The Cardiovascular system
Session1
Diffusionisaffectedby:
 The area available forexchange
 The difficultyof movementthro...
Regulatingbloodflow
 If a pumpisjust connectedtoa networkof vesselsbloodwillonlyflow tothe partsthat are
easiesttoperfuse...
containsemilunarpairedvalvesthatpermitbloodtoflow inonlyone direction;those veinsare
narrowerthan 1 mm in diameterandthose...
side of the heart pumpsbloodtothe lungs(pulmonarycirculation),the leftside tothe body – or
systemiccirculation.
CardiacMus...
Heart sounds
In the normal heartthere are alwaystwo sounds.Twoothersmaybe audible
 firstsound - ‘lup’ - closure of a/v va...
Loopingoccurs because itputs:
Primordiumof rightventricle closesttooutflow tract
Primordiumof leftventricle closesttoinflo...
Foetal circulation
 Lungs are non-functional
 Receivesoxygenatedbloodfrom
motherviaplacentaand umbilical vein
 By-passe...
The muscularportionformsmost of the septumand growsupwardstowardsthe fusedendocardi al
cushions.Thisleavesthe1o
interventr...
Parasympathetic division Sympatheticdivision
Craniosacral origin Thoracolumbarorigin
Preganglionicfibrestravel in cranial ...
Note that inthe PNSsome gangliainthe neck and abdomen are locatedfurtherawayfrom the
target organs.ANDsome gangliainthe ne...
Neurotransmission
1. Uptake of precursor
2. Synthesisof transmitter
3. Vesicularstorage of transmitter
4. Degradationof tr...
Noradrenalinerelease istriggeredby
depolarizationof the nerve terminal
membrane,Ca2+
entryand fusionof vesicles
withthe pr...
Functions ofthe ANS
 Regulatesphysiological functions
 Sympatheticactivityisincreasedunderstress
 Parasympatheticsystem...
Control of the CardiovascularSystem
It controls,heartrate,force of contractionand peripheral resistance.
BloodVessels
The ...
Parasympatheticactivitytendstoslowthe heartrate.In the absence of any autonomicactivitythe
heartrate isabout 100 bpm,so th...
Sympatheticactivityincrease slope.Parasympatheticactivitydecreasesslope of the pacemaker
potential.
Action of noradrenalin...
Session5 – Blood Flow
Flow:the volume of fluidpassingagivenpointper unittime
Velocity:the rate of movementof fluidparticle...
If flowisfixed –the higherthe resistance the greaterthe pressure change fromone endfothe
vessel tothe other
If pressure is...
Autoregulation– If supplypressure changes,bloodflow toatissue will change.Thisthenchanges
the metabolite concentrationanda...
Subsequently,endsystolicvolumeincreasesif venouspressure increases.
End systolicvolume depends on,howhardit contracts andh...
Exercise causes, obviously,amassive increaseindemandand‘muscle pumping’whichforcesblood
back to the heart.With nootherchan...
The equilibriumpotential –eachionhas
an EP whichisthe hypothetical
membrane potentialwhichwould
developif itwere the onlyi...
sympatheticactionandslowedbyparasympatheticactionviathe vagusnerve.
Drugs acting on the CVS
Drugs are usedtotreat, arrhyth...
Drugs
Cardiac glycosides– Ca2+
isextrudedviathe Na+
-Ca2+
exchanger.Itisdrivenbymovingdownconc.
Gradient.Cardiacglycosides...
large electrical signal whichmaybe recordedbyelectrodesattachedtothe bodysurface.Thisis
knownas the Electrocardiogram.
The...
bodysurface.The differential amplifiersusedtorecordthe ECGs take the signal cominginon their
negative input,invertitthenad...
It isa pathophysiological state inwhichanabnormalityof cardiacfunctionisresponsibleforthe
failure of the heartto pumpblood...
Sympathetic nervous system
Baroreceptor-mediatedresponse causesearlycompensatorymechanismtoimprove cardiacoutput,
such as ...
THIS LEADS to
Skeletal muscleschanges –reducedbloodblow flow,reductioninmass,contribute tofatigue and
exercise intolerance...
Special Circulations
Differentpartsof the circulationhave differentproperties.
The pulmonary circulation
The lungshave two...
Thoughincreasedcapillarypressurecausesmore fluidtofilterout  oedema.Canbe due to
increasedvenouspressure (duetomitral val...
Adenosineisapowerful
vasodilatorof cerebral
arterioles
Cushing’sReflex
Rigidcraniumprotectsthe
brain,but doesnotallowfor
v...
Skeletal muscle circulation
It mustincrease O2 and nutrient
deliveryandremoval of metabolites
duringexercise.Ithasanimport...
Stable angina
Symptom,nota diagnosis,commonestcause of coronaryartherosclerosis.One majorartery >70%
reductioninluminal di...
CardiacArrest
Heart has stoppedorhas ceasedtopumpeffectively.signsunresponsivenessassociatedwithlackof
pulse.
Asystole –lo...
Cardiogenicshock
Pumpfailure the ventriclecannotemptyproperly.OccursfollowingMIor due to seriousarrhythmias
or worseningof...
Symptoms  difficultybreathing,collapsed,tachycardia,strongpulse andred,warmextremities.
Needsadrenaline vasoconstrictionv...
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The Cardiovascular system.docx 2605KB Apr 11 2010 - LUSUMA - Home

  1. 1. The Cardiovascular system Session1 Diffusionisaffectedby:  The area available forexchange  The difficultyof movementthroughthe barrier.  The concentrationgradient. Capillariesare the site of diffusionandtheyare composed of single layerendothelial cells surroundedbybasal lamina. Small hydrophilicsubstancessuchasglucose diffuse throughaqueousporesbetweenendothelial cells. OthersubstancessuchasO2 andCO2 are lipophilicanddiffuse throughthe membrane. Capillarydensity–The more metabolicallyactivethe tissue the more capillarydenseitis. Generally area isnot the limitingfactor. Diffusionresistance –Resistance todiffusiondependsonthe nature of the barrier,the nature of the moleculeswhichare diffusingandthe pathlength.Pathisshortestinmostactive tissues. Concentrationgradient - Thisgradientdoesdependonthe concentrationof substancesinthe blood enteringthe tissue,butthe more importantvariableisthe flowof bloodthroughthe capillary. Unlessbloodissuppliedatan appropriate rate,the gradientsdrivingexchange willdissipate,and nutrientswill notbe suppliedatthe rightrate. Therefore maintainingthe rightflowof blood(perfusionrate) forthe prevailinglevel of metabolic activityisthe mostcritic thing. Tissue Minimumbloodflow (ml/min) Maximumbloodflow (ml/min) Brain– extremely intolerantofflow interruption 750 750 Heart – also intolerant 300 (rest) 1200 (extreme work) Kidney:highconstant flow 1200 1200 Gut: depends oningestion 1400 2400 Skeletal muscle 1000 16000 Skin– not very metabolic 200 2500 Other 200 200 Total 5050 24250 So the CVSmust supplybetween5-25l.min-1 of bloodtothe tissueswhilstatall timesmaintain perfusiontovital organssuchas the brain,heart andkidneys.
  2. 2. Regulatingbloodflow  If a pumpisjust connectedtoa networkof vesselsbloodwillonlyflow tothe partsthat are easiesttoperfuse.  The brain isharderto perfuse due togravity  To regulate bloodflowyouneedtoaddresistance tothe system  Reduce the ease withsome regionsare perfusedinordertodirectbloodflow tothe areas harderto perfuse to.  Arterioles are the resistance vessels  The total flowinthe systemhasto be able to change.Thisoccurs because the veinsactas a store of blooddue totheirabilitytocollapse ordistend. Structure of Blood vessels ElasticArteries permitelasticrecoil of vessel.Ensure bloodflow duringdiastole Muscular ArteriesBloodflow requirementsvary.Control flow tolarge arease.g.Femoral toleg Arterioles diametersare small,anychange in diameterhasagreat effectonperipheral resistance. Increasedperipheral resistance leadsincreasedbloodpressure.Some treatmentsforhypertension use drugs whichcause relaxationof arteriolar smoothmuscle. The diameterof the musculararteriesandarteriolesiscontrolledbythe ANS.The arteriolesbranch intosmallervessels(metarterioles),whichcarrybloodintothe smallestvesselsinthe body,the capillaries. Capillaries 1 cell thick The capillarywall maybe continuousorfenestrated.Boththese typesof the capillariesmaybe surroundedpartiallybypericytes. In additiontothese twotypesof capillaries,there isacategoryof vesselsfoundinthe liver,spleen and the bone marrow,called sinusoids,whichare generallylarge indiameterandmaycontain special liningcellsandanincomplete basal lamina.Undercertainconditions,some bloodcellsleave the circulatorysystemtoenter the tissue spaces. Venulesand veins Capillariesmerge intolarge vesselscalledthe venules whichmerge to form the veins. The constructionof a veinis essentiallysimilartothat of an artery;expectthatits wall is thinneranditslumenwider and irregular.The veinsusually
  3. 3. containsemilunarpairedvalvesthatpermitbloodtoflow inonlyone direction;those veinsare narrowerthan 1 mm in diameterandthose inthe thoracicand abdominal cavitiesdonothave valves. The veinscollapse if bloodpressure isnotmaintained;the bloodflow inarteriesisthe resultof cardiac systolicpressure,whereasbloodflow inveins,toagreat extent,determinedbythe “muscle- pump”action inthe legand pressure factorsinthe abdominal andthe thoraciccavities. Avascularstructuresinclude cartilage,epithelia,corneaandsome others. Arteriovenousshunts It is the passage of blooddirectlyfromarteriestaken,withoutgoingthroughthe capillarynetwork. Thisis achievedbydirectpassage throughthe channelsandthe contractionof the pre-capillary sphincters. Bloodsystem bloodsupply The vesselsare calledvasavesoremthatsupplythe largerbloodvesselswallswithblood.There purpose:Theyhelpwarmthe bloodinthose veinsandsupplynutrientstothe vessel wall. Vena comitantes Theyare an irregularbranchingnetworkof veinssurroundingandaccompanyingdeeparteries.This arrangementservesasa countercurrentheatexchangerbetweenwarmarteriesandcoldbloodin the peripheral veins.The veinsproduceavascularsheatharoundthe arteriesasa resulttheyare stretchesandflattenedasthe arterycontracts which aidsmovingvenousblood. Varicoseveins A thrombosisoccurswhichocclude the veintherefore blooddrainage backtothe heartis occluded. Weakenedveinsdilateunderthe pressure of supportingthe bloodagainstgravity,thisaffectis pronouncedinthiscondition. Heart Muscle Involuntaryyetstriated,contractsrhythmicallyandautomatically Elongatednuclei (1or 2 per cell) lie deepinthe fibre.Fibresmaybifurcate andformconnections givinga complex 3dnetwork.The cellsare joinedendtoendbyintercalateddiscs. Sarcoplasmicreticulumhasnoterminal cisterna. The muscle fibresbranchandanastomose. Session2 and 3 The heart as a pump The heart istwo pumpsinseries.Thinwalledatriaact as reservoirstosupplymuscularpumping chambers – the ventricles.Inflowandout-flow tothe ventriclesare separatedbyvalves.The right
  4. 4. side of the heart pumpsbloodtothe lungs(pulmonarycirculation),the leftside tothe body – or systemiccirculation. CardiacMuscle The myocardiumconsistsof individual cellsjoinedbylow electrical resistance connections.Cells contract whenactionpotential inmembrane.The actionpotentialcausesarise inintracellular[Ca2+ ]. The AP islong– a single contractionlasts280ms – systole.Actionpotentialstriggeredbyspreadof excitationfromcell tocell,sotoeach heartbear all the cellsinthe heartnormallycontract. Pacemakers In the normal heartthe pacemakerinsino-atrialnode- rightatrium.Activityfirstspreadsoverthe atria - atrial systoleto reachthe atrio-ventricularnode,where delayedforabout120 ms. Thenfrom a-vnode spreadsdownthe septumbetweenthe ventricles.Thisthenspreadsthroughthe ventricularmyocardiumfrominner(endocardial)toouter(epicardial) surface Thus the ventricle contractsfromthe apex up,forcesbloodtowardsthe outflow valves. Contractionof the atria is notforceful,butthe ventricularmuscle isorganisedintofigureof eight bandswhichsqueeze the ventricularchamberforcefullyinawaymost effective forejectionthrough the out flowvalve.The apex of the heartcontracts firstandrelaxeslasttopreventbackflow. The CardiacCycle It isthe sequence of pressureflowchangesandvalve operationsthatoccur witheachheartbeat. At restthe SA node generatesanAPaboutonce a second(60bpm).Thisproducesa shortatrial systole followedbyalongerventricularsystole,ventricularsystolelastsabout280ms. Thisis followedbya relaxationlastingabout700ms before the nextsystole. As the ventricularmuscle relaxes,the intra-ventricularpressure falls,andthe atrio-ventricularvalves (tricuspidandmitral) openasatrial pressure exceedsventricular.The atriahave beendistendedby continuingvenousreturnduringthe precedingsystole, soinitiallybloodisforcedrapidlyfromthe atria intothe ventricles –the rapidfillingphase. Fillingof the ventriclescontinue throughout diastole,ata steadilydecreasingrate until the intra-ventricularpressure risestomatchatrial pressure.Atlowheartratesthe ventriclesare more or lessfull before the nextsystole begins. Systole begins withatrial systole –contractionof the atria,whichforcesa small extraamountof bloodintothe ventricles.Afteradelayof about100-150ms the ventriclesbeingtocontract.As intra ventricularpressure rises,sobloodtendstoflow the ‘wrongway’throughthe A/V vales, producinga turbulence whichclosesthe valvesforcible.The ventriclesthencontract‘isovolumetrically’andthe intraventricularpressure risesrapidlyuntil itexceedsthe diastolicpressureinthe arteries,whenthe outflowvalvesopen.There isthenaperiodof rapidejectionof blood,andbothintraventricularand arterial pressure rise toa maximum.Towardsthe endof systole intraventricularpressure falls,and once it isbelowthe arterial pressure the outflow valvesclose,andwhenthe atrial pressure is reachedthe A/V valvesopen,andthe whole processstartsagain.
  5. 5. Heart sounds In the normal heartthere are alwaystwo sounds.Twoothersmaybe audible  firstsound - ‘lup’ - closure of a/v valves –onsetof ventricularsystole  secondsound - ‘dup’- closure of outflow valves –endof ventricularsystole  So roughly280ms betweenlupanddup.Theninterval of 700ms.  It can be normal tohear twomore sounds.The thirdsoundmaybe heardearlyindiastole, and a 4th sometimesassociatedwithatrial contraction. Qualityof soundsmaychange if valvesaltered. Sounds maysplitif valvesof rightand leftheartdonot close at same time. Murmurs - turbulentbloodflowgeneratesmurmurs Aortic valve- 2nd intercostal space,rightsternal edge Pulmonary valve- 2nd intercostalspace,left sternal edge Tricuspid valve- 4th intercostal space,left sternaledge Mitral valve- 5th intercostalspace,mid-clavicularline Narrowedvalve –stenosis Valve notclosingproperly –incompetence. Alsoduringexerciseinnormal individualsturbulentflow canoccur andgenerate murmurs. Cardiac Output = Stroke Volume X heart rate. (atrest 80ml X 60 = 5l.min-1 ) Heart Development Cephalocaudal foldingbringsheartintothoracicregion,lateral foldingcreateshearttube.Paired endocardial tubesfuse tocreate primitive hearttube.Thistube receives venousdrainage fromits caudal pole and beginningtopumpbloodoutthe 1st aorticarch intothe dorsal aorta. At thistime the hearttube issuspendedinthe pericardial cavitybyamembrane thatsubsequently degenerates. The heart tube continuestoelongate andbendonday23. Thisbending,due tocell shape changes, createsthe cardiac loopand iscompletedbyday28. Cephalicportion –Bendsventrally,caudally&to the right Caudal portion - Bends dorsally,cranially&tothe left
  6. 6. Loopingoccurs because itputs: Primordiumof rightventricle closesttooutflow tract Primordiumof leftventricle closesttoinflowtract Atriumdorsal to bulbuscordis,i.e.inflow isdorsal tooutflow NB: Primordium- the firstrecognizable,histologicallydifferentiatedstage in the developmentof an organ. Afterlooping,the atriumcommunicateswithventricleviaatrioventricularcanal Developmentofthe sinus venosus In the middle of the 4th week,the sinusvenosusreceivesvenousbloodfromthe rightandleftsinus horns. Initiallybothhornsare equal insize,venousreturnshiftstorightside,Leftsinushornrecedes.Then rightsinushorn isabsorbedbyenlargingrightatrium. Developmentofthe atria Rightatriumdevelopsfrommostof the primitive atrium,the sinusvenosusanditreceivesvenous drainage fromthe bodyand the coronary sinus. Leftatriumdevelopsfromasmall portionof the primitive atrium,absorbsproximalpartsof the pulmonaryveinsandreceivesoxygenatedbloodfromthe lungs.
  7. 7. Foetal circulation  Lungs are non-functional  Receivesoxygenatedbloodfrom motherviaplacentaand umbilical vein  By-passesthe lungs (ductus arteriosus)  Returnsto the placentaviaumbilical arteries  BUT -the change incirculationmust happenimmediately.  By-passthe liver(ductus venosus) – thisstopsit stealingall the oxygenated blood. Early arterial systembeginsasabilaterallysymmetrical systemof archedvessels.These undergo extensive remodellingtocreate the majorarteriesleavingthe heart. 4th arch – Rightbecomesthe Rightsubclavianartery,Leftbecomesthe aorticarch 6th arch – Rightbecomesthe rightpulmonaryartery,Leftbecomesleftpulmonaryarteryandductus arteriosus. Septation(day27 – 37) Once the primitive hearttube haslooped,the mostcomplexsequence of heartdevelopmentgets underwaytocreate the “two pumpsinseries”configurationrequired.Therefore inthe processof septation the primitive hearttube becomesdividedintochambers andthe outflow tractis subdividedintopulmonarytrunkandaorta. It starts byendocardial cushionsdevelopinginthe atrioventricular region;thisdividesthe developingheartintorightandleftchannels. Atrial septation Divisionof the common atriuminvolvesthe formationof twoseptawith3holes.Septumprimum growsdowntowardsthe fusedendocardialcushions.The ostiumprimumisthe hole presentbefore the septumprimumfuseswiththe endocardialcushions.Beforeostiumprimumcloses,asecond hole,the ostiumsecundumappearsinthe septumprimum.Finallyasecondcrescentshaped septum,the septumsecundumgrows;the hole inthe septumsecundumisthe foramenovale. The two holesnot liningup allow it to be closedat birth. The fossaovalisisthe adultremnantof the shuntused in utero to by-passthe lungs. Ventricularseptation Ventricularseptum hastwocomponents,the muscularandmembranous.
  8. 8. The muscularportionformsmost of the septumand growsupwardstowardsthe fusedendocardi al cushions.Thisleavesthe1o interventricularforamen. The membranousportionof the interventricularseptumformedbyconnective tissue isderived from endocardial cushionstofill the gap. Endocardial cushionsalsoappearinthe truncusarteriosus; forma spiral septumbetweenaortaand pulmonarytrunk. At birth – the change in circulationmusthappenimmediately. Respirationbegins,leftatrial pressure increasesandforamenovale closes (septumprimumpushed againstseptumsecundum) andductusarteriosuscontracts.Placental supportremovedandductus venosus closes. Congenital heartdefects Aetiology– The cause of a specificdisease. Can be due to genetice.g. – down’s,turner’s,Marfan’ssyndrome Or Environmental –teratogenicityfromdrugs, alcohol etc. Or maternal infections –rubella,toxoplasmosisetc. Classification  Acyanotic o Left to right shunts: atrial septal defects,ventricularSD,patentductusarteriosus o Obstructive lesions: Aorticstenosis,pulmonarystenosis,coarctationof the aorta (narrowingof aorta where ductusarteriosusinserts),mitralstenosis.  Cyanotic (complexrightto leftshunts) o Tetralogy of Fallot– pulmonarystenosis,ventricularseptal defect,rightventricular hypertrophy,over-ridingaorta. o Transpositionof the great arteries– RV connectedtoaorta, LV connectedto pulmonaryartery,notviable unlessa-vshuntorductal shuntspresent. o Total anomalous pulmonary venousdrainage o Univentricularheart – single ventricle. Session4 The Autonomic nervous system It isimportantfor regulatingmanyphysiological functions,it islargelyoutsidevoluntarycontrol and it acts on smoothmuscle,exocrine secretionandlastlythe rate andforce of contractioninthe heart. The definingcharacteristicof the ANSisthat one nerve cell inthe pathwayislocatedentirelyoutside of the CNS.The cell bodiesof these neuronesare locatedinthe structuresknownasganglia. 2 divisionsthe parasympatheticandsympathetic.
  9. 9. Parasympathetic division Sympatheticdivision Craniosacral origin Thoracolumbarorigin Preganglionicfibrestravel in cranial nerves(3, 7, 9 and 10 or sacral outflowfrom S2-4 Preganglionicneuronesarise fromsegmentsT1 to L2 (or L3) Synapse with neuronesin ganglia close to the target tissue Most synapse withpostganglionicneuronesin the paravertebral chainof ganglia Short postganglionicneurones Some synapse ina numberof prevertebral ganglia– coeliac,superiormesenteric,inferior mesentericganglia long pre-ganglionic,shortpost-ganglionic nerves Short pre-ganglionic,longpost-ganglionic nerves. Cell-bodiesinlateral hornof the greymatterof spinal cord
  10. 10. Note that inthe PNSsome gangliainthe neck and abdomen are locatedfurtherawayfrom the target organs.ANDsome gangliainthe neckand abdomenof the SNShave longerpre-ganglionic fibres. Most organs are innervatedbythe sympatheticNS,ratherfewerbythe parasympathetic.Some organs have both sympatheticandparasympatheticinnervationwhichgenerally,butnotalways, have opposingactions. Chemicaltransmitters intheANS Preganglionicneuronesof bothdivisionsreleaseacetylcholine.Achactson nicotinicAchreceptors on the postganglioniccell.NicotinicAchreceptors have anionchannel. Receptorsare categorised intotypesbytheirresponsestodifferentagonistsandantagonists. Postganglionicsympatheticneuronesare usuallynoradrenergic.Differenteffectororganshave differentreceptortypesforNA.There are twobroadtypesα andβ receptors,buteachissubdivided intheirresponsestodifferentdrugs. Postganglionicparasympathetic neuronesare usuallycholinergic. –They usuallyacton a different type of receptoron the effectorcell –the muscarinicsubtype The exceptionissympatheticinnervationof the sweat glands;here postganglionicneuronesrelease Ach whichacts onmuscarinicAch receptors. All adrenoreceptorsare G protein-coupledreceptorssohave nointegral ionchannel. Chromaffincells of the adrenal medullaare like specialisedpostganglionicsympatheticneurones.As theyrelease adrenalinewhichcirculatesinthe bloodstream. NANCnon-adrenergic,non-cholinergic–these are othertransmittersinthe ANS.NANCtransmitters are often co-releasedwitheitherAchor NA.Examplesinclude,ATP5-hydroxtryptamine (serotonin), nitricoxide andseveral neuropeptidesincludingneuropeptidesY;vasoactive intestinal peptideand substance P.
  11. 11. Neurotransmission 1. Uptake of precursor 2. Synthesisof transmitter 3. Vesicularstorage of transmitter 4. Degradationof transmitter 5. DepolarisationbypropagatedAP. 6. Influx of Ca2+ inresponse todepolarisation 7. Exocytoticrelease of transmitter 8. Diffusiontopost-synapticreceptors 9. Interactionwithreceptors 10. Inactivationof transmitter 11. Re-uptake of transmitterordegradationproduct 12. Interactionwithpre-synapticmembrane. Cholinergictransmission Ach issynthesisedbycholine acetyltransferase fromcholine andacetyl CoA incytoplasm.Some is degradedbycytoplasmiccholinesterase majorityistransportedintosynapticvesiclesbyanindirect active transportmechanism.ReleasedbyCa2+ - mediatedexocytosis.Wheninsynapse interacted withpre- and postsynapticcholinoceptors.Butrapidlydegradedbycholinesterase.Fasteratfast (nicotinic) synapseslimitingthe synapticclefthalf leftof Achto a few milliseconds.Mostcholine is recapturedbya choline transporterpresentinthe synapticterminal. Drugs: maindrug actionwithcholinoceptors,butcanuse cholinesterase inhibitorstodecrease the rate of Ach degradationandsoprolongthe lifetimeof Achwithinthe synapticcleft.  Nicotiniccholinoceptorsantagonists mayhave apreferential ganglionorneuromuscular blockingaction.Rarelyused,butneuromuscularusedtocause muscle paralysisduring anaesthesia.  Muscariniccholinoceptorsagonists varyintheirmuscarinicnicotinicselectivityand resistance todegradationbycholinesterase.NosignificantselectivitybetweenM1,M2, M3, receptors.Clinical use glaucoma.  Muscariniccholinoceptorsantagonists –againlittle selectivitybutvarietyinperipheral and central actions. Hyoscine usedas anaestheticpremedicationdecreasesbronchial and salivarysecretions,preventsreflexbronchoconstriction. Alsopupillarydilatationand paralysisof accommodationcanbe causedby muscariniccholinoceptorsantagonists.  Cholinesteraseinhibitors –differintheirlongevityof actionandtheirperipheral versus central effects.Theyare usedtoacutelyreverse the effects of non-depolarizing neuromuscularblockingagentsusedinanaesthesia,glaucomaandinmyastheniagravis. Adrenergic Transmission
  12. 12. Noradrenalinerelease istriggeredby depolarizationof the nerve terminal membrane,Ca2+ entryand fusionof vesicles withthe pre-synapticplasmamembrane. Releasednoradrenaline caninteractwith bothpre and postadrenoceptors.However, the opportunitytointeractwithreceptorsis limitedbyahighaffinityre uptake system (Uptake1).AnyNA escapingfromthe synapticcleftisremovedfromthe extracellularspace byanother,widespread, loweraffinityre-uptakesystemcalled uptake 2. It is eitherre-usedorbrokendownby monoamine oxidase. Drugs  α-methyl-tyrosine –competitivelyinhibitstyrosine hydroxylase,soblockssynthesisof NA. Onlyuse inpheochromocytoma.  Α-methyl-DOPA –is takenupby adrenergicneuronesandisconvertedtoα-methyl- noradrenaline.UnlikeNA,α-methyl-DOPAispoorlymetabolizedandtherefore accumulates inthe synapticvesiclesof noradrenergicterminals.ItisreleasedbyCa2+ -mediated exocytosis,butitpreferentiallyactivatespre synapticα2-adrenoceptorsreducing transmitterrelease. Treatmenthypertension.  Adrenergicblockingdrugs – (e.g.guanethidine) blockactiononreuptake of neurotransmitter,andcause depletionof NA fromsynapticvesicles.Rarelyused.  Adrenoceptoragonist – highlyselective receptorsubtypeshave beenmade. o β1 agonists– cause positive inotropicandchronotrophiceffects.Butcause cardiac arrhythmias. o β2 agonists – reverse bronchoconstrictioninasthmatics(salbutamol). o α1 agonists – nasal decongestants. o α2 agonists – are anti-hypertensive.  Adrenoceptorantagonists o α-adrenoceptorantagonistsare usedtocause peripheral vasodilatationinthe treatmentof peripheralvasculardisease.Notusedinhypertensionbecause they cause postural hypotensionandtachycardia o β- adrenoceptorantagonists(betablockers) usedtotreathypertension,cardiac arrhythmias,anginaandMI. Possible side-effectsinclude brochoconstriction, bradycardia,coldextremities,insomniaanddepression.
  13. 13. Functions ofthe ANS  Regulatesphysiological functions  Sympatheticactivityisincreasedunderstress  Parasympatheticsystemismore dominantunderbasal conditions  Theyboth worktogethertomaintainbalance *cardiac automaticity the abilityof the cardiacmusclestodepolarize spontaneously Sympatheticdrive todifferenttissuesisindependentlyregulated. Organ Action of sympathetic Receptor Action of parasympathetic Receptor Pupil of the eye Dilation α1 Contraction of sphincter muscle M3 Salivary gland secretion becomes more viscous (amylase) α1 β secretion becomes more watery M3 Airway of the lung Relax β 2 Contract M3 Heart- SAN Increase rate β1 decrease rate M2 Heart – atrial muscles Increase forceof contraction β1 Force decrease M2 Heart – ventricular muscle Increases forceand automaticity* β1 No effect M2 Blood vessels in most tissues Constriction α no effect - Organ Action of sympathetic Receptor Action of parasympathetic Receptor Blood vessels in skeletal muscle Dilation β2 No effect - Blood vessels in erectile tissue Constriction α Dilation M3 Gut- secretion No effect - Secretion M3 Gut- motility Decreases α1 α2 β2 Increases M3 Gut – sphincters Constrict α2 β2 Dilation, secretion M3 Adipose Tissue Increased Lipolysis β3 storage - Liver Glycogenolysis, gluconeogenesis α1 β2 No effect Kidney Renin secretion β1 No effect Sweat Glands Secretion M, α1 No effect Sweat Glands (palms of hand) Localised secretion α1 No effect Male Sex organs Ejaculation α Erection M3
  14. 14. Control of the CardiovascularSystem It controls,heartrate,force of contractionand peripheral resistance. BloodVessels The smoothmuscle inthe wallsof arteries,arteriolesandveinsisinnervatedbythe sympatheticNs. Exceptinspecialisedvessels,sympatheticactivitycausesvasoconstriction.There isconstantactivity inthe sympatheticNSthe sympatheticvasomotortone tendingtomake arteriolarsmoothmuscle contract. The tone variesfromorgan to organ,as doesthe magnitude of itseffect.Inskin,for example,vasomotortone is high,soarterioles,pre-capillarysphinctersandarterio-venous anastomosisare generallyshutdown.Variationinsympatheticoutflow produceslarge changesin skinbloodflow,usuallyforpurposesof thermoregulation. Vasodilationoccurs with lesssympatheticoutput Vasomotor tone occurs with normal sympatheticoutput Vasoconstrictionoccurs withincreasessympathetic output Most arteriesandveinshave α1-adrenoreceptos –but coronaryand skeletal musclevasculatures alsohave β2-receptors. In skeletal musclesvasomotortone ishighatrest,but inexercise isantagonisedbothbylocal release of vasodilatormetabolitesandbyspecialisedvasodilatornervousactivity. Smoothmuscle Activatingβ2 adrenoreceptorscausesvasodilation  increasescAMP  opensa type of potassiumchannel relaxationof smoothmuscle Activatingα1 adrenoreceptorscausesvasoconstriction  increase in[Ca2+ ]in fromstoresand viainflux of extracellularCa2+ contractionof smooth muscle Local metabolites– active tissue producesmore metabolites.Local increasesinmetaboliteshave a strongvasodilatoreffect.Soitismore importantforensuringadequate perfusionof skeletal and coronary muscle thanactivationof β2-receptors. On the otherhand the circulationtothe brainis virtuallyunaffectedbysympatheticactivity. Sympatheticoutflowtobloodvesselsiscontrolledfromthe hindbrain –viathe vasomotorcentresin the medullaoblongata Sympatheticactivityalsoproduces veno-constrictionwhichiscontractionof smoothmuscle inthe wallsof veins.Thistendstoincrease venouspressure andforce more bloodbacktowardsthe heart. The parasympatheticNSacts onlyonspecialisedbloodvessels,thoughitsstimulatingactionon organs suchas the guyis associatedwiththe releaseof mediatorswhichmayproduce dramatic vasodilatation. The Heart
  15. 15. Parasympatheticactivitytendstoslowthe heartrate.In the absence of any autonomicactivitythe heartrate isabout 100 bpm,so the normal restingheartrate of about 30 isproducedbya constant parasympathetictone.Initiallyincreasesinheartrate are broughtabout byreducing parasympatheticactivity. ItactsonM2 receptors,theyhave anegative chronotrophiceffectandit decreases AV node conductionvelocity. The synapse withpostganglioniccellsisonthe epicardial surface or withinwallsof heartatSA and AV nodes. Risesinheartrate beyond 100 bpmare broughtaboutby sympatheticstimulation.Both parasympatheticandsympatheticoutflow tothe heartiscontrolledbycentresinthe medulla oblongatawhichthemselvesreceive informationfromsensoryreceptorsdetectingbloodpressure (‘baroreceptors’). The postganglionicfibresarrive fromthe sympathetictrunk,theyinnervate SAN, AVN andmyocardium,release NA andthisactson β1 adrenoreceptors.Thisactsto increase heart rate (positivechronotrophiceffect) andthe force of contraction(positiveinotropiceffect). The force of contractionof heartmuscle – contractility –is increased by sympatheticactivity. The action of the parasympatheticsystemonheartrate is mediatedviaAchactingonmuscarinic receptors. The action of the sympatheticsystemonheartrate and contractilityismediatedviaNA actingonβ1 receptors.Adrenaline alsoactsonthe heart.The ANStherefore providesthe central nervouscentres responsible forcontrollingthe CVSwiththe meantoaffectthe total peripheral resistance and distributionof bloodflow,andthe cardiacoutput. The heart pacemaker Cellsinthe SAN steadilydepolarise towardthreshold.Itisa slow depolarisingpacemakerpotential; it turnson a slowNa+ conductance and opensCa2+ channels. Fig.21.13
  16. 16. Sympatheticactivityincrease slope.Parasympatheticactivitydecreasesslope of the pacemaker potential. Action of noradrenaline  NA acting onβ1 receptorsinmyocardiumcausesandincrease incAMP  phosphorylation of Ca2+ channels  increasedCa2+ entryduringAP  increasedforce of contraction  alsoincreaseduptake of Ca2+ insarcoplasmicreticulum Drugs actingon the ANS Sympathomimetics– α and β – adrenoceptoragonists CVSuses Administrationof adrenaline to restore functionincardiacarrestand for anaphylacticshock Β1 agonist– dobutamine maybe givenincardiogenicshock Adrenoceptorantagonists α adrenoreceptorantagonists –anti-hypertensive agentasinhibitsNA actiononvascularsmooth muscle α1receptors– vasodilation β-adrenoreceptorantagonists(betablockers) –Propanolol –slowsheartrate and reducesforce of contraction(β1) but alsoacts on bronchial smoothmuscle (β2) brochoconstriction. Cholinergics Muscarinicagonists – usedin treatment of glaucoma– as it activatesconstrictorpapillaemuscle Muscarinicantagonists – increasesheartrate,bronchial dilation,alsousedtodilate pupilsfor examinationof the eye.
  17. 17. Session5 – Blood Flow Flow:the volume of fluidpassingagivenpointper unittime Velocity:the rate of movementof fluidparticlesalongthe tube. Flowα pressure difference betweenthe endsof the vessel. The flowfor a givenpressure gradientisdeterminedbythe resistance of the vessel. Flowisthe same at all pointsalonga vessel.Velocitycanvaryalongthe lengthif the radiusof the rube changes. If flowconstantthen velocityα (surface area)-1 Vesselswithsmall crosssectional areahave ahighvelocitye.g.aorta Vesselswithlarge overall crosssectional areahave alow velocitye.g.capillaries. Types ofFlow  Laminar – velocityhighestin the centre,fluidonthe edge isstationary  Turbulent– flowresistance greatlyincreased Viscosity The mean velocitydependsontwofactors.Firstly,the viscosityof the fluidandsecondlythe radius of the tube. Definition:The propertyof afluidthatresiststhe force tendingtocause the fluidtoflow. The higherthe viscositythe lowthe meanvelocity Viscositydeterminesthe slopeof the gradientof velocity.Ataconstantgradient,the widerthe tube the fasterthe middle layersmove,so: Mean velocityα crosssectional areaof the tube. PoiseullesLaw:∆𝑃 = 𝐹𝑙𝑜𝑤× 𝑣𝑒𝑙𝑜𝑐𝑖𝑡𝑦×8×𝑙𝑒𝑛𝑔𝑡ℎ 𝜋𝑟4 P ispressure difference.Therefore resistance increasesasviscosityincreases,andresistance decreaseswiththe fourthpowerof the radius. Connectedbloodvessels(like electricity.)
  18. 18. If flowisfixed –the higherthe resistance the greaterthe pressure change fromone endfothe vessel tothe other If pressure isfixed –the higherthe resistance the lowerthe flow The Whole Circulation  Flowisconstant  Arteriesare lowresistance  Arteriolesare highresistance  Individuallycapillariesare highresistance butcollectivelylow asmanyinparallel.  Venulesandveinsare lowresistance  The pressure withinthe arteriesishighbecause of the highresistance of the arterioles  For a giventotal flow,the higherthe resistanceof the arterioles,the higherthe arterial pressure.  Therefore if the heartpumpsmore bloodandthe resistance forthe arteriolesremainsthe same – the arterial pressure willrise. Distensible vessels Bloodvesselshave distensible walls.Asthe vessel stretches,soresistance falls.Asthe pressure withinadistensible vessel fallseventuallycollapse andbloodflowsceasesbefore the driving pressure fallstozero. Distensible vesselsstore blood,veinsare mostdistensible. Cardiac Output Arterial pressure must rise highenoughtodrive the cardiacoutputthroughthe resistance of the arterioles. If arterieshadrigidwallspressure wouldrise enoughinsystoletoforce the whole stroke volume throughthe total peripheral resistanceandthenfall tozeroindiastole.Thisdoesn’thappenbecause arteriesstretch,more bloodflowsinthanout,sopressure doesnotrise somuch. Asarteriesrecoil in diastole,flow continuesthroughthe arterioles. Typical bloodpressure: 120mmHg/80mmHg Pulse pressure 40mmHg the difference. Average pressure calculatedasdiastolicplusone thirdof pulse pressure, becausesystoleisshorter than diastole (95mmHg) Reactive hyperaemia– if the circulationto,say an arm is cut off fora minute ortwo,thenblood flowisrestored,there isamassive increase inthe armfor a shortwhile. Thisoccursbecause when there isno bloodflow, metabolitesaccumulate,soarteriolesdilatemaximallyandwhenflow is retuned,resistanceisverylow.Therefore,crucially,flow isveryhigh.Thenashighflow washesaway the metabolites,the smoothmuscle constrictsagain. Simply –more metabolism,more bloodflow.
  19. 19. Autoregulation– If supplypressure changes,bloodflow toatissue will change.Thisthenchanges the metabolite concentrationandaltersthe resistanceof arteriolessobloodflow returnstoan appropriate levelformetabolism. Providedsupplypressure remainswithincertainlimitstissueswillautomaticallytake whatblood theyneed.If all the tissuesinthe bodyalterthe resistance of theirarteriolestomatchmetabolism then,total peripheral resistance will be inverselyproportional tothe body’sneedforbloodflow. Summary Arterial pressure mustbe highenoughtoensure tissuesgetwhatbloodtheyneed,astotal peripheral resistance fallsmore bloodisneeded.Lastly,central venouspressurefillsthe heartwith everybeat. Session6 – Control of the CVS The pumpingactionof the heartremovesbloodfromthe veins,andsotendstolowervenous pressure.The bloodispumpedintothe arteries,tendingtoelevate arterial pressure.Allotherthings beingequal,the more the heartpumpsthe lowerthe venouspressurewillbe,andthe higherarterial pressure will be. Situations TPR Cardiac output Arterial pressure Venouspressure ↓ = ↓ ↑ ↑ = ↑ ↓ = ↑ ↑ ↓ = ↓ ↓ ↑ TPR isinverselyproportionaltothe body’sneedforblood.If metabolismchangesTPRwill change and generate ‘signals’inthe formof changesinarterial andvenouspressure. If the bodyneedsmore blood,the heartneedstopumpmore tomeetthe demand. This will be achieved if the heartrespondsto rises in venouspressureand fallsin arterial pressureby increasing it output. Factors affecting Cardiac Output The cardiac outputis the product of stroke volume andheartrate. Ventricularfilling In diastole the ventricle isisolatedfromthe arteries,andconnectedtothe veins,the ventriclefills until the wallsstretchenoughtoproduce aninterventricularpressure equal tovenouspressure. Withinlimits,the higherthe venouspressure,the more the ventricle willfillindiastole. The greaterthe enddiastolicvolumethe harderthe ventriclecontracts,thisis starlingslaw. The harder itcontracts the biggerthe stroke volume.
  20. 20. Subsequently,endsystolicvolumeincreasesif venouspressure increases. End systolicvolume depends on,howhardit contracts andhow hardit isto ejectblood. Force of contraction isdeterminedbyenddiastolicvolume andcontractility,contractilityis increasedbsympatheticactivity. The harder itis to ejectbloodthe higherthe pressure risesinthe arteries. Stroke volume willrise if...venouspressure risesor...arterial pressurefalls Control of Heart Rate Sympatheticactivityincreasesheartrate,parasympatheticdecreasesit. The main factorinfluencingautonomiccontrol of the heartis the activityof baroreceptorswhich monitorarterial pressure.Stretchreceptorsinthe walls of the aortaand the carotid sinus.This informationisreleasedtothe medullainthe brain,where collectionsof neurones –modifythe behaviours of the heartandcirculationviathe ANS.Fallsinarterial pressure leadtorisesinheart rate andcontractility. Baroreceptorsensure thatif arterial pressure fallsbothheartrate and stroke volume tendtorise. There isalso a minoreffectof venouspressure onheartrate – if venouspressure rises,thenheart rate rises(alsoknowasthe Bainbridge reflex). How the aboveapplies toreal stuff Eating a meal – causesincreasedactivityof the gutleadstolocal vasodilation.SoTPRfalls,venous pressure risesandarterial pressure subsequentlyfalls. Continuingthat,the rise invenouspressurecausesa rise incardiac output,so fall inarterial pressure triggersrise inheartrate and so cardiac output.Venouspressure reducedbyextrapumpingof the heart,so arterial pressure alsoincreases sothe demandonthe systemistherefore met. Changesin heart rate alone – If HR increaseswithnootherchange initiallyCOwill tendtorise,but TPR the same.So rise inCO reducesvenouspressure sostroke volume fallsandcardiacoutput resumestooriginal value. So we can conclude the heartcannot drive the circulationitisdrivenbyit.
  21. 21. Exercise causes, obviously,amassive increaseindemandand‘muscle pumping’whichforcesblood back to the heart.With nootherchangesvenouspressure wouldrise greatlyandarterial pressure wouldfall greatly.The greatincrease invenouspressure isthe mainproblemasthistendstooverfill the heart,i.e.pushesthe ventriclesontothe flatpartof the Starlingcurve.Sothere isa risk of pulmonaryoedemabecausethe outputsof the rightandleftventriclescannotbe matched. Both sidesbeatatthe same rate so can onlymatch by matchingstroke volume whichreliesonthe Starlingcurve.If the right heartpumpsmore,the leftfillsmore,andsopumpsmore,butif on the top of the curve the leftheartcannot respondto the rightso bloodaccumulatesinthe lungs. Overfillingof the ventriclesispreventedbyarise inheartrate whichoccurs as exercise beginsthisis drivenbythe brain.So whenthe venouspressure startstorise,heartrate is alreadyhighthiskeeps stroke volume down. Standing up on standingblood‘pools’inthe superficial veinsof the legsthisisdue togravityso central venouspressure subsequentlyfalls.SobyStarlingslaw,cardiacoutputfallssoarterial pressure falls,sonowbotharterial andvenouspressure changinginthe same direction.Thiscannot be correctedby normal mechanisms.Sobaroreceptorsdetectfall inarterial pressure,raise heart rate, but venouspressure silllow.Sothe TPRincreasestodefendarterial pressure inthe skinand gut. If thisreflex doesn’t work thisresultinpostural hypotension. Haemorrhage – Reducedbloodvolumelowersvenouspressuresocardiacoutputfalls,arterial pressure falls.Baroreceptorsdetectthisfall,soheartrate risesand total peripheral resistance increased. But rise inheart rate lowersvenouspressurefurthermakesproblemworse.Heartrate can become veryhigh.Rise inTPR helpsarterial pressure butlowersvenous,sodoesnotsolve originalproblem. Needtoincrease venouspressurethisisdone byconstrictionof bloodvesselsconserve bloodfor vital organ.Alsofluidalsotenstomove fromextracellularspace intothe circulation(auto- transfusion). Water,electrolytesandRBCseventuallyreplaced. Note – control systemsfinditdifficulttocope if arterial andvenouspressure change inthe same direction. Long term increase in bloodvolume – the kidneycontrolsbloodvolume, if bloodvolumeincrease for days venouspressure increases,socardiacoutputincrease soarterial pressure rises.Thisforces more bloodthroughtissues,whichautoregulate andincreaseTPRsoarterial pressure risesfurther and staysup. Inlongterm bloodvolume control mechanismscontrol mean highbloodpressure. Session7 Cellular and Molecularevents inthe Heart Myocardial cells– force generatedbyacontractile apparatusof actin and myosin.Thisgenerates tensionwhen[Ca2+ ]I rises.Tensionα [Ca2+ ]I [Ca2+ ]I mustrise to produce systole andfall toproduce diastole.The rise isdue toan actionpotential.
  22. 22. The equilibriumpotential –eachionhas an EP whichisthe hypothetical membrane potentialwhichwould developif itwere the onlyionthatcould cross the membrane.If the permeability of the membrane todifferentions changesthenthe membrane potential will change. Actionpotentialsarise bythe actionof voltage-gatedchannels.The whole event istriggeredinanyone cell bya small startingdepolarisation,takingthe membrane potentialbeyondthe thresholdforopeningthe fastNa+ channels.Forall cellsexceptthe pacemaker,thissmall depolarisationcomesaboutbyspreadof activityfromadjacentcells. The Cardiac action potential In diastole the cell membrane of myocardial cellsismostlypermeable toK+ .So the membrane potential isclose tothe Ep for K about-80mv. Spreadof activitydepolarisesventricularcells.Thisinitial depolarisationistoa thresholdwhich opensfastvoltage-gatedsodiumchannels.Somove towardsthe sodiumEp.Thisinturnopensall the fastNa channels,butfastsodiumchannelsclose fastaswell.Tomaintaindepolarisationvoltage- gatedcalciumchannelsopen. [Ca2+ ]o muchgreaterthan [Ca2+ ]I.Calciumrushesintothe cell which stimulatesrelease of Ca2+ storesandcausesthe cell tocontract. Theystay openfor250ms so the cell contracts for a longtime – systole. Whentheyclose the membrane repolarises,aidedbyextraK+ channelsopening,andCa2+ is sequesteredwithinthe cell,so [Ca2+ ]i falls. Pacemaker Potential Theyhave no fastNa channels.The upstroke of theiractionpotential isdue toCachannelsopening and isslow.Cachannelsalsoclose quickly.Once anactionpotential hasendedthe membrane potential isnotstable itdepolarisesslowly(Kchannels open). Eventuallythe pacemakerpotential reachesthe thresholdtoopenthe voltage fatedcalciumchannels so a newactionpotential beginsspontaneouslyand spreadsoverthe whole heart. Control of heart rate The interval betweenbeatsdependsonhow fastthe pacemakerpotential depolarises.Itisspeededupby
  23. 23. sympatheticactionandslowedbyparasympatheticactionviathe vagusnerve. Drugs acting on the CVS Drugs are usedtotreat, arrhythmias,heartfailure,bloodclottingdisorders,anginaand hypertension. Theycan alterthe rate and rhythmof the heart;the force of myocardial contraction;peripheral resistance;bloodvolume;bloodflowtocoronaryarteries. Arrhythmias– tachycardia,bradycardia, Atrial flutter–atria contractingis disorganised Atrial fibrillation –electrical activitystrange resultingnocontractionof the atria Ventricularfibrillation –noco-ordinatedcontractionof the ventricles. Causes: Ectopic pacemakeractivity –due to damagedarea of myocardiumbecome depolarisedand spontaneouslyactive.Alsodue tolatentpacemakerregionactivateddue toischaemia. Re-entryloopsresultinconductiondelay. Drugs to treat arrhythmia There are 4 basic classesof anti-arrhythmias  Drugs that blockvoltage-sensitiveNachannels(e.g.lidocaine alocal anaesthetic)  Antagonistsof β-adrenoreceptors(betablockers) o Blocksympatheticaction,therefore decrease slopeof pacemakerpotential inSAN. o Usedfollowingmyocardial infarctionasthese increase sympatheticactivity.Also theyreduce O2 demandso isobviouslybeneficial. o Alsoslow conduction socan preventsupraventriculartachycardias.  Drugs that blockK channels o Prolongthe actionpotential,aslengthenthe absoluterefractoryperiodsoprevents anotherAPoccurring toosoon. o Notgenerallyusedbecause theycancause torsadesde pointes,anotherarrhythmia o Usedto treat tachycardiaassociatedwithWolff-Parkinson-White syndrome  Drugs that blockCa channels (e.g.verapamil) o Decreases...slopeof pacemakerpotential atSAN.Decreases...AVN conduction o Decreasesforce of contraction. o Alsocausescoronaryand peripheral vasodilation. Heart Failure It ischronic failure of the heartto provide sufficientoutputtomeetthe body’srequirements. Features:reducedforce of contraction,reducedcardiacoutput,reducedtissueperfusionand oedema.
  24. 24. Drugs Cardiac glycosides– Ca2+ isextrudedviathe Na+ -Ca2+ exchanger.Itisdrivenbymovingdownconc. Gradient.Cardiacglycosidesblockthese,socause arise in [Na+ ]i.Thisrise causesdecreasedactivity of the Na+ -Ca2+ exchanger.So[Ca2+ ]I increasesalongwiththe force of contraction. AlsoblocksNa+ /K+ ATPase,soincrease in[Na+ ]I soinhibitionof the Na+-Ca2+exchanger.Soincrease of [Ca2+ ]I meansapositive inotropiceffectandincreasedforce of contraction. Lastlyincrease vagal activity – soslowsAVN conductionandslowsheartrate. ACE-inhibitors- Theyare drugswhichinhibitthe actionof angiotensinconvertingenzyme. Theypreventthe conversionof angiotensin1to angiotensin2.Angiotensin2actson the kidneysto increase Na+ reabsorptionandisa vasoconstrictor. Its effects:Decrease vasomotortone (↓ BP),reducedafterloadof the heart,↓ fluidretention, reduce preloadof the heart,reduce workloadof the heart. Anti-thromboticDrugs Certainheartconditionscarryan increasedriskof thrombusformationsuchasatrial fibrillation acute MI, mechanical prostheticheartvalves. Anticoagulants  Heparin(IV) inhibitsthrombin  Warfarin(orally) antagonisesthe actionof vitaminK,usedlongterm.  Antiplateletdrugs – aspirin Angina It ismyocardial ischaemia,itoccurswhenO2 supplytothe heart doesnotmeetitsneed.Thiscauses chestpain,usuallypainwithexertion.Itis due tonarrowingof the coronary arteriesby atheromatousdisease. Treatment– Reduce heart work load - betablockers,Ca2+ channel antagonists,organicnitrates Andimprove the blood supplyto the heart – organicnitratesand Ca2+ channel antagonists NO isa powerful vasodilator. Hypertension Associatedwithincreasesinbloodvolume –Na+ and waterretentionbythe kidneys Treatment– diuretics,ACE-inhibitors,β-blockers, Ca2+ channel antagonists,andα-adrenoreceptor antagonists. Session8 – The Electrocardiogram Witheach beatof the hearta large numberof muscle cellsundergoelectrical changesinaprecisely definedsequence.The co-ordinatedactivityof sucha large massof muscle generatesarelatively
  25. 25. large electrical signal whichmaybe recordedbyelectrodesattachedtothe bodysurface.Thisis knownas the Electrocardiogram. The electrodesoutsideof cellsonlyrecordchangesinthe membrane potential.Thereforeskin electrodespickuptwosignalswhicheachsystole.One ondepolarisationandone onrepolarisation. Spreadof excitationoverthe myocardiumalsogeneratesachangingsignal whichelectrodesdetect. Therefore the ECGis explainedbyacombinationof the effectsof depolarisationand repolarisation and theirspreadoverthe heart. Conduction Is showntothe rightit isimportantto rememberthe ventricles depolarise inside (endocardial) surface to the outside (epicardial)surface. Repolarisationingreenisinthe opposite directionhappens280msafterthe depolarisation. Electrode ‘Views’  What yousee dependsonwhere youare lookingfrom  Depolarisationmovingtowardsanelectrode=upwardgoingsignal  Depolarisationmovingawayfromanelectrode =downwardgoingsignal  Repolarisationmovingtowardsanelectrode=downwardgoingsignal  Repolarisationmovingawayfromanelectrode =upwardgoingsignal.  The amplitude of the signal dependson: o How muchthe muscle isdepolarising o How directlytowardsthe electrodethe excitationismoving. Waves  P wave – atrial depolarisation  Q wave – septal depolarisationspreadingtoventricle  R wave – mainventriculardepolarisation  S wave – endventriculardepolarisation  T wave – ventricularrepolarisation. Atrial repolarisationoccursduringventriculardepolarisation i.e.QRScomplex soitdoesn’tshowup. Lead configurations By placingelectrode indifferentpositionswe can‘lookat’the heartfrom differentangle.Thisallowsdetectionand localisation of abnormal patternsof electrical activity. Amplifiers The amplifiersusedtorecordthe ECG have twoinputs, not one,so at leasttwoelectrodes have tobe attachedto the
  26. 26. bodysurface.The differential amplifiersusedtorecordthe ECGs take the signal cominginon their negative input,invertitthenadditto the signal cominginon the positive inputbefore multiplying the sum by a factor knownas the gainand thenoutputtingit.Byknowingthe viewsof the positive and negative youcantherefore combineittomake a single electrodeview. Interpretingthe ECG Rate - all ECG machinesrunat a standardrate.Each large square = 0.2s so 300/min HR = 300/number of squaresof the R-Rinterval.Normal rate approx.60bpm Rhythm – regularor irregular, presence of Pwave P wave – absentpwave inatrial fibrillation. P-R interval – time takenforimpulse toreachventricles3-5small squares.Prolongedinfirstdegree heartblockand erratic inseconddegree heartblock. QRS complex – orientation –dependentonthe electrical axisof the heart Width– dependentonthe time ittakesto depolarisethe ventricles –normally0.12s ProlongedQRSdue tobundle branchblockor due to ectopicsite andslow pathway. Axis– Findthe leadwiththe smallestandmostequiphasicdeflection.The netdeflectioniszero indicatingthatthe electrical axismustrunat rightanglestothat view usuallyparallel tolead2. If the axisisnormal thenthe depolarisingwave isspreadingtowardsleadsI,II & IIIand therefore the deflectionsinthese leadsare predominantlyupward. If there isrightaxisdeviationthe deflectionin leadI will become predominantlydownward. If there isleftaxisdeviationthe deflectionsinleadsII & III will become predominantlydownward. Bundle branch block - lengthens andchangesshape of QRScomplex,manyvariations.  ECG: leftvs. right bundle block"WiLLiaMMaRRoW": W patterninV1-V2and M patternin V3-V6isLeft bundle block. M patternin V1-V2and W in V3-V6isRight bundle block MI features– S-Televation,pathological QwavesandinvertedTwaves. Pathological Qwavesmore than0.04s wide >2mm deep,remainafterotherchangesresolve. SinusRhythm - Wheneach P wave isfollowedbyaQRS complex Small Square – 40ms Heart Failure It isa state inwhichthe heart failstomaintainanadequate circulationforthe needsof the body despite anadequate fillingpressure.
  27. 27. It isa pathophysiological state inwhichanabnormalityof cardiacfunctionisresponsibleforthe failure of the heartto pumpbloodat a rate commensurate with requirementsof the metabolising tissues. It isa clinical syndrome causedbyanabnormalityof the heartandrecognisedbyacharacteristic patternof haemodynamic,renal,neuralandhormonal responses. Causes:primarycause IHD,hypertension,dilatedcardiomyopathy,valvularheartdisease,restrictive cardiomyopathy,hypertrophiccardiomyopathy,pericardial disease,high-outputheartfailure & arrhythmias. Class1 – class 4 – No symptomaticlimitationof physical activity  Inabilitytocarry outphysical activitywithoutsymptoms,mayhave symptomsatrest,discomfortincreaseswithanydegree of physical activity. Morbidity – 0.2% of populationare hospitalisedannuallyforheartfailure Physiology of the heart  Cardiac output≈ 5 litres/min  Stroke volume ≈75ml/beat  LV endsystolicvolume ≈75ml  LV enddiastolicvolume≈150ml  Ejectionfraction50% or greater  Weight≈ 330g Systolic dysfunction  IncreasedLV capacity  ReducedLV cardiac output  Thinningof the myocardial wall o Fibrosisandnecrosisof myocardium o Activityof matrix proteases  Mitral valve incompetence  Neuro-hormonalactivation  Cardiac Arrhythmias Structural heart changes  Loss of muscle  Uncoordinatedorabnormal myocardial contractioni.e.ECGchanges  Changesto the extracellularmatrix - increase incollagen(3>1) from5% to 2% and slippage of myocardial fibre orientation  Myocytolysisandvacuolationof cells  Myocyte hypertrophy  SR dysfunction  Changesto Ca2+ availabilityand/orreceptorregulation
  28. 28. Sympathetic nervous system Baroreceptor-mediatedresponse causesearlycompensatorymechanismtoimprove cardiacoutput, such as increase cardiaccontractility,arterial andvenousvasoconstrictionandtachycardia. However long-termdeleteriouseffectsoccur.These are β-adrenergicreceptorsare down- regulated/uncoupled.Noradrenaline–inducescardiachypertrophy/myocyte apoptosisandnecrosis viaα-receptorsandinducesup-regulationof the RAAS.Alsolongtermreductioninheartrate variability. Renin-Angiotensin-Aldosterone System RAAScommonlyactivatedinHFand causesreducedrenal bloodflow andSNSinductionof renin frommacula densa. ElevatedAngiotensinII:  Potentvasoconstrictor  PromotesLVHand myocyte dysfunction  Promotesaldosteronerelease  PromotesNa+ /H2Oretention  Stimulatesthirstbycentral action. Anti-diuretichormone Hypo-natraemiaresultsfromH2Oinexcess of Na+ retentionandcanbe due to; increasedthirstandactionof ADH on V2 receptorsinthe collectingduct Normallyhypo-natraemia/hypo-osmolality inhibitsADHrelease –butADH isincreased inHF: IncreasedH2Oretentionandtachycardiaandreducedsystemicresistance resultinginincreasedCO. Endothelin– Secretedbyvascularendothelial cells,itisapotentsystemandrenal vasoconstrictor actingvia autocrine activitythus activatingRAAS.Canincrease withheart failure. Bradykinin – promotesnatruiresisand vasodilatationandstimulatesproduction of PGs. Increase in peripheral arterial resistance by SNS,RAAS,reducednitratesand increasedendothelin.
  29. 29. THIS LEADS to Skeletal muscleschanges –reducedbloodblow flow,reductioninmass,contribute tofatigue and exercise intolerance Renal effects - Glomerularfiltrationrate maintainedinearlyHFbyhaemodynamicchangesatthe glomerulus.IncreasedNa+ /H2Oretentiondue toneuro-hormonalactivation.Howevereventually renal bloodflowfallsleadingtoreducedglomerularfiltrationrate anda subsequentrise inserum ureaand creatinine.Thiscanbe exacerbatedbytreatmentinhibitingthe actionsof angiotensin2. Diastolic Dysfunction Factors: frequentlyelderlyandfemale,oftenhistoryof hypertension/diabetes/obesity Normal LV functionbutconcentricLVH. ReducedLV compliance,impairedmyocardialrelaxation,impaireddiastolicLV filing(withincreased LA and PA pressures).Unable tocompensate byincreasingLV EDP.Low cardiac outputresults,this triggersneuro-hormonal activationaspersystolicheartfailure. In clinical practice, heart failure is oftendividedinto: Rightsidedheartfailure,leftsidedheartfailure,biventricularcardiacfailure,systolicheartfailure, diastolicheartfailure.Itisrare forany part of the heartto fail inisolation. Left heart failure:fatigue,exertional dyspnoea,orthopnoea,paroxysmal nocturnal dyspnoea. Mild: tachycardia,cardiomegaly,3rd or 4th heartsound,functional murmurof mitral regurgitation, bascal pulmonarycracklesandperipheral oedema. Right heart failure:chroniclungdisease,pulmonaryembolism/pulmonaryhypertension, pulmonary/tricuspidvalvulardisease,lefttoright shunts,isolatedrightventricular cardiomyopathy. The most frequentcause issecondarytoleftheartfailure. Relatedtodistensionandfluid accumulation inareasdrainedbythe systemicveins: Jugularveinpressureincreased,tender, smoothhepaticenlargement,dependentpittingoedema,ascites (peritonealcavity) andpleural effusion. Management of Heart failure Lifestyle modification- reducesalt,decreasealcohol,increase aerobicexercise,decreaseBP. Pharmacological –diuretics,ACE,nitrate, β-blockers,spironalactone(diuretic),digoxin, antiarrhythmics Cardiac surgery – hearttransplantation,mechanical assistdevices,underlyingcause,valve surgery, revascularisation. Implantable pacemakers –biventricularpacing Implantable defibrillators.
  30. 30. Special Circulations Differentpartsof the circulationhave differentproperties. The pulmonary circulation The lungshave two circulations: The bronchial circulation –part of the systemiccirculationisthere tomeetthe metabolic requirementsof the lungs Pulmonarycirculation –bloodsupplytoalveoli,requiredforgasexchange.Entire rightoutputof the heartis directedthroughthis.Itisnot demandledlike the systemicbutinsteaditissupplydriven. The pulmonary circulation works withlow pressureand low resistance. Where Pressure (mmHg) Right atrium 0-8 Right Ventricle (15-30)/(0-8) Pulmonary artery (15-30)/(4-12) Left atrium 1-10 Left ventricle (100-140)/(1-10) Aorta (100-140)/(60-90) Low Resistance due toshort,wide vessels,lotsof capillariesandarterioleshave relativelylittle smoothmuscle. There isefficientgasexchange,asloadsof capillaries,shortdiffusiondistance 0.3цm. For efficientoxygenationwe needtomatchventilationof alveoliwithperfusionof alveoli.Sowe divertbloodfromalveoliwhichare notwell ventilated. Hypoxicpulmonaryvasoconstrictionensure optimal ventilationperfusionratio.Thisisthe most importantmechanismregulatingpulmonaryvasculartone,alveolarhypoxiaresultsin vasoconstrictionof pulmonaryvessels.Thisensuresthatperfusionmatchventilation Althoughchronichypoxicvasoconstrictioncancause RV failure,causedbyaltitudeorlungdisease. Chronicincrease invascularresistance meanschronicpulmonaryhypertension,highafterloadon rightventricle... Exercise Increase cardiacoutput.Small increase inpulmonaryarterial pressure,opensapical capillariesso increasedO2 uptake bylungs,asbloodflow increasescapillarytransittime isreduced. Fluid The pressure inthe pulmonarycapillariesisnormallylessthanthe colloidosmoticpressure.Sotissue fluidisnotnormallyformedinthe lungs.There isnooverall control of the pulmonaryresistance.But the pulmonaryarteriolescancontrol the distributionof the cardiacoutputoverthe lung.
  31. 31. Thoughincreasedcapillarypressurecausesmore fluidtofilterout  oedema.Canbe due to increasedvenouspressure (duetomitral valve stenosisandLV failure). Pulmonary oedemaimpairsgasexchange,use diureticstorelivedsymptomsandtreat underlying cause. Gravityalsoinfluencesthe distributionof bloodflow throughthe lungs,aswhenstanding,the transmural pressure withinbloodvesselsatthe base of the lungssiselevatedbygravity. Thismay leadto some filtrationof tissuefluid,butwill alsodistendthe vesselsandincrease flow tothose areas. Anexample of ventilation/perfusionmismatchiscausesbygravity,because gravityincreases bloodflowtothe base,where more isbeingdeliveredtothe top.So some bloodactuallypasses thoughwithoutbeingoxygenated - calledthe ‘physiological shunt’ Cerebral Circulation The brain gets15% of cardiac outputbut only2% of bodymass, butat restgreymatter accountsfor 20% of the bodiesoxygenconsumption. It meetsthisbyhavinga highcapillarydensity,shortdiffusiondistance,highbasal flow rate X10 average forwhole bodyandhighO2 extractionrate – 35% above average. Neuronesare verysensitive tohypoxia,lossof consciousnessafterafew secondsof cerebral ischaemia.Approximately4minsfor irreversiblebraindamage. Structurally – anastomosesbetweenbasilarandinternal carotidarteries Functionally –brainstemregulatesothercirculations,myogenicAutoregulationmaintainsperfusion duringhypotension.Metabolicfactorscontrol bloodflow. Areaswithincreasedneuronal activityhave increasedbloodflow
  32. 32. Adenosineisapowerful vasodilatorof cerebral arterioles Cushing’sReflex Rigidcraniumprotectsthe brain,but doesnotallowfor volume expansion.Increasesin intracranial pressure impairs cerebral bloodflow –couldbe due to cerebral tumouror haemorrhage.Impairedbloodflow to vasomotorcontrol regionsof the brainstemincrease sympathetic vasomotoractivitywhichinturn increasesarterial BPandhelpsmaintaincerebral bloodflow. Blood Brain barrier lipidsoluble moleculessuchasthe O2 and CO2 can diffuse freely,lipidinsoluble solutescan’t. Coronary Circulation Rightand leftcoronaryarteriesarise fromaorticsinuses,mustdeliverata highrate. Bloodflowintothe leftcoronaryarteryismainlyduringdiastole. Capillarydensityof cardiacmuscle ismuchhigherthan skeletal.Alsocontinuousproductionof NO by coronaryendothelium whichmaintainsahighbasal flow. Coronary arteries Fewarterio-arterial anastomosesprone to atheromas.Thisleadsto anginaon exercise.Bloodflow mostlyduringdiastole so diastole isreducedasheart rate increases.Stressandcold can alsocause sympathetic coronary vasoconstrictionand angina.Suddenobstructionby thrombuscausesmyocardial infarction.
  33. 33. Skeletal muscle circulation It mustincrease O2 and nutrient deliveryandremoval of metabolites duringexercise.Ithasanimportant role inhelpingtoregulate arterial bloodpressure –40% of adult body mass.Resistance vesselshave rich innervationbysympathetic vasoconstrictorfibres –Baroreceptor reflex maintainsbloodpressure. Capillarydensitydependsonmuscle type.Postual muscleshave higher capillarydensity. Theyall have veryhighvasculartone,whichpermitslotsof dilatationflowcanincrease 20 timesin active muscle.Atrestonly½ of capillariesare perfusedatanyone time – so allowsforrecruitment. VasodilatorsK+ ,osmolarity,inorganicphosphates,adenosineandH+ (all increase) Adrenalineaswell.Byactingonβ2 receptorsandvasoconstrictorresponse viaNA onα1receptors. Cutaneous Circulation Its mainfunctionistomaintaina constantbodytemperature.Skinisthe mainheatdissipating surface – thisisregulatedbycutaneousbloodflow. Acral (apical) skinhasspecialisedstructurescalledartereovenousanastomoses(AVAs). Apical skinhasa highsurface area to volume ration.Theyare underneurl control.Notregulatedby local metabolites.Decreasecore temperature increasessympathetictone inAVAsdecresesblood flowtoapical skin.Increasedcore temperature opensAVAs. Cardiac Disease Causesof chestpain:angina,MI, syndrome X,pericarditisaorticdissection,aorticaneurysm,PE, infection,heartburn,pepticulcer,costochondritisandcervical thoracicdiscdegeneration. Ischaemicheartdisease Coronary heart disease – causedentirelybyatherosclerosis.Startswithfattystreak,lipidladen foamcells – macrophagesandpartly smoothmuscle.Progressiontofibro-lipidplaque dependson age andrisk factors. Riskfactors forCAD Increasingage,male sex,familyhistory,hypertension,hightotal cholesterol,low HDL-cholesterol, cigarette smoking,diabetes,LV hypertrophy,obesity,lackof physical activity,alcohol.
  34. 34. Stable angina Symptom,nota diagnosis,commonestcause of coronaryartherosclerosis.One majorartery >70% reductioninluminal diameter,painonexercise. ECGmay be normal but sometimesSTdepressionis shown.Exercise testingandangiography. Treatment– angioplastyforsymptomaticrelief,coronarybypass(if 3vesselsblocked),control of BP, stopsmoking,lose weight,control diabetes,control lipidsandexercise. Drugs: aspirin,nitrates,betablockers,Ca2+ channel antagonists(arterial vasodilatation),Nicorandil (KATP channel activator– coronary vasodilatoractivity) Unstable Angina and Non S-T elevationMI(NSTEMI) Recentonsetangina,anginaoccurringwithincreasingfrequency occurringwithlessexertionandor at rest.Not rapidlyrelievedbyGTN,relatedtoplaque rupture andthrombusformation. >90% occlusion. Unstable angina:limited durationandextentof obstructionnonecrosis NSTEMI- makersof cardiac necrosiswill be present. Treatment:admittoCCU, oxygenate,painrelief,aspirin,clopidogrel(reductioninplateletadhesion), Heparin,glycoproteinreceptorantagonists(reducebindingof fibrinogen),thentreatlike stable angina. STEMI Myocardial necrosissecondarytoacute interruptionof coronarybloodsupply.Rupture of plaque, intra-coronarythrombusandhence coronaryocclusion. Necrosisof fullthicknessof myocardial wall. Chestpainismore severe andstrongsympatheticreaction. PresentationssimilartoNSTEMI butcomplicationin30%: Arrhythmias,cardiogenicshock,LV failure. ECG changes.FirsthoursST elevation,first24hours T wave inversion,pathological Qafter 24 hours. Long termQ wave stays (90% of cases) and T inversion (rarer) butSTelevationremaining is extremely rare. Maybe ST depressioninleadsnotnexttoinfarct. Enzymes:afterMI creatine kinase,SGOT,andlactase dehydrogenase are releasedpeakingatvarious timesafter,inthatorder.Alsotroponinspresentfrom the beginningand lasta longtime. Treatment:thrombolysisandangioplasty To maintainarterial patency –anti-platelettherapy:aspirin,clopidogrel.Anticoagulantsandbeta blockers.
  35. 35. CardiacArrest Heart has stoppedorhas ceasedtopumpeffectively.signsunresponsivenessassociatedwithlackof pulse. Asystole –lossof electrical andmechanical activity. Ventricularfibrillation –uncoordinatedelectrical activity  mostcommon formof cardiac arrest  May occur followingMIor can resultfromelectrolyte imbalance(e.g.hyperkalaemia) Treatment:BLS – chestcompressionandexternal ventilation  ALS– defibrillation,electrical currentdeliveredtoheartwhichdepolarisesall the cellsandputsthemintorefractoryperiodthat allowscoordinatedelectrical activitytorestart. Adrenaline enhancesmyocardialfunctionand increasesTPR. Shock – Session12 Shockis the acute conditionof inadequate bloodflowthroughoutthe body. A catastrophicfall inarterial bloodpressure leadstocirculatory shock. Bloodpressure = cardiac outputX total peripheral resistance. Eitherfall inCO or a fall inTPR beyond the capacity of the heart to cope.
  36. 36. Cardiogenicshock Pumpfailure the ventriclecannotemptyproperly.OccursfollowingMIor due to seriousarrhythmias or worseningof heartfailure.Centralvenouspressure (CVP) maybe normal orraised.Heartfills,but failstopumpeffectivelyresultingin↓BP.Tissuespoorlyperfusedsuchascoronary arteriesand kidneys. Mechanical shock Cardiactamponade: restrictsfillingof the heartandlimitsenddiastolicvolume,affectsbothsidesof the heart.High central venouspressure butlow arterial BP. Large Pulmonary embolism: Rightventricle cannotempty,pulmonaryarterypressureishigh, reducedreturnof bloodto leftheart,limitsfillingof leftheart.Leftarterial pressure islow,arterial bloodpressure islow.SHOCK.symptomschestpainanddyspnoea. Hypovolaemicshock Reducedbloodvolume,probablydue tohaemorrhage.>20% reductioninblood. Haemorrhage  venouspressure falls,COfalls,arterial pressure falls. Compensatoryresponse increasedsympathetic,tachycardia,positive inotropy, peripheral vasoconstrictionandvenoconstriction.Internaltransfusionincreasedperipheral resistancereduces capillaryhydrostaticpressure sonetmovementof fluidintothe capillaries. Symptoms:tachycardia,weakpulse,paleskinandcoldextremeties. Decompensation  peripheral vasoconstrictionimpairstissue perfusion.Tissue damage due to hypoxia,release of chemical mediations –vasodilators  TPRfalls  BPfalls vital organsnot perfusedresultinginmulti organfailure. Distributive shock Normovolaemicbutprofoundperipheralvasodilation - ↓ TPR.bloodvolume constant,butvolume of the circulationhasincreases. SplitintoSeptic/toxicshockandanaphylacticshock Toxic:Septicaemiacausedbyendotoxinsreleasedbycirculatingbacteria  cause massive vasodilation  ↓TPR↓arterialpressure ↓ perfusiontovital organs.Alsocapillariesbecome leaky whichreducesbloodvolume. Baroreceptorsnotice ↓ BPsoincrease sympatheticoutput. VasoconstrictionoverriddenbyvasodilatorsbutCOincreased. So patienthastachycardia,strongpulse andwarm, red extremities. Anaphylactic:Severeallergicreaction  histamine releasedfrommastcells(andothers)  vasodilatoreffect↓ TPR arterial pressure ↓  sympathetickicksinbutCO↑ can’t overcome vasodilation  impairedperfusionof organs.Mediatorsalsocausesbronchoconstriction.
  37. 37. Symptoms  difficultybreathing,collapsed,tachycardia,strongpulse andred,warmextremities. Needsadrenaline vasoconstrictionviaalpha1adrenoceptors. Hypertension Hypertensionisasustainedincrease inarterial bloodpressure.Regulationat3 sites:  Kidneys  bloodvolume  Heart  cardiacoutput  Vasculature  TPR longtermcausingLV hypertrophy  riskof heart failure Riskof arterial disease  of coronary arteries,cerebrovascularsystem, renal vasculature,retinaand aorta. Hypertension isdefinedasgreaterthan140 systolicor over90 diastolic. Treatment weightloss,exercise andlesssalt drugs:diuretics,vasodilators (calciumchannel blockers),ACEinhibitorsandbetablockers.

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