through urine content and concentration (ADH) + thirst (drink)
Key role: hypothalamus
Stimulus: plasma osmolarity and volume
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ET, EET,NO
ET
Osmoreceptors 1.
Kidney macula
densa cells
Osmoreceptors 2.
• Anterior hypothalamus (circumventricular organs that lack BBB; OVLT and SFO)
osmosensory transduction
Role of cell volume: ion channels underlying osmoreception (?)
their activity appears to be inhibited
by membrane stretch, reduces cation
conductance, relaxation (shrinkage)�
depolarization
Kidney International 2012 82, 1051-1053DOI: (10.1038/ki.2012.271)
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Potential role of TRPVs
Properties (as a putative transduction channel of osmoreceptorneurons):
• activated by cell shrinkage
• directly mechanosensitive
• ion permeability characteristic of a non-selective cation channel
• inhibited by pharmacological inhibitors
Why TRPV?
hypertonicity-induced responses of osmoreceptors can be blocked by ruthenium red, a broad-spectrum antagonist of TRPV channels
TRPV1,TRPV2 and TRPV4 are osmosensitive channels
δN-TRPV1: transfected cells response hypertonicity and heating
Kidney International 2012 82, 1051-1053DOI: (10.1038/ki.2012.271)
Sharif-Naeini et al., 2008
ADH release
AVP gene products
Point mutations�hereditary
hypothalamic diabetes
insipidus
Depolarization �Ca2+
Osmolarity ↑
Volume ↓
AP
exocytosis
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ADH acting mechanisms
Cheng et al., J Mol Endocr, 2009
A) Water reabsorption - ADH
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B) Urea recycling
Hyperosmotic renal medullary
interstitium is critically important in
concentrating the urine and
provides the driving force for
reabsorption of water from the
collecting duct
UT2
UT3UT1
Increased medullary blood flow
• Medullary blood flow is <10% of total renal blood flow (RBF)
• ”washout” of the cortico-medullary osmotic gradient
• impaired urinary concentrating ability
• sustained decrease � ischaemia, tissue (papillary) necrosis, scarring and chronic kidney injury
• Compensatory mechanisms:• governed upstream by renal arterial pressure
• Intrarenal paracrine mediators
• DVR pericytes? (Kennedy-Lydon et al., 2013)
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Osmotic vs. free water clearance
• To assess renal H2O handling
• CH2O= solute ”free”
• Total urine V=water (Cosm)solute-containing isosmotic with plasma + CH2O
• CH2O= V-Cosm
• Cosm=U*V/P
• V > Cosm�CH2O positive
• V = Cosm�CH2O zero
• V < Cosm�CH2O negative (! concentrated urine)
Coffe & alcohol
↓ ADH release via decreased Ca2+ conductivity of neurosecretory cells
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THIRST (craving for fluid)Osmoreceptors – Lateral hypothalamus
Effe
ren
tp
ath
wa
ys
Brain stem
Spinal cord
Drinking
DEPRIVE OF H2O
Plasma osmolarity
Osmoreceptors in hypothalamus
↑ ADH secretion - posterior pituitary
↑ H2O permeability of principal cells
(late distal tubule and collecting duct)
↑ H2O reabsorption
↑ Urine osmolarity and urine volume↓
PLASMA OSMOLARITY TOWARD NORMAL
Thirst
Water drinking
SUMMARY
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#Volume regulation
• Main purpose: maintain ECF volume
• EC volume proportional to proportional to NaClNaCl contentcontent
• Plasma volume decreases >10 % �volume regulation is dominant
Hypovolemic thirst
Sodium consumption
• Daily uptake
• Daily excretion
Filtration: 150 l/day; 140 mmol/l Na+ � 21 000 mmol/day
Excreted: 1 to 50 mmol/day
isoosmotic
hypervolaemia: NaCl
intake results in plasma plasma
volume increase volume increase
because of the rapid
compensatory
mechanism of
osmoregulation
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Volume sensors
•Baroreceptors:
•High pressure BRs:
•Sinus caroticus → n. glossopharyngeus
•Aortic arch → n. vagus
•Low pressure BRs
•Atria
• (veins & aa. pulmonares)
BRs
De Castro, 1926 (Cajal’s disciple)
distribution of the baro-receptors
Diffuse baroreceptors
circumscribed baroreceptors
baroreceptor fine terminals
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The arterial baroreflex
Benarroch, Neurology, 2008
sympathoinhibitory pathway
Effector - GFREffective filtration
pressure ↑
GFR ↑
Na+ excretion ↑
Plasma volume ↓
(minor importance)
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Effector - RAAS
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Effector - RAAS
Angiotensins
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Aldosteron
Aldosterone-induced Na+ retention & K+
excretion• Antagonists: spironolactone, eplerenone
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Atrial natriuretic peptide
ANP & co-workers
Atrial natriuretic peptide, also
known as ANP � alternative form
in kidney: urodilatin
Brain natriuretic peptide, also
known as BNP
C-type natriuretic peptide, also
known as CNP
Atrial natriuretic
peptide
Structure of the human
natriuretic peptides.Potter et al., Handb Exp Pharmacol., 2009
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Receptors for natriuretic peptides
• half-life of ANP in humans is approximately 2 min; elimination: neutralendopeptidase (neprilysin, NEP), binding to the natriuretic peptide clearance receptor (NPR-C)
Massimo Volpe et al. Clin. Sci. 2016;130:57-77
receptor-mediated
internalization and
degradation
Kidney
Increased GFR by inducing vasodilatation of afferent arterioles and vasoconstriction of
efferent arterioles
Induction of natriuresis by inhibiting Na+, H+ exchanger in the proximal tubule, Na+, Cl− co-
transporter in the distal tubule and Na+ channels in the collecting duct
Induction of diuresis due to inhibition of AVP-induced acquaporin-2 incorporation into
collecting ducts' apical membrane
CardiacReduction in preload leading to fall in cardiac output
Inhibition of cardiac remodelling
Haemodynamic
Vasorelaxation
Elevating capillary hydraulic conductivity
Decreased cardiac preload and afterload
Endocrine
Suppression of the following:
- Renin–Ang–aldosterone axis
- Sympathetic outflow
- AVP
- Endothelin
Actions of NPs
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Escape phenomenon
• Na+ intake ↑ � Na+ excretion ↑ + E.C. volume increase
• Aldosterone � temporary decrease in Na+ excretion (Na+ escapes)
• E.C. still high
• 2 processes:• Pressure natriuresis
• Decreased proximal sodium resorption
• primary hyperaldosteronism does not cause oedema
Prostaglandins (PGE2, PGI2) in kidney
Blood vessel dilatation Inhibition of TAL NaCl reabsorption Inhibition of ADH effect
in collecting duct
Urea-exit ↓ Water reabsorption ↓
Medullary gradient ↓
Kidney dilutes
Vasa recta blood flow ↑
Feed back
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Overview
Overview
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Osmo- and volumeregulation
> 10 % in volume � volume reulation is dominant