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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