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Discuss the physiological mechanisms that contribute to the

regulation of plasma osmolarity. What clinical conditions are


associated with disturbances of plama osmolarity homeostasis
Introduction
Osmolarity is defined as the number of osmoles (moles of
solute) of solute per liter of solution (Osm/L). (essentially a
measure of concentration).
Normal plasma osmolarity is 290mOsm.
Plasma osmolarity is tightly regulated, as changes in plasma
osmolarity exert a significant impact on intracellular
osmolarity; which can cause cell shrinkage or swelling.

Myocytefunction,signalingpathways,cellmembraneintegrity,andneuronaldepolarization
arejustafewexamplesofcrucialaspectsofourphysiologythatdependontheconstancyof
theambientosmolarity
Asthesinglemostimportantdeterminantofextracellularosmolarity,theconcentrationof
sodiumintheserummustbetightlyregulatedalongsidewatercontentforthesemyriad
cellularprocessestobedischargednormally.
Thestabilityoftheserumsodiumconcentrationwithinanarrowrangedespitewidevariations
inwaterintake,soluteingestion,andnonurinarywaterlossesistheresultofastrictbalance
betweenwaterintakeandwateroutput.
WaterBalance
Waterbalanceisachievedbyensuringthattheamountofwaterconsumed=waterexcreted.

Thisbalanceismaintainedthroughtheregulationofthetwovariables:
Urinarywaterloss:
Whenanyamountoffluidinexcessofthe650mLisingested(whichiscommondueto
normaldrinkinghabitsdictatedbysocialnorms),theadditionalfreewaterisexcretedthrough
dilutionoftheurine.Conversely,whenanindividualdrinkingtheaverage2Loffluidperday
developsincreasedwaterlossesabovenormal(fromdiarrhea,sweating,increasedrespiratory
losses,etc.),balanceismaintainedthroughconcentrationoftheurine.Thisisachieved
throughthesecretionofADH.
ControlofADHrelease

ADHissynthesisedinthehypothalamusandstoredinposteriorpituitarysecretoryhranules
untilitsreleaseispromptedbyeitherosmoticornonosmoticstimuli(decreasedblood
pressureorintravasculartone).

Osmoticstimuli
TheosmotictriggerforADHreleaseismediatedbyosmoreceptorcellsinthe
circumventricularorgans(whichhavealeakyBBB,exposingneuronstoosmoticflux)OVLT
andtheSFO,whichsenseECFosmolaritythroughcellularswellinginhypotonicconditions
andshrinkageinhypertonicconditions;openingandclosingstretchsensitiveTRV1or4
channels.
ExEvTRPV1KOmiceshowpronouncedserumhyperosmolarityundernormalconditions,
andseverelycompromisedADHresponsestoosmoticstimulationinvivo.Thiswasquantified
usingrutheniumreddyetomonitorchangesinmembraneconductanceanddepolarising
potentialsinresponsetohyperosmolarity.(Naeinietal,2006).
TheosmoreceptorsoftheOVLTandtheSFOpossessprojectionstothesupraopticand
paraventricularnucleioftheanteriorhypothalamus,allowingthemtocommunicatewithADH
stores.
ExEvMcKinleyetAlin2004retrogradetracingstudiesusinganeurotropicvirususedto
identifytheseprojections.
ClinRelDestructionoftheSONandPVNcausesdiabetesinsipiduspresentswithexcessive
urinationandthirstduetolackofADH.
ResponseoccurstoanincreaseinECFosmolarityofaslittleas1%,witha1%decrease
resultingincompletesuppression.Thissensitivityispossiblyduetoimportanceofwaterasa
substrate,yetalsoitspotentialthreattocellularintegrity.
NonOsmoticstimuli
Lowpressuerbaroreceptorsintheatriaandhighpressurebarorecptorsinthecarotidarteries
andaortadetectbloodvolumeandpressure.Inconcert,theserecpetorswillpromptADH
releasewhentheyperceiveadropinbloodvolumeorpressure,sendingafferentsignalstothe
brainviavagusandglossopharyngealnerves.
ThisADHreleaseislesssensitivethanADHreleaseinresponsetoosmoticstimuli,
generatingreleaseata7%change.However,theADHreleaseissignificantlystrongerthan
wheninducedbyosmoticstimuli(duetoitsinvolvementindefenceagainstcirculatory
collapseasopposedtodehydration),andwillprevailoveranycontradictoryosmoticsignals.

ADHincreaseswateruptakeinthekidneys,decreasingosmolarity:
ADHstimulates4actionswhichpromoteantidiuresis:
1. CollectingductADHbindstotheV2receptorsonthebasolateralmembraneofcollecting
ductprincipalcells,resultingintranslocationofaquaporin2(AQP2)waterchannelsintothe
luminalmembranesthroughacyclicAMPsignalingpathway.Thismakestheusually
impermeablecollectingductextremelypermeable,causingpassivewaterreabsorptiondown
itsconcentrationgradientintothehypertonicmedullaryinterstitium.Thisoccurswithin
minutes,allowingrapidandshorttermregulationofwaterloss.Itisnotablethatwhen
elevationsinplasmaADHlevelsaresustainedforlongerthan24h,theexpressionofAQP2is
increased,andthegreaternumberofAQP2channelsavailablefortranslocationintothe
luminalmembraneallowforevengreatermaximalwaterpermeabilityinthecollectingduct.
ExEvFreezefractureofbrattelbororatswhomsufferneurogenicdiabetesinsipidus,and
presentwithoutindentationsintheapicalmembrane.WhenADHisinfused,pimpleclusters
appear,indicatingAQP2hasinsertedinthemembrane.
2. IncreasesureapermeabilityWhenADHbindstoV2,italsostimulatesincreasesurea
permeabilitythroughphosphorylationandupregulationofureatransporterA1(apical)and
A3(basolateral).Thisleadstoalargeeffluxofurea,whichcontributesroughlyhalfofthe
soluteresponsibleforproducingthenecessaryhypertonicmedullaryinterstitium.
ExEvimportanceofureainplasmaosmolarityregulationshowninratsonlowproteindiets,
whomcannotconcentratetheirurine.
3. LoopofHenleAmplificationofcountercurrentmultipliersystemADHstimulatesthe
activityoftheNKCCpumplocatedintheTALH,drawingmoreionsfromthelumenintothe

4.

interstitium.AstheTALHisimpermeabletowater,watercannotfollowtheseions,making
theinterstitiummorehypertonic.Thisdrawsmorewateroutofthefiltratepassingthroughthe
waterpermeableDLH,concentratingthefiltrateasitsnotNaClpermeable.Thisfacilitates
increaseddiffusionofNa+outofthethinALHpassively,increasingmedullaryinterstitial
osmolarity(drawingmorewateroutoftheDLH)andenablingtheNKCCtopumpmore
sodiumintotheinterstitiumastheconcentrationgradientisreduced.Thisestablishesa
corticopapillarygradient,withincreasedinterstitialconcentrationdrawingwateroutofthe
nowpermeableCDandconcentratingtheurine.
VasarectaThiscorticopapillarygradientismaintainedbythevasarecta,whichprevents
washoutofthegradientduetoitsUshape.Thisisfacilitatedbytheslowbloodflowinthe
vasarecta,allowingtimefortheplasmawithinittoequilibratewiththesurrounding
interstitialfluid.

ADHbindstoV1,PLClinkedreceptors,triggeringcontractionofvascularsmoothmuscle
throughraisedcalciumlevels.Thisvasoconstrictionslowsbloodflowinvasarectaevenmore,
furtherminimisingdepletionofmedullarysolutes.
ClinRelDiuretuicsareusedtherapeuticallytoreducewaterreabsorption,inducingpolyuriato
easeeffectsofhighBPorOedema.LoopdiureticssuchasfurosemideinhibittheNKCCand
haveavasodilatoryeffectonthevasarecta,actingantagonisticallytoADH.
Electivewaterintake:
Thisiscontrolledthroughstimulationofthirstandsaltcravings.
Thirstcontrolisundoubtedlysensitivetoplasmaosmolarity.Forexample,anincreaseofonly
2%plasmaosmolarityproducesastrongdesiretodrink,comparedtoa15%decreaseinblood
volumetostimulatethesameeffect.
Thismechanismiscontrolledbythemedianpreopticnucleus,activatedbyosmosensitive
neuronsintheorganumvasculosumofthelaminaterminals(OVLT)andthesubfornical
organ(SFO).
ExEvDestructionofthisregionofthehypothalamusinhumansresultsinpartialortotalloss
ofdesiretodrink,evenwithextremelyhighsaltconcentrationintheextracellularfluid.
However,thirstcontrolislesssensitivethanADHregulation,andiscomplicatedbyavariety
ofotherinfluences.
Thirststimulationoccursataplasmatonicityapproximately10mOsmhigherthandoes
osmoticstimulationofADHrelease;thus,a23%increaseinplasmaosmolarityisrequired
tostimulatethirst,incontrasttothe1%increaserequiredtostimulateADHrelease.Infact,
theosmoticsetpointforthirststimulationroughlycorrelateswiththepointatwhichurineis
maximallyconcentratedthroughADHsaction,soincreasedwaterintakeispromptedonly
whenthekidneysabilitytoconservewaterisnearlyatitscapacity,therebyservingasa
secondlineofdefenseagainstseverehypernatremia.
UnlikeAVPsminutetominutecontroloverurinarywaterexcretion,thesethirstcontrol
mechanismsdonotreflectregulationofplasmaosmolaritypersebutinsteadexisttoprevent
overcorrectionofhyperosmolarity,asgastrointestinalabsorptionofingestedwatercantakeup
toanhour.Thedefenseagainstovercorrectionisfurtherbolsteredbythefactthatfluidintake
rapidlycausesatransientsuppressionofboththirstandAVPlevels,significantlybeforeany
resultantdropinplasmaosmolarity.

Thirstcontrolisalsoinfluencedbyotherfactorsthanosmolarity,suchasdrymouthand
hypotension.

Sodiumbalance
Regulationofosmolaritycannotbeachievedwithoutbalancingtheintakeandexcretionof
sodiumwiththatofwater.
ADHplaysaroleinloweringosmolarity,byincreasingwaterreabsorptioninthekidneys,
thusdilutingthebodilyfluids.Thisisimportantinsituationssuchasdehydration,whereyou
loseproportionatelymorewaterthansolute(sodium),sotheosmolarityofyourbodilyfluids
increases.Inthissituation,thebodymustconservewaterbutnotsodium,stemmingtherisein
osmolarity.
Topreventosmolarityfromdecreasingtobelownormal,thekidneysalsohavearegulated
mechanismforreabsorbingsodiuminthedistalnephron.Thismechanismiscontrolledby
aldosterone
However,ifinasituationwhereyourlosesofsodiumandwaterandproportionatetothe
compositionofbodilyfluids,suchassignificantbleedingfromtraumaorsurgery,thebody
needstoconservebothwaterandsodium.

http://mediwikis.com/wiki/index.php/Regulation_of_Plasma_Osmolarity_(water)_and_Volume_(sodiu
m)
https://www.ncbi.nlm.nih.gov/pubmed/7766344
https://www.scribd.com/presentation/249343118/RegulationofBodyFluidVolumeandPlasma
Osmolarity
file:///Users/totunla/Downloads/Surmacz%20Regulation%20of%20Fluid%20and%20Electrolyte
%20Balance1.pdf
https://mcb.berkeley.edu/courses/mcb135e/kidneyfluid.html