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SarahBasel

MahmoudOdeh

Linaabdelhadi

Faisal

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{ Intheprevioussheetwewentovertheshort-termregulatorsofBP,inthislecturewe

willcontinuetalkingaboutBPregulationbutovera“long-period”oftime.{ Factors affecting TPR:

Ä ThemaindeterminantofTPRistheadjustablearteriolarradius.Twomajorcategoriesinfluencearteriolarradius:

a) Local (intrinsic) control:“selfishadjustmentstoincreasebloodflow”thiscontrolisimportantinmatchingbloodflowwiththetissue’smetabolicneeds.DecreasedO2,increasedCO2oracid[H+]producesarteriolarrelaxation(toincreasebloodflowduringincreasedmetabolicactivity).

b) Extrinsic control of arteriolar radius:recallthatacertainlevelofongoingsympatheticactivitycontributestovasculartone.Increasedsympatheticactivityproducesgeneralizedarteriolarvasoconstriction(↑TPR),whereasdecreasedsympatheticactivityleadstogeneralizedarteriolarvasodilation(↓TPR).EverysingleaspectofthesympatheticactionsovertheTPRandtheconsequentBPwillbecoveredinthissheetasweproceed.

Ä TPRisalsodirectlyproportionaltothebloodviscositywhichisprimarilycontrolledbythenumberofRBCsandplasmaproteins.(relativelystablevariableexceptinsomepathologicalconditionslikesevereanemia).

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{ Theadjacentfiguresummarizesthenervouscontrolovertheheart.

{ Afferentfibersreachthecardiovascularcenterofthebrainwhichrespondbyincreasingordecreasingthetoneoftheefferent(sympatheticorparasympathetic)neuronstoadjusttheTPR,COandconsequentlytheMAP.(Thedetailsofthisprocessareexplainedintheprevioussheet).

{ Intermediate / Long term Regulation of BP: 1. Epinephrine – Adrenal medulla system:

Sympatheticstimulationoftheadrenalmedullacausesthisglandtoreleaseepinephrine(80%)andnor-epinephrine(20%)intotheblood,toproducegeneralizedvasoconstriction→↑TPR→↑MAP.ThismechanismworksasanintermediatetermofBPregulationbecauseitisactivatedafter10minutesofbloodpressuredropping.Extra:pleaserememberthatthisgeneralizedvasoconstrictionisachievedbytheactivationofα1receptorsfoundinalmostallarterioles.Arteriolesoftheheartandskeletalmusclesareequippedwithβ2receptorsthatresultinvasodilationonceactivatedbythesamehormones,butthroughdifferentsignalingpathways.

2. ADH (vasopressin) system:(Thissystemrequires30minutestostartworking).Vasopressinisinvolvedinmaintainingwaterbalancebyregulatingtheamountofwaterkidneysretainforthebodyduringurineformation.Tomaintainwaterbalanceontheintakeside,thirstinfluencestheamountoffluidingested,andontheoutputside,thekidneyscanadjusttheamountofurineformedundertheinfluenceofmanyregulatorsincludingADH.Now,what’stheultimategoalofADH?Beforeweanswerthisquestion,weshouldclarifywhenandwhyADHissecretedinthefirstplace?

Ä Doyourememberthestoryoflow-pressurereceptors(foundmainlyintheRt.Atrium)?Thesereceptorsaresensitivetochangesinvolume(ECFvolume),inotherwordsthesereceptorsmonitorthe“fullness”ofthevascularsystem.Howmuchvolumeispassingthroughthevessels?

Ä IfthesereceptorssensethattheECFvolumeisreduced(decreasedMAP),reflexesareimmediatelyinitiatedtorestoreBP.

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Ä Oneofthesereflexesistheatrial-hypothalamicreflexwhichinducesthereleaseofADHtostimulatethekidneystoabsorbmorewaterandformlessurine,thisretainedvolumewouldincreasetheECFvolume.

Ä Whataboutthirst?ThehypothalamiccenterregulatesADHsecretion(andthusurinaryoutput)andthirst(andthusdrinking).ADHandthirstarebothstimulatedbylowH2Olevelsandsuppressedbyfreewaterexcess.

Ä ADHisalternativelyknownasvasopressin,becauseitisapotentvasoconstrictorandthusitincreasestheTPR.

§ ↓ECFvolume→increasethereleaseofADHdirectlyorindirectlythrough

activationoftheatrialhypothalamicreflex+↑thirst→↑H2Oretention→↓urineformation→↑ECFvolume→↑MSFP→↑Venousreturn→↑CO(accordingtoFra…🚶"#$%&')

Also,vasopressinincreasesTPR.SincebothTPRandCOareelevated,MAPpressureisraised.

3. Renin-Angiotensin-Aldosterone system:thissystemrequires1hourtobeeffective.

Ä RAASisactivatedinresponseto:↓Na+,↓ECFvolume,and↓BP.ThecellsoftheafferentarteriolessecreteRenin(anenzymatichormone)intothebloodinresponsetodecreasedbloodpressure.Also,themaculadensacellsofthejuxtaglomerularapparatusworkassensorsforNa+.InresponsetofallinNaCl,themaculadensacellsstimulatetheafferentarteriolarcellstosecreterenin.Oncesecretedintotheblood,reninactsasanenzymetoactivateangiotensinogen(α2-globulin,14a.apeptide)intoangiotensinI(10a.apeptide).Angiotensinogenissynthesizedbytheliverandpresentintheplasma.AngiotensinIisconvertedintoangiotensinIIbyangiotensinconvertingenzymeACE,whichisabundantinthepulmonarycapillaryendothelialcells.

Ä AngiotensinIIisthemostpotentvasoconstrictor,andthemainstimulusforthesecretionofthehormonealdosteronefromZonaglomerulosalayeroftheadrenalcortex.AldosteroneincreasesNa+reabsorption.RAASthuspromotessaltretentionandaresultingwaterretention→↑ECFV→↑MSFP→↑venousreturn→↑CO+↑TPR→↑MAP

Ä AngiotensinogenIIisalsoapositiveinotropicagent(increasestheSVbyincreasingthecontractility).

Ä TheoppositesituationexistswhentheNa+load,ECFvolume,andarterialbloodpressureareabovenormal.Underthesecircumstances,reninsecretionisinhibited.Therefore,angiotensinogenisnotconvertedtoangiotensinIandII,andaldosteronesecretionisalsonotstimulated.

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Ä ↓Na+→↓H2O(lostinurine)→↓ECFV→↓venousreturn→↓CO→↓MAP(similartohowdiureticswork?)

Ä Extra:angiotensinIIalsostimulatesthirstandvasopressin.

{ UntilnowwehavementionedthreemechanismsstimulatedbydecreasedBP→theirstimulationraisestheBPtonormallevels.

{ Before discussing the fourth mechanism, let’s revise the influence of BP over the GFR (Glomerular filtration rate):

§ ↑MAP→sympathetictoneisreduced→afferentarteriolesofkidneyaredilated→morebloodenterstheglomeruli→↑GFR→↑urineformation→↓ECFV(normalagain)→MAPisreduced.

§ ↓MAP→↑sympatheticstimulation→vasoconstrictionofafferentarterioles→lessbloodenterstheglomeruli→↓GFR→↓urineformation→↑waterretention→↑ECFV→MAPisraised

§ TheGFRisinfluencedbymanyfactorsthatadjustBP,includingtheatrio-renalreflex.

{ Atrial Natriuretic peptide (ANP): Ä Abloodpressure-loweringsystemthatinvolvesthe

hormoneANP,thishormoneisproducedmainlybytherightatrium,althoughbothatriacansecreteit.ThemainactionofANPistoinhibitNa+reabsorptionandconsequentlypromotesitsexcretion,waterwillosmoticallyfollowNa+.

§ ↑ECFVand↑MAP→theadditionalvolumestretchestheheartmuscles→releaseofANP→↑Na+andwaterexcretion→moreurineisformed→↓ECFVandMAP

§ ANPcausesvasodilationintheafferentarterioles→↑GFR→moreurineisformed→Na+andwaterarelost→↓ECFVandMAP

§ TheoppositehappenswhenMAPisreduced(ANPsecretionisinhibited).

{ Increaseinbloodvolumeactivateslow-pressurereceptorswhichinturnlowerarterialpressure.§ Activation of low-pressure receptors enhances Na+ and water

excretion by: a) Decreasingtherateofantidiuretichormone(atrial-hypothalamic

reflex).b) Increasingglomerularfiltrationrate(atrio-renalreflex).c) DecreasingNa+reabsorption.

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{ CNS Ischemic Response: Ä whenbloodflowtothevasomotorcenterisdecreasedseverelyenoughto

causecerebralischemia,thevasoconstrictorandcardioacceleratorneuronsinthevasomotorcenterresponddirectlyandbecomestronglyexcited.Thiseffectisbelievedtobecausedbyfailureofbloodtocarrycarbondioxideawayfromthebrainstemvasomotorcenter.

Ä theCNSischemicresponseisoneofthemostpowerfulactivatorsofthesympatheticvasoconstrictorsystem(extensivestimulation).Itissometimescalledthe“last-ditchstand”(last-chance)pressurecontrolmechanism.

Ä Thisresponseoccurstopreventmultipleend-organfailureanddeathinseverelyhypotensivepatients.

Ä CNSIschemicresponseisnotactivateduntilpressurefallsbelow60mmHg;greatestactivationoccursatpressuresof15-20mmHg.

Ä Cushingreaction(brainedema)isaspecialtypeofCNSischemicresponse.Ä ProlongedCNSischemiahasadepressanteffectonthevasomotorcenter.

{ Bainbridge Reflex: Ä Whenrightatrialpressureincreases,theresultantvolumestretchestheSA

nodeandthusincreasesitsdischarge→HR↑Ä Also,thestretchofatriasendsafferentsignals(throughthevagus)tothe

braintoactivatethevasomotor(vasoconstrictor+cardio-acceleratory)tofurtherincreasetheHRandcontractility(toalesserdegree)oftheheart.

Ä ThisreflexPreventsdammingofbloodinveinsatriaandpulmonarycirculation.

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{ Renal Body Fluid System for Long-Term Arterial Pressure Control: Ä Avolumeofbloodisinfusedintravenously

andthustheECFVisincreased.Ä TheextravolumewillraisetheMSFP.

Consequently,thevenousreturnandCOareincreased.

Ä TheresultantincreaseinCOwillraisetheMAP.

Ä themiddlecurveistheeffectofthisincreasedarterialpressureonurineoutput,whichincreasestomultiplefolds.Alongwiththistremendouslossoffluidintheurine,boththecardiacoutputandthearterialpressurereturnedtonormal.

Ä Kidneyshaveextremecapabilitytoeliminateexcessfluidvolumefromthebodyinresponsetohigharterialpressure,toreturnthearterialpressurebacktonormal.

{ The adjacent figure represents the renal output curve for water and salt in response to rising arterial pressure.

Ä Theeffectofpressuretoincreasewaterexcretion→diuresis.

Ä TheeffectofpressuretoincreaseNa+excretion→natriuresis.

{ To maintain a constant BP, sodium and water intake must equal their output (urinary volume). Ä Thehorizontallinerepresentsthenetwater

andsaltintake,andtheredcurveisthesamerenaloutputcurve.

Ä Theonlyplaceonthegraphatwhichoutputequalsintakeiswherethetwocurvesintersect,calledtheequilibriumpoint.

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{ The two primary determinants of the long-term arterial pressure level are:

1. Thedegreeofpressureshiftoftherenaloutputcurveforthesamewaterandsaltintake.

2. Thelevelofwaterandsaltintake.a) Inthiscase,thenormalcurveisshiftedtothe

right.Theintakeisnotaltered.Butthekidneysarefunctioningabnormally(forexampleangiotensinIIlevelsareelevated).Shiftingtherenalcurvetoahighervaluewillincreasethearterialpressure(theequilibriumpointisalsoshiftedtotheright).

b) Changingthelevelofsaltandwaterintakealsocanchangethearterialpressure(equilibriumpointisalsoshiftedtoahighervalue).Conversely,adecreaseintheintakelevelwouldreducethearterialpressure.

c) Luckily,withnormalfunctioningkidneys,increasedsaltintakecausesonlysmallchangesinarterialpressure.Overalongperiodofchronicintakeofsalt,therenalcurvebecomesmuchsteepertomaintainnormalBP.(I’veaddedthisfiguretoclarifythemeaningofsteepness).

{ Renal body fluid feedback system has an infinite gain: Ä Oneofthecausesthatbaroreceptorsdonotplayaroleinlong-termregulation

ofBP(otherthanbeingadaptable)isbecausetheirgainissmall.Incontrast,therenalsystemhasalmostinfinitegain.

Ä Now,whatdoesgainmean?Itisameasureofeffectivenessofaparticularcontrolsystemtoresistchangesinhomeostasis.

Gain=Correction/errorÄ Thehigherthegainthehighertheeffectivenessofacontrolsystem.For

example,ifbloodpressureiselevatedfrom100mmHgto150mmHg,thebaroreceptorreflexcandecreasethepressuretoalmost120mmHg.Whatisthegaininthissituation?

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§ Gain=(120-150)/20=-1.5,thenegativesignindicatesanegativefeedbackmechanism.Youcannoticethatthegainissosmallbecausetheshort-termcompensatorymeasureshavelimitedabilitytominimizeachangeinbloodpressure.

Ä Ontheotherhand,therenalsystemreturnsthebloodpressureexactlytotheoriginalvalue(100mmHg).Becausetheerrorisalmostzero,thegainisinfinite.

{ Failure of Total Peripheral Resistance to Elevate Long-term Arterial Pressure: Ä ChangingtheTPRhasnoeffectonarterial

pressureonthelongterm,becausewhenthekidneysarenormallyfunctioning,bloodpressurewillbeadjustedbyincreasingordecreasingthecardiacoutput.

Ä IfTPRisdecreased(aftertheingestionofvasodilatorsforexample),thekidneysrespondandretainmorefluidstoincreasetheCOandmaintainaconstantarterialpressure.That’swhydiureticsareprescribedwithvasodilators(tocounteractthecompensatorymeasures→decreaseCOandconsequentlydecreasearterialpressure).

Ä Conversely,ifTPRisincreased,thekidneysrespondandexcretemoreNa+andwaterintheurinetodecreasetheECFVandconsequentlytheCO.

Ä Onemustaltertherenalfunctioncurveinordertohavelong-termchangesinarterialpressure.Changingrenalvascularresistancedoesleadtolong-termchangesinarterialpressurenottheTPR.

{ Sodium is a Major Determinant of ECFV: Ä Whysodium?Becauseitisthemajorcationin

theECF.ChangingNa+concentrationwillchangetheECFVbecausewaterfollowssodiumosmotically.

Ä AsNa+intakeisincreased;Na+stimulatesdrinking,increasedNa+concentrationstimulatesthirstandADHsecretion.

Ä ChangesinNa+intakeleadstochangesinextracellularfluidvolume(ECFV).

Ä ECFVisdeterminedbythebalanceofNa+intakeandoutput.

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{ Volume Loading Hypertension: a) IncreasingtheECFV.b) IncreasedECFVincreasesbloodvolume.c) Theincreasedvolumeincreasesvenous

returnandthusCO.d) IncreasingtheCOdecreasestheTPRalittle

bitthroughreceptiverelaxationofthevessels.

e) Thiswillincreasethearterialpressure,butifthekidneysarenormal,theBPwillbeadjusted.

{ Actions of the Renin Angiotensin System: Ä theeffectofhemorrhageonthearterial

pressureundertwoseparateconditions:1. withtherenin-angiotensinsystemis

functioning,thearterialpressurerosebacktoahighervalue.

2. withoutthesystemfunctioning,moretimeisspenttoelevateBP,andthemaximumvalueisfarlessthanthenormalvalue.

Ä Therenin-angiotensinsystemispowerfulinreturningthearterialpressurebacktoalmostnormalvaluesafterseverehemorrhage.Therefore,sometimesitcanbelifesaving,especiallyincirculatoryshock.

Ä ThefigureshowsdifferentlevelsofAngiotensinIIintheblood.Thenormallevelissomethinginbetweentheblueandredcurves(theadditionalgreencurve).

Ä WhentheangiotensinsystemisblockedandnoAngiotensinIIisformed,therenalcurveisshiftedtotheleft(equilibriumpointisshiftedtotheleft→lowerBPatthesamesaltintakelevel).

Ä WhenangiotensinIIlevelisabovethenormallevel(likeinhypertension),thecurveisshiftedtotheright(equilibriumpointisalsoshiftedtotheright→higherBPatthesamesaltintakelevel).

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Ä AngiotensinIICausesvasoconstrictionandNa+retentionbydirectandindirectacts(throughaldosterone)onthekidney→Causesshiftinrenalfunctioncurvetotheright.

Ä ACEinhibitors(captopril)andangiotensinreceptorblockersareusedtotreathypertension,becausetheyshifttherenalcurvetotheleft(towardsnormallevels).

{ RAS is important in maintaining a normal AP

during changes in Na+ intake. • AsNa+intakeisincreasedreninlevelsfallto

near0.• AsNa+intakeisdecreasedreninlevels

increasesignificantly.{ Factors Which Decrease Renal Excretory

Function and Increase Blood Pressure: 1. AngiotensinII 2. Aldosterone3. Sympatheticnervousactivity4. Endothelin(vasoconstrictorreleasedbyendothelialcells).

{ Factors Which Increase Renal Excretory Function and Reduce Blood Pressure:

1. Atrialnatriureticpeptide2. Nitricoxide(localvasodilator)3. Dopamine(vasodilator)

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{ Everythinginthepreviousfigurehasbeenexplainedindetails.JustgooveritquicklytorevisethemainconceptsofBPregulation.

{ Consequences and Compensations of Hemorrhage: 1. Followingseverebloodloss,thereducedvolumeleadstoadecreasein

venousreturnandafallinCOandarterialbloodpressure.2. Thebaroreceptorreflexincreasesthesympatheticanddecreasesthe

parasympatheticactivitytotheheart.3. TheheartrateisincreasedtocompensateforthedecreasedSV.4. Increasedsympatheticactivitytotheveinsproducegeneralizedveno-

constriction,increasingthevenousreturn.5. Sympatheticstimulationincreasesthecontractilityoftheheart,tobeat

moreforcefullyandejectmoreblood→increasedSV.6. TheincreasedHRandSVcollectivelyincreasetheCO.7. Sympatheticallyinducedgeneralizedarteriolarvasoconstrictionleadstoan

increaseinTPR.8. Together,theincreaseinCOandTPRincreasethearterialpressure.9. Urinaryoutputisreduced,therebyconservingwaterthatnormallywould

havebeenlostfromthebody.Thisadditionalvolumehelpsexpandthereducedplasmavolume.

§ Reductioninurinaryoutputresultsfromdecreasedrenalbloodflow(afferentarteriolevasoconstriction→↓GFR).10. ThereducedplasmavolumetriggersthesecretionofADHandactivatesthe

renin-angiotensin-aldosteronehormonalpathway,whichfurtherreducesurinaryoutputandelevateBP.

11. Thirstisalsostimulated;theresultantfluidintakehelpsrestoreplasmavolume.

§ I’veonlymentionedthepointsthatarerelatedtoourlecture.§ Somefiguresarenotaddedtothissheet,pleaserefertotheslidesandcheckthem.

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