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G. VESCOVO MD G. VESCOVO MD PhDPhD FESCFESCMedicina I VicenzaMedicina I Vicenza
Agonismo ed Antagonismo Agonismo ed Antagonismo ββadrenergicoadrenergico ::
Ruolo dei Ruolo dei ββ bloccanti di ultima bloccanti di ultima generazionegenerazione
ββ11 and and ββ22 adrenoceptorsadrenoceptors whatwhatdo do wewe knowknow??
InotropicInotropic EffectEffectChronotropicChronotropicLusitropic Lusitropic
MC Schaub 2006
0.1mm
MyocyteMyocyte
Isolation ofIsolation of myocytesmyocytes from the ventricle of the heartfrom the ventricle of the heart
©© Dr GiorgioDr Giorgio VescovoVescovo
Philip Poole WilsonPhilip Poole WilsonSianSian HardingHardingMary JonesMary JonesFederica del MonteFederica del MonteGiorgioGiorgio VescovoVescovoPeterPeter O’GaraO’Gara
LONDON NHLI 1985LONDON NHLI 1985
CalciumCalcium and and ContractilityContractility
S Harding, G Vescovo JMCC 1991
LEC Ca++ 10 -3 M
Cytosol Ca++1-2 -7 M diastole
1-6 M systole
AmAm J J PhysiolPhysiol 19911991
The The syndromesyndrome of of HeartHeart FailureFailure
CHFCHFLeft Left VentricularVentricularDysfunctionDysfunction
CongestionCongestionLungsLungsLimbsLimbsGutsGuts
DyspnoeaDyspnoeaFatigueFatigue
ArrhythmiasArrhythmias
JMCC 1991
Rec
epto
r Den
sity
R
ecep
tor D
ensi
ty
(( fmol
fmol
/mg)
/mg)
NonNon--failingfailing
Failing (IDC)Failing (IDC)
* P < 0.05 vs. non* P < 0.05 vs. non--failingfailingIDC = Idiopathic Dilated IDC = Idiopathic Dilated CardiomyopathyCardiomyopathy Bristow MR et al. Bristow MR et al. ClinClin Drug Drug TherTher 19891989
Adrenergic Receptor Densities Adrenergic Receptor Densities in Human LV Myocardiumin Human LV Myocardium
7070
6060
5050
4040
3030
2020
1010
00ββ11 ββ22 αα11
**
**
BroddeBrodde O.E. J O.E. J PharmacolPharmacol Sci 2006Sci 2006
ββ--ARK1 (GRK2) in ARK1 (GRK2) in HeartHeart Failure Failure and and ββ--blockersblockers treatmenttreatment
LONDON NHLI 1985LONDON NHLI 1985
McLEODMcLEOD VESCOVOVESCOVOEurEur HeartHeart J 1991J 1991
A. Marks Circulation 2001
β-AR Desensitisation andβ-Blockers in Heart Failure
LondonLondon 19861986ApoptoticApoptotic MyocyteMyocyte DeathDeath in in RealReal TimeTime
LondonLondon 1886 Jack the 1886 Jack the RipperRipper
IwaiIwai--KanaiKanai E E CirculationCirculation 19991999
RegulationRegulation of of ApoptosisApoptosisbyby αα-- and and ββ adrenergicadrenergicpathwayspathways
CommunalCommunal C. C. CirculationCirculation 19981998
NorepinephrineNorepinephrine producesproduces myocytemyocyte apoptosisapoptosisbyby activationactivation of the of the ββ--receptorreceptor pathwaypathway
ILIL--11ββ
ILIL--66
TNFTNF--αα
MurrayMurray D D CirculationCirculation 20002000
ββ--adrenoceptoradrenoceptorstimulationstimulationAnd And MyocardialMyocardialCytokineCytokineExpressionExpression
MJ MJ LohseLohse 20032003
GradoGrado didi selettivitàselettività didi diverse diverse molecolemolecole ββ bloccantibloccanti
Rapporto di selettività ß1/ß2 valutato attraverso Rapporto di selettività ß1/ß2 valutato attraverso radioliganteradioligante su miocardio umano (ventricolo sinistro)su miocardio umano (ventricolo sinistro)
PrisantPrisant, J. , J. ClinClin. . PharmacolPharmacol. 2008; 48: 225. 2008; 48: 225--239239
BetaBeta--3 3 adrenergicadrenergic receptorreceptor ADRB3ADRB3
BuprenololBuprenololCarvedilolCarvedilol
LL--796568796568CL 316,243CL 316,243LY 368842LY 368842RoRo 4040--21482148BRL 37344BRL 37344NebivololNebivolol
((partialpartial?)?)
GsGsadenylateadenylatecyclasecyclase
cAMPcAMP
LipolysisLipolysisArrestinArrestin
mediatedmediateddesensitdesensit
NANA--A A mediatedmediatedvasodilatvasodilat
+ + regulatregulatMAPK MAPK cascadecascade
Negative Negative inotropicinotropic and and lusitropiclusitropicefffectefffect
cNOScNOSiNOSiNOS
ISO=NA>AISO=NA>Aββ33
AntagonistAntagonistAgonistAgonistMechanismMechanismActionActionAgonistAgonistPotencyPotency
ReceptorReceptorTypeType
ββ33 RECEPTORS IN RECEPTORS IN MYOCARDIAL CELLSMYOCARDIAL CELLS
C C GauthierGauthier J J ClinClin InvestInvest 19931993
ββ11 ββ2 2 stimulationstimulation
ββ3 3 agonistsagonists
H Le Marec J Clin Invest 1998
G Lembo G Lembo CirculationCirculation 20072007
ββ22 antagonistantagonist
ββ33 antagonistantagonist
? ? ββ33 partialpartial agonistagonist
G Lembo G Lembo CirculationCirculation 20072007
D. Bers Circulation 2001
iNOSiNOS CaCa--releasereleaseLPS LPS iNOSiNOS
In LPS In LPS myocytesmyocytes
AG lAG l--aminoamino--guanidineguanidineiNOS antagonistiNOS antagonist
RJ Lefkowitz PNAS 2007
ββ--arrestin stimulates arrestin stimulates MAPKMAPKIP3K AKT IP3K AKT cJun kinase cJun kinase ERKERK
A A MorimotoMorimoto AmAm J J PhysiolPhysiol 20052005
S S MoniotteMoniotte CirculationCirculation 20012001
S S MoniotteMoniotte CirculationCirculation 20012001
JL JL BalligandBalligand CirculationCirculation 20052005
ββ33AR AR eNOSeNOS iNOSiNOS
ββ33
contractilitycontractility
eNOSeNOS
agonistagonist
NormalNormal HeartHeart FailureFailureUpregulationUpregulation
AgonistAgonist
ββ33
eNOSeNOS
?? iNOSiNOS
ContractilityContractility
HeartHeart FailureFailureBetaBeta--blockerblocker ββ33 activeactive
ββ33 blockerblocker
ββ33
eNOSeNOS
? ? iNOSiNOS
ContractilityContractility
β1 desensit
ββ33 RECEPTORS IN THE RECEPTORS IN THE VASCULAR CELLSVASCULAR CELLS
C. Gauthier Br J Pharmacol 2006
MAW MAW BroedersBroeders CirculationCirculation 20002000
β1 ARSer or Glyβ1 ARSer or Gly
β2 ARArg or Glyβ2 ARArg or Gly
β2 ARGln or Glu
β2 ARGln or Glu
β2 ARMet or Valβ2 ARMet or Val β2 AR
Thr or Ileβ2 ARThr or Ile
β1 ARGly
or Arg
β1 ARGly
or Arg
16164949
27273434
164164
389389
Gln27GluC79Gbetabeta 22
Gly16ArgG46Abetabeta 22
Gly389ArgG1165Cbetabeta 11
Ser49GlyA145Gbetabeta 11
Arg492CysC1441Talphaalpha 1A1A
EffectEffectPolymorphismPolymorphismARAR--subtypesubtype
αα-- and and ββ--receptorsreceptors polymorphismpolymorphism
RathzRathz DA JBC 2002DA JBC 2002
ββ11((GlyGly--Arg389)Arg389)--ββ22 ((ThrThr--Ill164) Ill164) adrenoceptoradrenoceptorpolymorphismpolymorphism and and desensitisationdesensitisation
ββ22--AR Polymorphisms Influences the AR Polymorphisms Influences the Response to Response to CarvedilolCarvedilol Therapy in Heart Therapy in Heart
FailureFailure
Glu27Glu = Glu27Glu = ββ22--AR AR downregulationdownregulation::ββ22 sensitivitysensitivity
ββ22--AR Gln27GluAR Gln27Glu
∆∆Ej
ectio
nEj
ectio
nFr
actio
nFr
actio
n(( a
bsol
ute
abso
lute
units
units
))
PolymorphismPolymorphism
MetraMetra M M etet al. HF 2003al. HF 2003
00
55
1010
1515
2020
Gln27GlnGln27Gln
P < 0.01P < 0.01
Gln27GluGln27Glu Glu27GluGlu27Glu
Liggett J.Clin.Invest
wild-type β2
β2allele
ββ--adrenergicadrenergic polymorphismpolymorphism and and survivalsurvival
JCI 1998
ResponseResponse totoBucindolol Bucindolol in in ArgArghomozygoteshomozygotes and and GlyGly--389 389 carrierscarriers
K K MasuoMasuo CirculationCirculation 20082008
TrpTrp 64/64/ArgArg 64 64 polymorphismpolymorphism
EFFECT OF SARCOMERIC EFFECT OF SARCOMERIC PROTEIN OXIDATION PROTEIN OXIDATION
ON EXERCISE CAPACITYON EXERCISE CAPACITY
C C chf nebichf nebi bisobiso
ProteinProtein OxidationOxidation in CHF andin CHF andEffectEffect of of NebivololNebivolol and and BisoprololBisoprolol
BetaBeta--blockersblockers skeletalskeletal musclemuscle oxidationoxidationand in vitro and in vitro contractilitycontractility
CHFCHF
BISOPROLOLBISOPROLOL
NEBIVOLOLNEBIVOLOL
C
EFFECTS OF NEBIVOLOL AND BISOPROLOL EFFECTS OF NEBIVOLOL AND BISOPROLOL ON SKELETAL MUSCLE APOPTOSIS AND ATROPHYON SKELETAL MUSCLE APOPTOSIS AND ATROPHY
CONCLUSIONSCONCLUSIONSββ33ADR ADR stimulationstimulation decreasesdecreases contractilitycontractility and and lusitropismlusitropism in the in the heartheart
•• In CHF In CHF ββ33 overexpressionoverexpression furtherfurther depressesdepressesinotropisminotropismThe The improvementimprovement in in contractioncontraction and and relaxationrelaxationafter after ββ--blockadeblockade isis a a balancebalance betweenbetween ββ11 and and ββ33blockade blockade
•• At At endothelialendothelial levellevel PE and PE and EndoEndo producesproducesvasoconstrictionvasoconstriction..ββ33 agonismagonism ((nebivololnebivolol) ) inducesinduces NO NO dependentdependentvasodilatationvasodilatation
•• ItIt isis possiblepossible thatthat changeschanges occurringoccurring at at musclemusclelevellevel are are partiallypartially mediatedmediated byby ββ11 and and partlypartly bybyββ33 agonismagonism (NO production)(NO production)
NEBIVOLOLONEBIVOLOLO
•• ß1ß1--antagonismo antagonismo altamente selettivoaltamente selettivo
•• Vasodilatazione NOVasodilatazione NO--mediatamediata
NEBIVOLOLONEBIVOLOLONebivololoNebivololo 5 mg è 5 mg è unauna miscelamiscela racemicaracemica costituitacostituita dada ugualiuguali
quantitàquantità didi due due enantiomerienantiomeri: :
L L -- nebivololonebivololo 2,5 mg e D 2,5 mg e D -- nebivololonebivololo 2,5 mg2,5 mg
2,5 mg L 2,5 mg L -- nebivololonebivololo•• ATTIVITA’ VASODILATANTE ATTIVITA’ VASODILATANTE NONO--MEDIATAMEDIATA
2,5 mg D 2,5 mg D -- nebivololonebivololo••ATTIVITA’ ß1ATTIVITA’ ß1--BLOCCANTE BLOCCANTE ALTAMENTE SELETTIVAALTAMENTE SELETTIVA••ATTIVITA’ VASODILATANTE ATTIVITA’ VASODILATANTE NONO--MEDIATAMEDIATA
NEBIVOLOLO: VASODILATAZIONE NO-MEDIATANEBIVOLOLO: VASODILATAZIONE NONEBIVOLOLO: VASODILATAZIONE NO--MEDIATAMEDIATA
RitterRitter. J . J CardiovascCardiovasc PharmacolPharmacol 2001;38(s3):132001;38(s3):13--6.6.*L*L--NMMA (LNMMA (L--N monoN mono--metilmetil--argininaarginina): ): antagonistaantagonista selettivoselettivo dell’edell’e--NOSNOS
0
1
2
3
4
5
6
0 12 24 36 48 60 72
AVAMBRACCIO NON INFUSO AVAMBRACCIO INFUSO CON NEBIVOLOLO
88,5
177
354
88,5
177
354
Soluzione fisiologica L-NMMA (2 mg/min)
Nebivololoµg/min
EffettoEffetto sulsul flussoflusso ematicoematico dell’avambracciodell’avambraccio dell’infusionedell’infusioneintraintra--arteriosaarteriosa didi nebivololonebivololo e e nebivololonebivololo+L+L--NMMA*NMMA*
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