András Varró Department of Pharmacology and Pharmacotherapy University of Szeged, Hungary Albert Szent-Györgyi Medical Center 2006 CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS
Feb 05, 2016
András Varró
Department of Pharmacology and PharmacotherapyUniversity of Szeged, Hungary
Albert Szent-Györgyi Medical Center2006
CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS
CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS
HEART FAILURE
GENETIC (CPVT)
DRUGS
ATRIAL FIBRILLATION
GAP JUNCTIONS
Ca2+
SR
Na+
INa
NaHX
H+
Na+
NHE
ATP
3Na+
2K+
Na+ pump
K+
Myofilaments
Ca2+
Ca2+
Ca2+
NaCaX
NaCaX
3Na+ Ca2+
NaCaXForward Reverse
3Na+
SL Ca2+
pump
ATP
Mitochondria
Ca2+
PKA
-ARAC
ATP
cAMP
PLB
SERCA
P
ATP
T-T
ub
ule
Ca2+
ICa
PDE
AMPR
yR
CARDIAC CELLULAR Ca2+ HANDLING
Control
Control Heart failure
Heart failure
Heart failureControl
IKs
IKr
Ito
Control
Heartfailure
CL 1000 ms
Tsuji et al. Cardiovasc. Res. 2000. 48: 300-309
DECREASED REPOLARIZATION RESERVE IN HEART FAILURE
Ik1
Fadi G.Akar et al. Am J Physiol 288:2887-2896, 2005
W Xiong et al, Circ Res. 2005;97:207-209.
UPREGULATION OF NCX IN HEART FAILURE
Sipido et al. Circulation. 2000;102:2137-2144.
Ca2+ DEPENDENT DOWNREGULATION OF IK1
J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212
J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212
Rose et al. Am J Physiol 288: H2077–H2087, 2005.
mRNA protein
M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391
INCREASED Ca2+ RELEASE FROM SRIN HEART FAILURE
ZA. Nagy, et al, British Journal of Pharmacology (2004) 143, 827–831
INHIBITION OF NCX ABOLISHES EAD AND DAD
Pogwizd et al. Circ Res. 2001;88: 1159-1167.
ENHANCED DEPOLARIZATION EVOKED BY INTRACELLULAR Ca2+ IN HEART FAILURE
Ca2+
SR
Ry
R
Na+
INa
NaHX
H+
Na+
NHE
ATP
3Na+
2K+
Na+ pump
Myofilaments
Ca2+
Ca2+
Ca2+
NaCaX
NaCaX
3Na+ Ca2+
NaCaXForward Reverse
3Na+
SL Ca2+
pump
ATP
Mitochondria
Ca2+
PKA
-ARAC
ATP
cAMP
PLB
SERCA
P
ATP
T-T
ub
ule
Ca2+
ICa
PDE
AMP
ARRHYTHMIA IN HEART FAILURE
K+ Ik1
K+ IKs
K+ Ito
K+ IKr
RE
PO
LA
RIZ
AT
ION
RE
SE
RV
E
Cl- ICl
Na+
If
DAD
extra beat
DAD
Upregulated NCX
Increased sympathetic tone
EAD
spont.extra beat
Lehnart et al. Circulation. 2004;109:r113–r119Terentyev et al. Circ Res. 2005;96:651-658.
ENHANCED Ca2+ RELEASE DUE TO LEAKY SR
M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391
ENHANCED Ca2+ RELEASE DUE TO MUTATIONOF THE SR RELEASE CHANNEL
Ca2+
SR
Ry
R
Na+
INa
NaHX
H+
Na+
NHE
ATP
3Na+
2K+
Na+ pump
Myofilaments
Ca2+
Ca2+
Ca2+
NaCaX
NaCaX
3Na+ Ca2+
NaCaXForward Reverse
3Na+
SL Ca2+
pump
ATP
Mitochondria
Ca2+
PKA
-ARAC
ATP
cAMP
PLB
SERCA
P
ATP
T-T
ub
ule
Ca2+
ICa
PDE
AMP
ARRHYTHMIA IN FPVT (Familial Polymorphic Ventricular Tachycardia) AND CPVT (Catecholaminergic Polymorphic
Ventricular Tachycardia)
K+ Ik1
K+ IKs
K+ Ito
K+ IKr
RE
PO
LA
RIZ
AT
ION
RE
SE
RV
E
Cl- ICl
Na+
If
DAD
extra beat
DAD
Upregulated NCX
Increased sympathetic tone
EAD ?
Ca2+
SR
Ry
R
Na+
INa
NaHX
H+
Na+
NHE
ATP
3Na+
2K+
Na+ pump
K+
Ca2+
Ca2+
Ca2+
NaCaX
NaCaX
3Na+ Ca2+
NaCaXForward Reverse
3Na+
SL Ca2+
pump
ATP
Mitochondria
Ca2+
PKA
-ARAC
ATP
cAMP
PLB
SERCA
P
T-T
ub
ule
Ca2+
ICa
PDE
AMP
DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLING Ca2+ release activation
McGarry and Williams Br.J. Pharmacol. 1993, 108: 1043-1050
Drug:
DigoxinActodiginOubainFPL-64176
DAD
extra beat
DAD
DIGOXIN 1nM
Ca2+
SR
Ry
R
Na+
INa
NaHX
H+
Na+
NHE
ATP
3Na+
2K+
Na+ pump
K+
Myofilaments
Ca2+
Ca2+
Ca2+
NaCaX
NaCaX
3Na+ Ca2+
NaCaXForward Reverse
3Na+
SL Ca2+
pump
ATP
PKA
-ARAC
ATP
cAMP
PLB
SERCA
P
ATP
T-T
ub
ule
Ca2+
ICa
PDE
AMP
DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGBeta-adrenoceptor stimulation
Drugs:
dopaminedobutamine iv.norepinephrinedenopamine iv. oral ?
Tsien et al. J Mol Cell Cardiol 1986; 18:691-710
DAD
extra beat
DAD EAD
Ca2+
SR
Ry
R
Na+
INa
NaHX
H+
Na+
NHE
ATP
3Na+
2K+
Na+ pump
K+
Myofilaments
Ca2+
Ca2+
Ca2+
NaCaX
NaCaX
3Na+ Ca2+
NaCaXForward Reverse
3Na+
SL Ca2+
pump
ATP
PKA
-ARAC
ATP
cAMP
PLB
SERCA
P
ATP
T-T
ub
ule
Ca2+
ICa
PDE
AMP
DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGCa2+ channel activation
Drug:
Bay K 8644Bay Y 5959CGP 28-392
Hess et al. Nature 1984;311:538-44
DAD
extra beat
DAD EAD
Ca2+
SR
Ry
R
Na+
INa
NaHX
H+
Na+
NHE
ATP
3Na+
2K+
Na+ pump
K+
Myofilaments
Ca2+
Ca2+
Ca2+
NaCaX
NaCaX
3Na+ Ca2+
NaCaXForward Reverse
3Na+
SL Ca2+
pump
ATP
Mitochondria
Ca2+
PKA
-ARAC
ATP
cAMP
PLB
SERCA
P
ATP
T-T
ub
ule
Ca2+
ICa
PDE
AMP
DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGPDE inhibition
Drugs:
amrinonemilrinoneolprinonevesnarinone
Varró and Papp, J. of Cardiovascular Pharmacology 1995; 26: S32-S44
DAD
extra beat
DAD
Shin-Ann Chen et al. PACE 2003; 26:1576-1582
MECHANISM OF ATRIAL FIBRILLATION DUE TO Ca2+ OVERLOAD OF THE PULMONARY VEIN
CELLS