The Dynamic Response of Intraocular Pressure and Ocular ...

Our results suggest that eyes with ocular hypertension are more susceptible to IOP variability induced by hemodynamic fluctuations. Introduction. Intraocular ... JumpTo... Introduction MaterialsandMethods Results Discussion Conclusions Acknowledgments References Free Glaucoma  |  October2013 TheDynamicResponseofIntraocularPressureandOcularPulseAmplitudetoAcuteHemodynamicChangesinNormalandGlaucomatousEyes JonathanC.Li;VivekK.Gupta;YuyiYou;KeithW.Ng;StuartL.Graham AuthorAffiliations&Notes JonathanC.Li DepartmentofOphthalmology,AustralianSchoolofAdvancedMedicine,MacquarieUniversity,NorthRyde,NewSouthWales,Australia VivekK.Gupta DepartmentofOphthalmology,AustralianSchoolofAdvancedMedicine,MacquarieUniversity,NorthRyde,NewSouthWales,Australia YuyiYou DepartmentofOphthalmology,AustralianSchoolofAdvancedMedicine,MacquarieUniversity,NorthRyde,NewSouthWales,Australia KeithW.Ng DepartmentofOphthalmology,AustralianSchoolofAdvancedMedicine,MacquarieUniversity,NorthRyde,NewSouthWales,Australia StuartL.Graham DepartmentofOphthalmology,AustralianSchoolofAdvancedMedicine,MacquarieUniversity,NorthRyde,NewSouthWales,AustraliaSaveSightInstitute,SydneyUniversity,Sydney,NewSouthWales,Australia Correspondence:JonathanC.Li,DepartmentofOphthalmology,AustralianSchoolofAdvancedMedicine,MacquarieUniversity,NorthRyde,NewSouthWales2109,Australia;[email protected].  InvestigativeOphthalmology&VisualScienceOctober2013,Vol.54,6960-6967.doi:https://doi.org/10.1167/iovs.13-12405 Views FullArticle Figures Tables PDF Share E-mail Facebook Twitter Google Digg Delicious Tumblr StumbleUpon Tools Alerts UserAlerts Youareaddinganalertfor: TheDynamicResponseofIntraocularPressureandOcularPulseAmplitudetoAcuteHemodynamicChangesinNormalandGlaucomatousEyes Youwillreceiveanemailwheneverthisarticleiscorrected,updated,orcitedintheliterature.YoucanmanagethisandallotheralertsinMyAccount Thealertwillbesentto: Confirm × Thisfeatureisavailabletoauthenticatedusersonly. SignIn or CreateanAccount × GetCitation Citation JonathanC.Li,VivekK.Gupta,YuyiYou,KeithW.Ng,StuartL.Graham;TheDynamicResponseofIntraocularPressureandOcularPulseAmplitudetoAcuteHemodynamicChangesinNormalandGlaucomatousEyes.Invest.Ophthalmol.Vis.Sci.2013;54(10):6960-6967.doi:https://doi.org/10.1167/iovs.13-12405. Downloadcitationfile: Ris(Zotero) EndNote BibTex Medlars ProCite RefWorks ReferenceManager ©ARVO(1962-2015);TheAuthors(2016-present) × GetPermissions Supplements AbstractPurpose.: Toevaluatetheeffectsofacutearterialbloodpressure(ABP)andvenouspressurechangesonIOPinratswithexperimentalglaucoma.Methods.: UnilateralexperimentalocularhypertensionwasestablishedinSprague-Dawleyratsbyweeklyintracameralinjectionofmicrobeads.Ocularpulseamplitude(OPA)andIOPwererecordedfromtheanteriorchamberusing1.2-Frmicrosensorsunderurethaneanesthesia.TheeffectsonIOPduringhemodynamicchallengesusingphenylephrine(PE)(50μg/kg/minintravenous[IV])andrapidsalineloading(20mL/kg/minIV)werestudied.Results.: Overan8-weekperiod,IOPwassignificantlyelevatedby60%intheunilateralocularhypertensiveeyes.BothABPandIOPweresignificantlyincreasedbyPEinfusion.AsignificantlygreaterIOPincreasewasfoundintheexperimentaleyescomparedwithcontroleyes(1.32±0.18mmHgvs.0.90±0.09mmHg).Correspondingly,higherOPAsandanamplificationoftheOPAduringarterialhypertensionwerefoundintheexperimentaleyes.AsustainedriseinIOPsecondarytoIVsalineloadingwasobserved,withagreaterriseobservedamongexperimentaleyes(0.74±0.13mmHgvs.0.37±0.005mmHg).Conclusions.: SympatheticaccelerationofABPusingPEresultedinsurgesinIOPandOPA.Incontrast,increasedvenouspressureresultedinamoresustainedriseinIOPbuttoalesserextent.Theseresponsesweremorepronouncedineyeswithexperimentalglaucomacomparedwithcontroleyes,whichmayreflectthehigherstartingIOPcontributingtoareducedocularcompliance.OurresultssuggestthateyeswithocularhypertensionaremoresusceptibletoIOPvariabilityinducedbyhemodynamicfluctuations. Introduction Intraocularpressureisawell-knownriskfactorinthedevelopmentofglaucomatousopticneuropathy(GON),characterizedbytheirreversiblelossofretinalganglioncellswiththenaturalhistoryofprogressivevisualfieldloss.  ThemechanismbywhichraisedIOPresultsinGONisunclear,butalinearcorrelationbetweenarterialbloodpressureandIOPhavebeenwellestablishedbothbycross-sectionalpopulationstudies1–4andbyanimalmodels.1–6Ithasbeenestimatedinhumansthatforapproximatelyevery10mmHgriseinsystolicbloodpressure,thereisanassociated0.2to0.3mmHgriseinIOP.7Real-timeanalyseshavealsorevealedthatIOPcanriseandfallinsynchronywithacutehemodynamicchangesthatoccurduringphysicalexerciseaswellasduringpharmacologicstimulationbyvasoactiveagents.8,9  DespitethegrowingspeculationofavascularbasisofPOAG,10,11therelationshipbetweenPOAGandhypertensionisnotwelldefined,withepidemiologicstudiesshowingdisparateresultswithanoverallsuggestionofaweakassociationbetweenhypertensionandPOAG.1,12,13Usingarodentmodel,weaimedtoevaluatethedynamicrelationshipbetweenIOPandacutehemodynamicfluctuationsandtoshowhowtheirrelationshipisalteredinthecontextofreducedfacilityofaqueousoutflow.  MaterialsandMethods Animals AllanimalproceduresconformedtotheARVOStatementfortheUseofAnimalsinOphthalmicandVisionResearchandwereapprovedbytheMacquarieUniversityAnimalEthicsCommittee.MaleSprague-Dawleyratsof8weeksold(220–250g)weresourcedfromtheAnimalResourceCenter,Perth,Australia.Theanimalswerehousedinanenvironmentallycontrolledroomat25°Cand12-hourlight/12-hourdarkcyclewithadlibitumaccesstofoodandwater.Animalswerequarantinedandkeptuntiltheageof16weekspriortothecommencementoftheexperimentsandwerelaterkilledattheageof24weeksuponcompletion.  MicrobeadInjectionandGlaucomaInduction Thetechniqueofintracameralinjectionofmicrobeadstoinduceocularhypertensionandglaucomahasbeenadaptedfrompreviousreports.14–17Polystyrenemicrospheresof10μminsizewereused,withaconcentrationof3.6×106beads/mL(FluoSpheres;Invitrogen,Carlsbad,CA).Theywereinjectedusinga25-μLHamiltonsyringeconnectedtoadisposable33-gaugeneedle(TSKLaboratory,Tochigi,Japan).Allintracameralprocedureswereperformedundermagnificationusinganoperatingmicroscope(OPMIVarioS88,CarlZeiss,Oberkochen,Germany)withcaretakentoavoidneedlecontactwiththeirisorlens.  Tosimulateamodelofchronicocularhypertensionandglaucoma,theinjectionswereperformedweeklyover8weeks.Injectionswereperformedunderanesthesiafromanintraperitonealmixtureofketamine(75mg/kg)andmedetomidine(0.5mg/kg).Animalswereplacedonaheatingpadduringtheprocedure,andbothpupilsweredilatedwithtopicaltropicamide1%andanesthetizedwithproparacaine0.5%drops.Duringanesthesiaandpriortoeachweeklyinjection,IOPwasmeasuredbyusingahandheldelectronictonometer(IcareTonovet,Helsinki,Finland).TheIOPdisplayedonthetonometerwasthemeanofsixconsecutivemeasurements.TheaverageofthreeconsecutiveIOPreadingswasrecorded.Therighteyewasusedastheexperimentaleye,andthelefteyeservedasapairedcontrol.Theneedlewasinsertedbeveldown,tangentiallybeneaththecornealsurface,tofacilitateself-sealingofthepuncturewound.Oncetheneedletipwasvisualizedwithintheanteriorchamber,5μLmicrobeadsolutionwasinjected.Attheendoftheprocedure,anesthesiawasreversedusingatipamazole(0.75mg/kgsubcutaneousinjection[SCI]),and0.3%ciprofloxacindrops(Ciloxan;AlconLaboratories,FrenchsForest,NSW,Australia)and0.1%dexamethasoneeyedrops(Maxidex,AlconLaboratories)wereinstilledinbotheyes.Anointment(Lacri-lube;Allergan,Gordon,NSW,Australia)wasalsoappliedtoprotectagainstcornealdryinguntiltheanimalrecovered.  SimultaneousArterialandIntraocularPressureRecording Followingthe8weeks,ratswereanesthetizedwithanintraperitonealinjectionof10%urethane(1.3g/kg)forinvasiveABPandIOPrecording.Depthofaesthesiawasassessedbyperiodicalassessmentofwithdrawalandcornealreflexes.Animalswereventilatedspontaneouslywithouttheuseofparalyzingagents.Bodytemperaturewasmonitoredusingarectaltemperatureprobeandmaintainedat37°Cusingaheatingpad.  Solidstatemicrosensorcatheters(Scisense,London,ON,Canada)withapressureresolutionof10μV/V/mmHgwereusedtorecordtheABPandIOP.Priortoeachuse,thecatheterswerecleanedandthenstabilizedbyimmersioninsalineandcalibratedusingelectroniccalibrationaspermanufacturer'srecommendations.ContinuousABPrecordingwasmeasuredusinga1.9-Frcatheterinsertedintothefemoralartery.Intravenousaccesswasviathefemoralveinusingpolyethylenetubing(PE-50).  Aftertheinitialsurgicalpreparation,animalswereimmobilizedinthesphinxpositionwiththeheadsecuredinarodentstereotaxicframe.The1.2-Frcatheterswereinsertedintotheanteriorchambersofbotheyes.Dilationandanestheticdropswereappliedtobotheyespriortosensorinsertion.Asmallself-sealingincisionthroughthecorneawasmadebyastabincisionsuperiorlyandlateraltothelimbusatthe12o'clockpositionusinganophthalmicblade(AlconA-Ok15°AngleBlade;AlconLaboratories).Thecathetertipwasmanuallyadvancedthroughthecorneaandpositionedtositfreelyintheanteriorchamber(Fig.1).Eyelubricantwasappliedaftercatheterinsertiontopreventdryingofthecornea.  Figure1ViewOriginalDownloadSlide Positioningofintracameralmicrosensorcatheterinanteriorchamber.Thesensorappears“bent”owingtoopticalrefraction.Figure1 Positioningofintracameralmicrosensorcatheterinanteriorchamber.Thesensorappears“bent”owingtoopticalrefraction.ViewOriginalDownloadSlide HemodynamicManipulation Hemodynamicmanipulationswereperformedoncestabilityoftherecordingparametersheartrate(HR),ABP,andIOPwereconfirmed.SimulationsofanacuteABPrisewereachievedusingIVinfusionofphenylephrine(PE)50μg/kg/min(Sigma-Aldrich,St.Louis,MO)deliveredover2minutes.Simulationsofacutecentralvenouspressureexpansionwereperformedbytheinfusionofisotonicsaline(20mL/kg)over1minute.Infusionsweredeliveredusinganinfusionpump(HarvardPump11Plus;HarvardApparatus,Holliston,MA).  DataAcquisitionandStatisticalAnalysis DatarecordedfromtheintracameralsensorswereanalyzedforchangesinIOPfrombaseline.TheabsolutevalueofIOPwasnotusedforanalysisbecauseoftheknownvariablenegativeoffsetofseveralmillimetersofmercurythatoccursuponimmersionandre-immersionofthemicrosensorcatheters.18Outputfromthecatheterswassampledat2kHzandrecordedusingadataacquisitionsystem(Power1401-2interfacewithSpike2Softwareversion6;CambridgeElectronicDesign,Cambridge,UK).Datawereanalyzedin5-secondbins.Ocularpulseamplitude(OPA)wascalculatedusingautomaticdetectionofthewaveformpeaksandtroughbythesoftware.ThemeanOPAduringbaselineandduringraisedIOPwasaveragedover20seconds.Statisticalanalysiswasperformedusingcommerciallyavailablestatisticalsoftware(Prism6;GraphPadSoftware,LaJolla,CA).Student'st-testandone-wayANOVAwereusedforcomparisonofmeans.DifferenceswithP<0.05wereconsideredstatisticallysignificant.  Results Atotalof30ratswereusedinthisstudy.Theweeklyinjectionswerewelltolerated,withanimalsgainingweightduringthestudyperiod.Afterthe8-weektimepoint,theratsweighed500to550g.Oneratdevelopedcataractandanotherdevelopedcornealneovascularizationintheexperimentaleyeandwereexcludedfromthestudy.Theremaining28ratsweredividedevenlybetweenPEandsalineinfusiongroups.  MicrobeadInjectionandIOP AsustainedincreaseinIOPcanbeachievedusingrepeatedmicrobeadinjections(Fig.2A).AsingleintracameralinjectionwassufficienttoinduceasustainedincreaseinIOPasshownbythehigherIOPamongstexperimentaleyescomparedwithcontroleyesafterweekone(12.5±0.53mmHgforexperimentaleyecomparedwith10.2±0.2mmHgforcontrol;mean±SEM,P<0.001,n=28).Withsubsequentweeklyinjections,ocularhypertensionwasmaintainedamongtheexperimentaleyeswithamaximalincreaseof1.52-foldoverthe8-weekperiod(16.0±0.75mmHgforexperimentaleyecomparedwith10.56±0.24mmHgforcontrol;mean±SEM,P<0.001,n=28).NosignificantchangeinIOPwasobservedinthecontroleyes.  Figure2ViewOriginalDownloadSlide (A)WeeklyIOPreadingsmeasuredfromexperimentaleyesandcontralateralcontroleyes.MeasurementswereobtainedusingIcaretonometerduringketamineandmedetomidineanesthesiaimmediatelybeforetheintracameralinjectionofmicrobeads.Valuesaremean±SEM;n=28;unpairedt-test;*P<0.005.(B)SimultaneousincreaseinABP(red)andIOP(blue)duringPEinfusioninasinglerat.Toprecordinginblackrepresentsheartratederivedfromthepressurewaveformfrequency,illustratingtheresponseofthebaroreceptorreflex.(C)SimultaneousrecordingoftheABPandIOPpressurewaveformsindicatingareal-timesynchronousrelationshipbetweenABPandIOP.Figure2 (A)WeeklyIOPreadingsmeasuredfromexperimentaleyesandcontralateralcontroleyes.MeasurementswereobtainedusingIcaretonometerduringketamineandmedetomidineanesthesiaimmediatelybeforetheintracameralinjectionofmicrobeads.Valuesaremean±SEM;n=28;unpairedt-test;*P<0.005.(B)SimultaneousincreaseinABP(red)andIOP(blue)duringPEinfusioninasinglerat.Toprecordinginblackrepresentsheartratederivedfromthepressurewaveformfrequency,illustratingtheresponseofthebaroreceptorreflex.(C)SimultaneousrecordingoftheABPandIOPpressurewaveformsindicatingareal-timesynchronousrelationshipbetweenABPandIOP.ViewOriginalDownloadSlide OcularHypertensionDuringSurgesinABP ThesimultaneoussamplingofABPandIOPallowedthetracingofIOPfluctuationsinresponsetochangesinABP(Fig.2B).Thehighfrequencysamplingalsoallowedpressurerecordingtotheresolutionoftheirpulsewaveforms(Fig.2C).  PriortohemodynamicmanipulationwithPE,thebaselinemeanarterialpressure(MAP)was94.1±2.3mmHg(mean±SEM).PhenylephrineinfusionresultedinatransientbutstatisticallysignificantriseinMAPthatpeakedatthecompletionofinfusion(157.1±5.5mmHg,mean±SEM,P<0.0001).Meanarterialpressurerevertedtobaselinelevel2minutesfollowingthePEinfusion(95.1±2.3mmHg,mean±SEM,P=0.92).  Similarly,theIOProseandfellinsynchronywithABP,inboththeexperimentalandcontroleyesduringthePEinfusion(Fig.3).AplotofthemeanchangeinIOPwiththemeanchangesinMAPshowedthatalinearrelationshipwaspresentbetweenIOPandABPduringboththeupwardanddownwardmovementofABPinboththeexperimentalglaucomaandcontroleyes.(Figs.4A,4B).  Figure3ViewOriginalDownloadSlide PressorresponseofmeanMAP(A)andthechangeinIOPinexperimentalandcontroleyesduringPEinfusion(B).Arrowsrepresentthestartandfinishofinfusion.Valuesaremean±SEM;n=14;student'st-test;*P<0.05.Figure3 PressorresponseofmeanMAP(A)andthechangeinIOPinexperimentalandcontroleyesduringPEinfusion(B).Arrowsrepresentthestartandfinishofinfusion.Valuesaremean±SEM;n=14;student'st-test;*P<0.05.ViewOriginalDownloadSlide Figure4ViewOriginalDownloadSlide PlotofthechangeinIOPversusthechangeinmeanarterialpressureduringthePEinfusion.(A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively.Valuesaremean±SEM;n=14.Figure4 PlotofthechangeinIOPversusthechangeinmeanarterialpressureduringthePEinfusion.(A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively.Valuesaremean±SEM;n=14.ViewOriginalDownloadSlide OcularHypertensiveResponseinEyesWithExperimentalGlaucoma Inexperimentaleyes,theamplificationofIOPduringtheacutehypertensionwasgreaterthantheriserecordedinthecontroleyes(Fig.3B).ThemaximalgaininIOPobservedinexperimentaleyeswasapproximately1.5timesthemaximalIOPincontroleyes(1.32±0.18mmHg,comparedwith0.90±0.09mmHg;mean±SEM;P=0.04;n=14).ComparingtheslopeofthechangeinIOPversusthechangeinABPalsoshowedthattherateofchangeinIOPtoABPwasgreaterintheexperimentaleyes(comparingFig.4Awith4B).  OcularPulseAmplitude TheocularpulseamplitudeisthedifferenceinIOPduringcardiacsystoleanddiastole.OcularpulseamplitudewasexaminedusingdatarecordedfromfiveratsbeforeandduringPEinfusionwithdataexpressedasmean±SD.Intheanesthetizedrat,thebaselineIOPoscillatedatapproximately0.1mmHgwitheachcardiaccycle(Fig.2C).ThebaselineOPAwasgreaterinexperimentaleyes,withadifferencethatwasstatisticallysignificant(0.137±0.008mmHginexperimentaleyesversus0.085±0.005mmHginthecontroleye;one-wayANOVA;P≤0.0001;n=5).UponacuteABPstimulationwithintravenousPE,therewasasubstantialgaininOPAamongsttheexperimentaleyeswithover50percentincreasefrombaselineOPA(OPAofexperimentaleyes=0.21±0.02mmduringABPsurge)(Fig.6).ThetransientsystemichypertensioninducedbyPEhadnosignificanteffectontheOPAamongstthecontroleyes(Fig.6).  IOPResponseDuringIVSalineChallenge Inboththeexperimentalandcontroleyes,despitethesubstantialfluidloading,theIOPrespondedwithasmallbutstatisticallysignificantriseandplateauingfrombaselineforboththeexperimentalandcontroleyes(0.366±0.005mmHg,P≤0.001forcontroleyes;0.742±0.130mmHg,forexperimentaleyes,mean±SEM,n=14,unpairedt-test,P≤0.001).Pairedt-testanalysisbetweenthetwosamplesyieldedasignificantdifferenceinIOPbetweentheexperimentalandcontroleyesduringthepostinfusionperiod(P<0.0001)(Fig.7B).ThesalineinfusionalsoyieldedapersistentelevationinABPduringthe5-minutepostinfusionperiod(Fig.7A).AplotofthemeanIOPandmeanMAPduringtherapidsalinechallengeshowedthatinboththecontrolandexperimentaleyes,therateofIOPincreasewasinitiallyproportionallyslowerthantherateoftheincreaseinABP(Figs.5A,5B).  Figure5ViewOriginalDownloadSlide (A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively,duringsalineinfusion.NotethegreaterIOPresponseperunitchangeinMAPduringthesalineinfusion.Valuesaremean±SEM;n=14.Figure5 (A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively,duringsalineinfusion.NotethegreaterIOPresponseperunitchangeinMAPduringthesalineinfusion.Valuesaremean±SEM;n=14.ViewOriginalDownloadSlide Figure6ViewOriginalDownloadSlide ComparisonofthemeanOPAbetweencontrolandexperimentaleyesduringacutesystemichypertensiveresponsetoIVPE.Mean±SD;one-wayANOVA;Tukey'stest;****P≤0.0001;NS(notsignificant)P>0.05.Figure6 ComparisonofthemeanOPAbetweencontrolandexperimentaleyesduringacutesystemichypertensiveresponsetoIVPE.Mean±SD;one-wayANOVA;Tukey'stest;****P≤0.0001;NS(notsignificant)P>0.05.ViewOriginalDownloadSlide Figure7ViewOriginalDownloadSlide Arterialbloodpressure(A)andIOP(B)recordingsfrombaselineto5minutesduringandfollowingtherapidsalineinfusion.Arrowsrepresentstartandfinishoftheinfusiondeliveredover1minute.Valuesaremean±SEM;n=14;pairedt-test;*P<0.0001.Figure7 Arterialbloodpressure(A)andIOP(B)recordingsfrombaselineto5minutesduringandfollowingtherapidsalineinfusion.Arrowsrepresentstartandfinishoftheinfusiondeliveredover1minute.Valuesaremean±SEM;n=14;pairedt-test;*P<0.0001.ViewOriginalDownloadSlide Discussion Ourpresentstudyreportsthreeimportantfindings:   Intheoutflowobstructionmodelofglaucoma,thereisanamplificationoftheIOPduringacuteelevationsinbloodpressure(Fig.3); Duringacuteincreasesinbloodpressure,thereisanassociatedincreaseintheOPAintheeyeswithexperimentalglaucoma(Fig.6);and IntravenousvolumeloadingresultsinamildbutsustainedIOPelevationineyes,withagreaterresponseineyeswithexperimentalglaucoma(Fig.7). Ourstudyconfirmedthepreviouslyreportedreal-timelinearrelationshipbetweenIOPandABP8,9,19(Figs.2B,2C).Ofinterest,theplotofABPversusIOPduringthePEinfusionshowedahysteresisrelationshipbetweenABPandIOPasshownbythedifferenceintherateofchangeinIOPduringtheriseofABPcomparedwiththefallinABP(Fig.4).ThelimitedoutflowfacilityoftheexperimentalocularhypertensioneyesmayhavepreventedacompensatoryincreaseinoutflowfiltrationinresponsetotheIOPelevationthusresultinginagreaterchangeinIOPperunitchangeinABP.However,thismechanismdoesnotexplainthemarkedincreaseinthebaselineOPAobservedamongeyeswithexperimentalocularhypertension(Fig.6).Althoughthemechanismisbeyondthescopeofthisstudy,wehypothesizethatthehigherOPAmayberelatedtothehigherbaselineIOPintheexperimentaleyes.Higherbaselinepressureswouldtendtodecreasethecompliancepropertyoftheeyeowingtoincreasedscleralwalltension,whichinturntranslatestoagreaterriseinIOPduringtheexpansionofchoroidbloodflowresultinginanincreaseinboththemagnitudeofIOPaswellasOPA.  ThegreaterOPAineyeswithexperimentalocularhypertensionobservedduringbaselineaswellasduringthebloodpressure–inducedriseofIOPsuggeststhereisbothastaticanddynamiccomponentofreducedocularcomplianceineyeswithocularhypertension.OurresultofelevatedOPAintheexperimentaleyeswithocularhypertensionagreeswiththefindingsfromstudiesthathaveshownthatadirectrelationshipexistsbetweenOPAandIOP.20,21StudieshavealsoreportedpatientswithglaucomatohaveanormalorreducedOPAandthatthehighestOPAsarefoundinpatientswithocularhypertension.20–22Ofinterest,ithasalsobeenreportedthatarelativelyhigherOPAwascorrelatedtopatientswithlessseveredisease.23  OurstudyalsofoundthattheOPAmagnitudeofthecontroleyeswasunaffectedbythetransientelevationinbloodpressure,suggestingthattheabilityforABPtoincreaseOPAmaybedependentonthepresenceofelevatedIOPorreducedaqueoushumoroutflow.  Thereal-timemirroredfluctuationsofIOPwithchangestoABPmaybeexplainedbytheocularpressure–volumerelationshipmodel.24Givenexternalenergyisrequiredtofurtherpressurizetheocularcompartment,thetransmissionofpulsatileenergyfromthearterialsystemintotheintraocularspaceislikelyowingtothesuddenriseinocularbloodflowthatoccursduringsystoleorduringanacutehypertensivechallenge.Pulsatileenergyispredominatelytransmittedbythechoroidgivenitrepresentsthemajorityoftheophthalmicbloodflow.25ItislikelythattheobservedsynchronousriseinIOPresultsfromanexpansionofchoroidalvolumebroughtonbytheincreaseinocularbloodflow.26TheexpansionofthechoroidagainsttherigidsclerawouldthereforeexplainthetransientriseinIOP,withtheamountofIOPincreasedeterminedbyboththemagnitudeofABPriseaswellthecompliancepropertyofthesclera.  Inratsthatreceivedtherapidsalineinfusionprotocol,themagnitudeofIOPincreasewasnotuptothesameextentasobservedduringPEinfusion.ThepatternofelevationfollowingthesalineinfusiondifferedbyelicitingasustainedformofIOPelevationthatpersistedfollowingthesalineinfusion(Fig.7B).Sincechangesincentralvenouspressuretendtoaffectcardiacpreloadandcardiacoutputinvivo,itispossiblethatanincreaseinbloodpressureduringtherapidsalineinfusioncontributedtotheriseinIOP(Fig.7A).However,theABP–IOPrelationshipobtainedduringthesalineinfusion(Fig.5)differedfromtherelationshipobservedforthePEinfusion(Fig.4).DespitetheoverallsmallermaximalIOPresponseobservedduringthesalineinfusion,therewasagreaterIOPelevationperunitMAPelevationduringthesalineinfusioncomparedwiththePEinfusion.Thisfindingsuggeststhatothermechanisms,apartfromtheinducedchangeinbloodpressure,maybecontributingtotheIOPriseduringthesalineinfusion.  AsustainedincreaseinIOPandOPAhasalsobeenlinkedtotheexpansionofthechoroidinglaucomapatientsundergoingthewater-drinkingtest.27Duringthewater-drinkingtestinhumans,IOPtypicallypeaksby2.5mmHginthenormaleye28andapproximately4mmHg29forglaucomatouseyes30minutesaftertheingestionofwater.Themechanismbehindtheocularresponsetothewater-drinkingtestremainsunclear.30Oursaline-infusiontestisnotequivalenttothewater-drinking,butourfindingssuggestthathemodynamicchangesfromtheexpansionofcentralvenouspressurecancontributepartlytotheIOPriseduringthewater-drinkingtestinglaucoma.  TheeffectivenessofintracameralinjectionofmicrobeadstoinduceocularhypertensionwithsubsequentGONhasbeenvalidatedbypreviousstudies.14,15,31Weacknowledgethatmechanicalobstructionwithmicrobeadsisnotdirectlyrepresentativeoftheaqueousoutflowobstructionseeninhumanglaucoma;however,itprovidesacharacterizationofrestrictedfiltrationthatdoesnotinvolvedestructionoftissueasseeninotherlaserorcauterymodels.32,33  Alimitationofourstudyisthepotentialforpressuremeasurementstobeconfoundedbygeneralanesthesia.TheweeklyIOPreadingswereobtainedwhilstanimalswereundertheeffectofketamineanesthesia.Ithasbeenreportedthatketamine-basedanesthesiacanreduceIOPby25%to40%inrats(ChenB,etal.IOVS2002;43:ARVOE-Abstract4074),suggestingthatouranimalsmayhavehadhigherIOPduringtheirunanaesthetizedstate.Allourinvasivepressuremeasurementswereobtainedfromouranimalsusingastandardizeddosageofurethaneanesthesia.UrethanedeliveredbyintraperitonealinjectionhasnotbeenshowntoaffecttheIOPofrats(ChenB,etal.IOVS2002;43:ARVOE-Abstract4074).However,urethaneanesthesiahasbeenshowntoreducetherestingcardiovascularparametersofMAPandheartrate;stillthisisunlikelytoconfoundourresultssinceboththevasopressorresponsetoPEandthebradycardicresponsefromthebaroreceptorreflexarepreservedduringurethaneanesthesia.34,35  Thesteady-stateaqueoushumordynamicsdescribedbytheGoldmannequationassociatesIOPwiththedifferencebetweenaqueoushumorformationandaqueousoutflow.36Inrodents,thenormalaqueousformationrate,alsoknownasturnoverrate,hasbeenestimatedtobe2%to3%oftotalaqueousvolumeperminute.37,38ArapidformationofaqueoushumorduringtransientincreasesinABPwouldthereforebeunlikelytocontributetothesimultaneousriseinIOPgiventherateofaqueousproductionislimitedbymetabolicdependentprocesseswithciliaryperfusionpressurebeingunaffectedbyhypertension.39–41  Last,althoughwedidnotspecificallyinvestigatethedirectpharmacologicinfluenceofPEonIOP,webelievetheIOPriseobservedduringtheintravenousPEinfusionisaresultofarterialhypertension.ThepharmacologicactionofPEismediatedbyα-adrenoreceptorsandtheiractivationwilltendtolowerIOPthroughthereductionofaqueoushumorproductionbyitsactionontheciliarybody42andalsothroughitsvasoconstrictiveactionontheophthalmicarteriesowingtotheartery'srichsympatheticinnervation.43,44Thenonselectiveactivationofα2selectiveadrenergicreceptorbyPEmayalsohavetheeffectofloweringIOP,similartotheactionoftheselectiveα2adrenergicagonistssuchasapraclonidinebydecreasingaqueousproduction.45,46Ineffect,thestimulationofarterialhypertensionbyPEinourstudyisanalogoustothesympathoadrenalactivationofarterialhypertensionobservedduringthestressresponse47aswellasduringisometricexercises.48  Conclusions OurstudyshowedthatthereisanamplificationoftheIOPthataccompaniesasympathomimeticaccelerationofABP.Usingarodentmodel,wehaveshownforthefirsttimethattheIOPandOPAresponsetoacutesystemicblood-pressuresurgesisheightenedinthecontextofocularhypertension.AlessprominentbutprolongedincreaseinIOPwasachievedinourattempttorapidlyaltervenouspressurebyrapidsalineinfusion.Furtherstudiesarerequiredtovalidatethedynamicreal-timerelationshipbetweenhemodynamicfluxesandIOPinhumansasourresultssuggestthatindividualswithocularhypertensionareatagreaterriskofhavingocularpressuresthataremoresusceptibletobloodpressurevariations,whichoveralongperiodmaybeofclinicalsignificance.  Acknowledgments SupportedbyOphthalmicResearchInstituteofAustralia(ORIA),AllerganAustralia,andNovartisAustralia.  Disclosure:J.C.Li,None;V.K.Gupta,None;Y.You,None;K.W.Ng,None;S.L.Graham,None  References 1. 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[CrossRef][PubMed] Figure1ViewOriginalDownloadSlide Positioningofintracameralmicrosensorcatheterinanteriorchamber.Thesensorappears“bent”owingtoopticalrefraction.Figure1 Positioningofintracameralmicrosensorcatheterinanteriorchamber.Thesensorappears“bent”owingtoopticalrefraction.ViewOriginalDownloadSlide Figure2ViewOriginalDownloadSlide (A)WeeklyIOPreadingsmeasuredfromexperimentaleyesandcontralateralcontroleyes.MeasurementswereobtainedusingIcaretonometerduringketamineandmedetomidineanesthesiaimmediatelybeforetheintracameralinjectionofmicrobeads.Valuesaremean±SEM;n=28;unpairedt-test;*P<0.005.(B)SimultaneousincreaseinABP(red)andIOP(blue)duringPEinfusioninasinglerat.Toprecordinginblackrepresentsheartratederivedfromthepressurewaveformfrequency,illustratingtheresponseofthebaroreceptorreflex.(C)SimultaneousrecordingoftheABPandIOPpressurewaveformsindicatingareal-timesynchronousrelationshipbetweenABPandIOP.Figure2 (A)WeeklyIOPreadingsmeasuredfromexperimentaleyesandcontralateralcontroleyes.MeasurementswereobtainedusingIcaretonometerduringketamineandmedetomidineanesthesiaimmediatelybeforetheintracameralinjectionofmicrobeads.Valuesaremean±SEM;n=28;unpairedt-test;*P<0.005.(B)SimultaneousincreaseinABP(red)andIOP(blue)duringPEinfusioninasinglerat.Toprecordinginblackrepresentsheartratederivedfromthepressurewaveformfrequency,illustratingtheresponseofthebaroreceptorreflex.(C)SimultaneousrecordingoftheABPandIOPpressurewaveformsindicatingareal-timesynchronousrelationshipbetweenABPandIOP.ViewOriginalDownloadSlide Figure3ViewOriginalDownloadSlide PressorresponseofmeanMAP(A)andthechangeinIOPinexperimentalandcontroleyesduringPEinfusion(B).Arrowsrepresentthestartandfinishofinfusion.Valuesaremean±SEM;n=14;student'st-test;*P<0.05.Figure3 PressorresponseofmeanMAP(A)andthechangeinIOPinexperimentalandcontroleyesduringPEinfusion(B).Arrowsrepresentthestartandfinishofinfusion.Valuesaremean±SEM;n=14;student'st-test;*P<0.05.ViewOriginalDownloadSlide Figure4ViewOriginalDownloadSlide PlotofthechangeinIOPversusthechangeinmeanarterialpressureduringthePEinfusion.(A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively.Valuesaremean±SEM;n=14.Figure4 PlotofthechangeinIOPversusthechangeinmeanarterialpressureduringthePEinfusion.(A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively.Valuesaremean±SEM;n=14.ViewOriginalDownloadSlide Figure5ViewOriginalDownloadSlide (A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively,duringsalineinfusion.NotethegreaterIOPresponseperunitchangeinMAPduringthesalineinfusion.Valuesaremean±SEM;n=14.Figure5 (A,B)representtheABP/IOPrelationshipinnormalandexperimentaleyes,respectively,duringsalineinfusion.NotethegreaterIOPresponseperunitchangeinMAPduringthesalineinfusion.Valuesaremean±SEM;n=14.ViewOriginalDownloadSlide Figure6ViewOriginalDownloadSlide ComparisonofthemeanOPAbetweencontrolandexperimentaleyesduringacutesystemichypertensiveresponsetoIVPE.Mean±SD;one-wayANOVA;Tukey'stest;****P≤0.0001;NS(notsignificant)P>0.05.Figure6 ComparisonofthemeanOPAbetweencontrolandexperimentaleyesduringacutesystemichypertensiveresponsetoIVPE.Mean±SD;one-wayANOVA;Tukey'stest;****P≤0.0001;NS(notsignificant)P>0.05.ViewOriginalDownloadSlide Figure7ViewOriginalDownloadSlide Arterialbloodpressure(A)andIOP(B)recordingsfrombaselineto5minutesduringandfollowingtherapidsalineinfusion.Arrowsrepresentstartandfinishoftheinfusiondeliveredover1minute.Valuesaremean±SEM;n=14;pairedt-test;*P<0.0001.Figure7 Arterialbloodpressure(A)andIOP(B)recordingsfrombaselineto5minutesduringandfollowingtherapidsalineinfusion.Arrowsrepresentstartandfinishoftheinfusiondeliveredover1minute.Valuesaremean±SEM;n=14;pairedt-test;*P<0.0001.ViewOriginalDownloadSlide Copyright©AssociationforResearchinVisionandOphthalmology 1,385 Views 8 Citations ViewMetrics × RelatedArticles QuantificationoftheEffectofDifferentLevelsofIOPintheAstrogliaoftheRatRetinaIpsilateralandContralateraltoExperimentalGlaucoma IntraocularPressure,BloodPressure,andRetinalBloodFlowAutoregulation:AMathematicalModeltoClarifyTheirRelationshipandClinicalRelevance DeformationoftheEarlyGlaucomatousMonkeyOpticNerveHeadConnectiveTissueafterAcuteIOPElevationin3-DHistomorphometricReconstructions ChangesofOsteopontinintheAqueousHumoroftheDBA2/JGlaucomaModelCorrelatedwithOpticNerveandRGCDegenerations ChangesintheBiomechanicalResponseoftheOpticNerveHeadinEarlyExperimentalGlaucoma FromOtherJournals Interocularsuppressioninstrabismicamblyopiaresultsinanattenuatedanddelayedhemodynamicresponsefunctioninearlyvisualcortex LatrunculinBReducesIntraocularPressureinHumanOcularHypertensionandPrimaryOpen-AngleGlaucoma TranscornealElectricalStimulationInhibitsRetinalMicroglialActivationandEnhancesRetinalGanglionCellSurvivalAfterAcuteOcularHypertensiveInjury RelatedTopics EyeAnatomyandDisorders Glaucoma Advertisement Copyright©2015AssociationforResearchinVisionandOphthalmology. 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