Novel Therapeutic Targets for Antiarrhythmic Drugs

613 Pages·2010·6.13 MB·English

by  George Edward Billman

NOVEL THERAPEUTIC
TARGETS FOR
ANTIARRHYTHMIC DRUGS

NOVEL THERAPEUTIC
TARGETS FOR
ANTIARRHYTHMIC DRUGS
Edited by
George Edward Billman
Professor of Physiology andCellBiology
TheOhio State University
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LibraryofCongressCataloging-in-PublicationData:
Noveltherapeutictargetsforantiarrhythmicdrugs/[editedby]GeorgeE.Billman.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-26100-2(cloth)
1. Myocardialdepressants.2. Arrhythmia–Chemotherapy. I.Billman,GeorgeE.
[DNLM:1. AntiarrhythmiaAgents.2. Arrhythmias,Cardiac–drugtherapy.
QV150N9372010]
RM347.N682010
616.1028061–dc22
2009020796
PrintedintheUnitedStatesofAmerica
10 9 8 7 6 5 4 3 2 1
ToRosemary,friend,confidante,soulmate,andlifepartner—sempergaude.

CONTENTS
Acknowledgments xix
Contributors xxi
1. Introduction 1
GeorgeE.Billman
References 3
þ
2. Myocardial K Channels: Primary Determinants of
ActionPotential Repolarization 5
NorikoNiwaandJeanneNerbonne
2.1 Introduction 5
þ
2.2 ActionPotentialWaveformsandRepolarizingK Currents 7
þ
2.3 FunctionalDiversityofRepolarizingMyocardialK Channels 9
þ
2.4 MolecularDiversityofK ChannelSubunits 12
2.5 MolecularDeterminantsofFunctionalCardiacI Channels 16
to
2.6 MolecularDeterminantsofFunctionalCardiacI Channels 18
K
2.7 MolecularDeterminantsofFunctionalCardiacKirChannels 23
2.8 OtherPotassiumCurrentsContributingtoAction
PotentialRepolarization 27
þ
2.8.1 MyocardialK ChannelFunctioninginMacromolecular
ProteinComplexes 28
References 32
3. The ‘‘Funny’’Pacemaker Current 59
AndreaBarbuti,AnnalisaBucchi,MirkoBaruscotti,and
DarioDiFrancesco
3.1 Introduction:TheMechanismofCardiacPacemaking 59
3.2 The‘‘Funny’’Current 60
3.2.1 HistoricalBackground 60
3.2.2 BiophysicalPropertiesoftheI Current 61
f
3.2.3 AutonomicModulation 63
3.2.4 CardiacDistributionofI 63
f
vii
viii CONTENTS
3.3 MolecularDeterminantsoftheI Current 64
f
3.3.1 HCNClonesandPacemakerChannels 64
3.3.2 IdentificationofStructuralElementsInvolvedin
ChannelGating 66
3.3.3 RegulationofPacemakerChannelActivity:“Context”
DependenceandProtein-ProteinInteractions 70
3.3.4 HCNGeneRegulation 71
3.4 BlockersofFunnyChannels 72
3.4.1 Alinidine(ST567) 73
3.4.2 Falipamil(AQ-A39),Zatebradine(UL-FS49),
andCilobradine(DK-AH269) 73
3.4.3 ZD7288 75
3.4.4 Ivabradine(S16257) 75
3.4.5 EffectsoftheHeartRateReducingAgentsonHCN
Isoforms 78
3.5 GeneticsofHCNChannels 78
3.5.1 HCN-KOModels 78
3.5.2 PathologiesAssociatedwithHCNDysfunctions 79
3.6 HCN-BasedBiologicalPacemakers 81
References 84
4. ArrhythmiaMechanismsin Ischemia and Infarction 101
RubenCoronel,WenDun,PenelopeA.Boyden,and
JacquesM.T.deBakker
4.1 Introduction 101
4.1.1 ModesofIschemia,PhasesofArrhythmogenesis 102
4.1.2 Trigger-Substrate-ModulatingFactors 103
4.2 ArrhythmogenesisinAcuteMyocardialIschemia 103
4.2.1 Phase1A 103
4.2.2 Phase1B 113
4.2.3 ArrhythmogenicMechanism:Trigger 114
4.2.4 Catecholamines 115
4.3 ArrhythmogenesisDuringtheFirstWeekPostMI 115
4.3.1 Mechanisms 115
4.3.2 TheSubendocardialPurkinjeCellasaTrigger
24–48HPostOcclusion 116
4.3.3 FiveDaysPost-Occlusion:EpicardialBorderZone 120
4.4 ArrhythmiaMechanismsinChronicInfarction 128
4.4.1 ReentryandFocalMechanisms 128
4.4.2 HeterogeneityofIonChannelExpressioninthe
HealthyHeart 129
4.4.3 RemodelinginChronicMyocardialInfarction 131
4.4.4 StructuralRemodeling 133
4.4.5 RoleofthePurkinjeSystem 135
References 136