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András Varró Department of Pharmacology and Pharmacotherapy University of Szeged, Hungary

CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS. András Varró Department of Pharmacology and Pharmacotherapy University of Szeged, Hungary Albert Szent-Györgyi Medical Center 2006. CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS. HEART FAILURE GENETIC (CPVT) DRUGS ATRIAL FIBRILLATION GAP JUNCTIONS.

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András Varró Department of Pharmacology and Pharmacotherapy University of Szeged, Hungary

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  1. CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS András Varró Department of Pharmacology and PharmacotherapyUniversity of Szeged, Hungary Albert Szent-Györgyi Medical Center 2006

  2. CALCIUM HANDLING AND CARDIAC ARRHYTHMIAS HEART FAILURE GENETIC (CPVT) DRUGS ATRIAL FIBRILLATION GAP JUNCTIONS

  3. SL Ca2+ pump NHE INa Na+ Na+ Na CaX Na HX Na CaX ATP ATP H+ P Ca2+ RyR PLB SERCA ICa K+ Ca2+ ATP Mitochondria Myofilaments CARDIAC CELLULAR Ca2+ HANDLING NaCaX Forward Reverse Na+ pump 2K+ 3Na+ Ca2+ b-AR cAMP AC ATP PDE Ca2+ 3Na+ 3Na+ PKA AMP Ca2+ SR Ca2+ T-Tubule Ca2+

  4. Control Heart failure Ito Control Heart failure CL 1000 ms IKs Heart failure Control Heart failure Control IKr DECREASED REPOLARIZATION RESERVE IN HEART FAILURE Ik1 Fadi G.Akar et al. Am J Physiol 288:2887-2896, 2005 Tsuji et al. Cardiovasc. Res. 2000. 48: 300-309

  5. UPREGULATION OF NCX IN HEART FAILURE Sipido et al. Circulation. 2000;102:2137-2144. W Xiong et al, Circ Res. 2005;97:207-209.

  6. Ca2+ DEPENDENT DOWNREGULATION OF IK1 J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212 mRNA protein J. Fauconnier et al. Cardiovasc Res 68 (2005) 204– 212 Rose et al. Am J Physiol 288: H2077–H2087, 2005.

  7. INCREASED Ca2+ RELEASE FROM SRIN HEART FAILURE M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391

  8. INHIBITION OF NCX ABOLISHES EAD AND DAD ZA. Nagy, et al, British Journal of Pharmacology (2004) 143, 827–831

  9. ENHANCED DEPOLARIZATION EVOKED BY INTRACELLULAR Ca2+ IN HEART FAILURE Pogwizd et al. Circ Res. 2001;88: 1159-1167.

  10. SL Ca2+ pump Na+ pump NHE INa Na+ 2K+ Na+ ATP Na HX ATP Na CaX Na CaX H+ 3Na+ P Ca2+ RyR PLB SERCA ICa Ca2+ ATP K+ Cl- K+ K+ K+ Ik1 Ito IKr IKs Mitochondria Myofilaments extra beat DAD EAD DAD Na+ spont. extra beat ARRHYTHMIA IN HEART FAILURE Upregulated NCX NaCaX Forward Reverse Increased sympathetic tone 3Na+ Ca2+ b-AR cAMP AC ATP PDE Ca2+ 3Na+ PKA AMP Ca2+ SR Ca2+ REPOLARIZATION RESERVE T-Tubule Ca2+ ICl If

  11. ENHANCED Ca2+ RELEASE DUE TO LEAKY SR Lehnart et al. Circulation. 2004;109:r113–r119 Terentyev et al. Circ Res. 2005;96:651-658.

  12. ENHANCED Ca2+ RELEASE DUE TO MUTATIONOF THE SR RELEASE CHANNEL M.Yano et al. Pharmacology & Therapeutics 107 (2005) 377 – 391

  13. ARRHYTHMIA IN FPVT (Familial Polymorphic Ventricular Tachycardia) AND CPVT (Catecholaminergic Polymorphic Ventricular Tachycardia) SL Ca2+ pump Na+ pump NHE INa Na+ 2K+ Na+ ATP Na HX ATP Na CaX Na CaX H+ 3Na+ P Ca2+ RyR PLB SERCA ICa Ca2+ ATP K+ K+ K+ Cl- K+ Ik1 Mitochondria Myofilaments extra beat DAD EAD DAD Na+ Upregulated NCX NaCaX Forward Reverse Increased sympathetic tone 3Na+ Ca2+ b-AR cAMP AC ATP PDE Ca2+ 3Na+ PKA AMP Ca2+ IKs SR Ca2+ REPOLARIZATION RESERVE Ito T-Tubule Ca2+ IKr ? ICl If

  14. DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGCa2+ release activation INa SL Ca2+ pump Na+ pump NHE Na+ Na+ 2K+ Na CaX Na CaX Na HX ATP ATP H+ 3Na+ Ca2+ RyR ICa K+ Ca2+ Mitochondria extra beat DAD DAD NaCaX Forward Reverse 3Na+ Ca2+ b-AR cAMP AC ATP PDE Ca2+ 3Na+ PKA AMP P PLB Ca2+ SERCA SR Ca2+ T-Tubule Ca2+ DIGOXIN 1nM Drug: Digoxin Actodigin Oubain FPL-64176 McGarry and Williams Br.J. Pharmacol. 1993, 108: 1043-1050

  15. SL Ca2+ pump Na+ pump NHE INa Na+ 2K+ Na+ Na CaX Na CaX Na HX ATP ATP H+ 3Na+ P Ca2+ Ca2+ RyR PLB SR SERCA ICa K+ ATP extra beat Myofilaments DAD EAD DAD DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGBeta-adrenoceptor stimulation NaCaX Forward Reverse 3Na+ Ca2+ b-AR cAMP AC ATP PDE Ca2+ 3Na+ PKA AMP Ca2+ T-Tubule Ca2+ Drugs: dopamine dobutamine iv. norepinephrine denopamine iv. oral ? Tsien et al. J Mol Cell Cardiol 1986; 18:691-710

  16. DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGCa2+ channel activation SL Ca2+ pump Na+ pump NHE INa Na+ 2K+ Na+ Na CaX Na HX Na CaX ATP ATP H+ 3Na+ P Ca2+ Ca2+ RyR PLB SR SERCA ICa K+ ATP extra beat Myofilaments DAD EAD DAD NaCaX Forward Reverse 3Na+ Ca2+ b-AR cAMP AC ATP PDE Ca2+ 3Na+ PKA AMP Ca2+ T-Tubule Ca2+ Drug: Bay K 8644 Bay Y 5959 CGP 28-392 Hess et al. Nature 1984;311:538-44

  17. DRUG INDUCED ARRHYTHMIAS DUE TO ALTERED Ca2+ HANDLINGPDE inhibition SL Ca2+ pump Na+ pump NHE INa Na+ 2K+ Na+ Na CaX Na CaX Na HX ATP ATP H+ 3Na+ P Ca2+ Ca2+ RyR PLB SR SERCA ICa K+ ATP extra beat Myofilaments DAD DAD NaCaX Forward Reverse 3Na+ Ca2+ b-AR cAMP AC ATP PDE Ca2+ 3Na+ PKA AMP Ca2+ Ca2+ T-Tubule Ca2+ Mitochondria Drugs: amrinone milrinone olprinone vesnarinone Varró and Papp, J. of Cardiovascular Pharmacology 1995; 26: S32-S44

  18. MECHANISM OF ATRIAL FIBRILLATION DUE TO Ca2+ OVERLOAD OF THE PULMONARY VEIN CELLS Shin-Ann Chen et al. PACE 2003; 26:1576-1582

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