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PharmacologyofRenin-AngiotensinSystem(p156)yshaojian@Case159yrsoldfemaleHadpittingedemaonbothlegs,chestandabdominalwalls,seroperitoneum(腹腔積液).PE:HR128/min,BP130/85mmHgDiagnosedasCHF.Fosinopril10mgperday,edemawasgoneandcardiacfunctionimproved2weekslater.§1Renin-AngiotensinSystemComposition(組成)ofRASRenin(腎素),Angiotensin(血管緊張素)andangiotensinreceptors,Aldosterone(醛固酮)RASisanimportantparticipantinboththeregulationofnormalcardiovascularphysiologicalfunctionsandthepathologicalprocessofhypertension,cardiachypertrophyandcongestiveheartfailure.Reninisanglycoproteinenzyme.Mostoftherenininthecirculationcomesfromthekidney.Thejuxtaglomerularcellsarethesiteofsynthesis,storage,andreleaseofrenin.Reninsecretioniscontrolledbyavarietyoffactors:①Renalvascularreceptor(decreasedstretchincreasesreninrelease)②Maculardensa(致密斑sensitivetothechangeofNa+)③Sympatheticnervoussystem(stimulationofreninsecretion)④Angiotensin(AngIIinhibitsreninsecretion)⑤IntracellularcAMP(augmentsreninrelease)⑥D(zhuǎn)rugs(vasodilators,diureticsandβ-agonistsincreasereninrelease)Angiotensinogen(血管緊張素原):synthesizedinliver,istheproteinsubstrate(底物)forrenin。Catalyzedbytheenzymerenin,thedecapeptide(十肽)AngIissplitoff(裂解下來(lái))fromthesubstrateangiotensinogenAngiotensinI(AngI):Ithaslittleornobiologicactivity.Instead,itmustbeconvertedtooctapeptide(八肽)
angiotensinII(AngII)byconvertingenzyme.Angiotensin-convertingenzyme(ACE).:Ithas2substrates①AngI,whichconvertedtoAngII,and②bradykinin,whichbeeninactivated.Inthehumanheart,theenzymechymase(糜蛋白酶)
alsocatalyzestheformationofAngII.AngIIisconsideredthemaineffectoroftherenin-angiotensinsystem.AngIIactsonAT1andAT2receptors.AngiotensinIIreceptors(AT1andAT2)aremembersoftheGprotein-coupledreceptorfamily,TheAT1receptoriswidelydistributedinmanyorganandtissues(i.e.bloodvessels,heart,kidney,adrenalcortex,liver,brainandlung).TheAT2
receptorisfoundinhighconcentrationinfetal(胎兒)tissues,butitsdensityrapidlydeclinesafterbirth.MostoftheknownactionsaremediatedbytheAT1receptor.vasoconstrictionandariseinbloodpressure;enhancedreleaseofaldosterone;enhancedresponsestoendogenouscatecholamines;cellularproliferation(增殖)andremodeling(重構(gòu))oftheheartandbloodvesselsAngIIAlteredperipheralresistance
MECHANISMSRESULTRapidpressorresponseDirectvasoconstrictionEnhancementofperipheralnoradrenergicneurotransmissionA.increasedNEreleaseB.decreasedNEreuptakeC.increasedvascularresponsivenessIII.Increasedsympatheticdischarge(CNS)IV.ReleaseofcatecholaminefromadrenalmedullaAngIIAlteredrenalfunctionMECHANISMSRESULTSlow-pressorresponseDirecteffecttoincreaseNa+reabsorptioninproximaltubuleReleaseofaldosteronefromadrenalcortex(increasedNa+
reabsorptionandincreasedK+excretionindistal
tubule)AlteredrenalhemodynamicsA.directrenalvasoconstrictionB.enhancednoradrenergicneurotransmissioninkidneyC.increasedrenalsympathetictone(CNS)AngIIAlteredcardiovascularstructureMECHANISMSRESULTVascularandcardiachypertrophyandremodelingNon-hemodynamically-mediatedeffects:A.increasedexpressionofproto-oncogenesB.increasedsynthesisofgrowthfactorsC.increasedsynthesisofextracellularmatrixproteinsII.Hemodynamicallymediatedeffects:A.increasedafterload(cardiac)B.increasedwalltension(vascular)AngiotensinogenAngiotensinIAngiotensinIIVasoconstrictionIncreasedperipheralvascularresistanceIncreased
bloodpressureAldosteronesecretionIncreasedsodiumandwaterretentionBradykininInactiveIncreasedprostaglandinsynthesisVasodilationDecreasedperipheralvascularresistanceDecreasedbloodpressureReninConvertingEnzyme12DiagramforRASRASinhibitors①Beta-blockers②Renininhibitors:Enalkiren,Remikiren③ACEinhibitors④AT1receptorantagonists⑤AldosteronereceptorantagonistSpironolactone(螺內(nèi)酯)§2ACEinhibitor----ACEIApeptideinhibitorofconvertingenzymewasoriginallyisolatedfromthevenom(蛇毒)ofsouthAmericanpitvipers(蝮蛇)in1960s.Thesyntheticformofthispeptide,teprotide(替普羅肽),isaneffectiveinhibitorofconvertingenzyme.Itisactiveonlywhenadministeredintravenously.NowmanyACEinhibitorshavebeensynthesizedandusedorallyinclinic.I.Chemicalstructural&classificationofACEI1.Thestructure-effectrelationshipActivegroupinACEincludeaZn2+,ACEwillloseitsactivityifthispartcombinedwithoneoffollowgroups:-SH(captopril,卡托普利,含巰基)-COOH(enalapril,依那普利,
含羧基)-POO(fosinopril,福辛普利,
含磷酸基)2.ACEIandprodrugsSomeACEIhavegroup–COOC2H5havenoactivity,mustchangeinto–COOH,or–POORchangeto-POOHII.Pharmacologicaleffects&clinicalusagebasicpharmacologyofACEI1).decreaseAngIIproduction2).Protectbradykininfromdegradation3).Protectendotheliumcells,fightatherosclerosis4).Cardiacischemicprotection5).IncreaseinsulinreceptorsensitivitySchematicdiagramofACEI1.InhibitionoftheformationofAngIIanditsactionsSuppressionofthebiosynthesisofAngIIviaACE-inhibitionwillleadtovasodilation,reducedreleaseofaldosterone,bluntingofsympatheticstimuli,andimpairmentmyocardialandvascularhypertrophy.Alloftheseeffectsarebeneficialfortreatmentofhypertension,congestiveheartfailureandcardiovascularremodeling.basicpharmacologyofACEI2.ACEIinhibitkininaseII,leadtoreducedbreakdownofbradykinin.TheaccumulationofbradykininmaypotentiatethehypotensiveeffectofACEinhibitors.BradykininstimulateNO(一氧化氮)productionthroughtheB2receptor.Bradykinincanalsostimulatethesynthesisofprostaglandins(PGI2).BothNOandPGI2havevasodilation,antiaggregationofplateletandpreventionofcardiovascularremodelingeffects.ClinicalusesofACEinhibitorsHypertension&itscomplication(并發(fā)癥)CHFandcardiacinfarctionRenaldiseasefromdiabetesIII.AdverseReaction1.hypotension:occurredafterthefirstdose2.drycough:in5%-20%ofpatients3.lessaldosterone
hyperkaliemia(高血鉀),4.moresensitivetoinsulinhypoglycemia,5.inrenalarterydamagedpatientofbothsides,ACEIcandamagerenalfunction,6.fetalanomalies:
secondorthirdtrimesterofpregnancy7.angioneuroticedema;skinrash8.others:parageusia(味覺(jué)異常);albuminuria;IV:SomemarketedACEIsCaptopril(卡托普利):-SH,drycoughEnalapril(依那普利)&benazepril(貝那普利):-COOH,prodrugLisinopril(賴諾普利)Fosinopril(福辛普利):-poo,prodrugDrugsPro-drugActivecomponentcaptoprilNocaptoprilenalaprilYesenalaprilatebenazeprilYesbenazeprilatecilazaprilYescilazaprilatelisinoprilNolisinoprilperindoprilYesperindoprilatequinaprilYesquinaprilateramiprilYesramiprilate§3AngIIReceptor(AT1)Blockers(ARBs)I.BasicPharmacologicaleffects&clinicalusesBlockAT1receptor,decreasetheeffectsofAngIIfrombothreninandchymasepathways.Usedinhypertention,anginapectoris,CHF,diabeticrenaldamageHavenoeffectonbradykininsystem,nodrycohugh;havefetapathicpotentialII.CommonlyusedARBsLosartan(氯沙坦)
Valsartan(纈沙坦)Erbesartan(厄貝沙坦)Candesartan(坎替沙坦)AT1-receptorblockers
ACEinhibitorAT1receptors
DirectlyblockedIndirectlyinhibitedACENoinfluenceDirectlyinhibitedPlasmareninlevel↑↑PlasmaAngIIlevel↑AT2receptorIndirectlystimulatedIndirectlyinhibitedBradykinin→
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