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)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→