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1、抗心律失常药Anti-Arrhythmic Drug,正常心脏电生理,Cardiac electrical activity and ECG,Cardiac electrical activity,Heterogeneous APs in heart,Ion channels and AP,0,1,2,3,4,Ion currents underlying AP in ventricle,窦房结细胞动作电位时程中的参与电流（Currents underlying depolarization in SA nodal cells）,心律失常发生机制,折返自律性升高后除极 早后除极 迟后除极基因缺
2、陷,折返形成机制(Unidirectional block and reentry),预激综合症中房室折返环路的形成Atrioventricular reentry in the Wolff-Parkinson-White syndrome,心肌细胞的早后除极和迟后除极(Two forms of abnormal activity,early and delayed afterdepolarizations),抗心律失常药物作用,降低自律性减少后除极消除折返,降低自律性的四种方式(Four ways to reduce the rate of spontaneous discharge in
3、automatic tissues),心律失常类型,Atrial flutter,Atrial fibrillation,Atrial fibrillation,Ventricular beat,Ventricular fibrillation,Cardiac arrhythmias,Tachy-cardiac arrhythmias-Atrial-premature beats-Atrial flutter-Atrial fibrillation(AF)-Ventricular-premature beats(contractions)-Ventricular-tachycardia(VT)
4、-Ventricular fibrillation(VF)Brady-cardiac arrhythmias-Bundle branch blocks-Sinus bradycardia(Sick Sinus Syndrome),抗心律失常药物分类,Summary of antiarrhythmic drugs,End!,Problems to be solved,Pro-arrhythmias of antiarrhythmic drugsi.e.lack of selectivity when they are used to treat atrial fibrillation.No ef
5、fective drugs for arrhythmias in patients with heart failure.No drugs available for Sick Sinus Syndrome.,Pro-arrhythmia of antiarrhythmic drugs,Arrhythmogenic action in rabbit heart,Quinidine(5 M),E-4031(0.5 M),Asono et al.(1997)JMCC,29:831,Lack of IKur in human ventricle,Atrial cell,Ventricular cel
6、l,A Control,D Control,B 4-AP 50 M,C 4-AP-sensitive,E 4-AP 50 M,F 4-AP-sensitive,+50,50 mV,200pA,30 ms,Li et al(1996):Circ Res 78:689,Ion currents in human atrium&ventricle,Atrium,Ventricle,Human atrial IKur-A target for developing selective anti-atrial fibrillation drug,Atrial Fibrillation(AF),AF is
7、 the most common arrhythmia in elderly persons,AF is a potent risk factor for ischemic stroke,increasing the risk of stroke 5-fold and accounting for about 15%of all strokes in USA.,Symptomatic AF may also reduce quality of life,functional status,and cardiac performance.,It is associated with higher
8、 medical costs as well as an increased risk of death.,Go,A.S.et al.JAMA 2001;285:2370-2375.,Projected Number of Adults With Atrial Fibrillation in the United States Between 1995 and 2050,A population-based study of the long-term risks associated with atrial fibrillation 20-year follow-up of the Renf
9、rew/Paisley study,Stewart et al.Am J Med.2002;113:359-64,It is important to develop selective anti-atrial fibrillation drugs,Life-threatening VF in heart failure,Heart failure-mortality,15%,Within 1 year after diagnosis,Kannel,et al.Br Heart J 1994;72:S3-S9,80%,In 6 years after diagnosis,Heart failu
10、re-mortality,Kannel,et al.Br Heart J 1994;72:S3-S9,Of deaths,up to 50%are sudden or unexpected,50%,Heart failure-mortality,Tendera 16:180,Lethal arrhythmias:VT or VF,VF,VT,Prolongation of ECG Q-T interval in HF patients,Choy et al.Am Heart J,1998;136:664-71,Cellular mechanisms of arrhythmias in HF,E
11、ADs,Control,APs and Ito,IKs in dog ventricle,Liu et al.Circ.Res.1993;72:671,1995;76:351,Question How the heterogeneous electrophysiology of the transmural ventricular wall is remodeled in heart failure?,Dog HF model and human HF,Human explanted heart,Regional ventricular cells,Endo,M cell,Epi,EADs,E
12、ADs,EADs,EADs in regional cells from dog HF,No change of ICa in cells from dog HF,A,Control,Heart failure,-50 mV,0 mV,500 pA,100 ms,IK1 reduction in dog HF,Control,Heart failure,2 nA,100 ms,-40,A,B,Reduction of regional IK1 in dog HF,Control,TP(mV),-80,-70,-60,-50,-40,-30,Current(pA/pF),0,2,4,6,8,*,
13、*,*,*,*,HF,-110,-90,-70,-50,-30,-30,-20,-10,0,10,HF,Control,*,*,*,*,*,*,*,TP(mV),Current(pA/pF),A,B,Reduction of regional Ito1 in dog HF,TP(mV),-30,0,30,60,2,4,6,8,10,Epi,M,Endo,A,TP(mV),-30,0,30,60,2,4,6,8,10,Epi,M,Endo,Control,Heart Failure,B,Down-regulation of IKs in dog HF,Epi,M,Endo,IKs.tail(+3
14、0mV),B,Current(pA/pF),0,2,4,6,8,A,Control,Epi,M,Endo,400 pA,2 sec,No change of IKr in dog HF,+40 mV,Control,E-4031,E-4031-sensitive,+20 mV,0 mV,*,*,*,*,*,I=0,A,170 pA,1.3 sec,+40 mV,-60,-,30,No change of ICa in human HF,A,B,Control,HF,IK1 reduction in human HF,Control,Heart failure,Current(pA/pF),B,
15、TP(mV),-100,-80,-60,-40,-20,-18,-15,-12,-9,-6,-3,0,3,Control,FH,*,*,A,TP(mV),-80,-60,-40,-20,0.0,0.5,1.0,1.5,2.0,2.5,*,*,*,*,*,Reduction of Ito1 in human HF,A,TP(mV),-30,0,30,60,pA/pF,2,4,6,8,10,Control,FH,*,*,*,*,*,*,*,Control,HF,B,A,Control,HF,250 pA,1.2 sec,-50,+50,-30,B,Down-regulation of IKs in
16、 human HF,Summary,IKs,IK1,Ito1,Summary,0,EADs,IK1,IKs activators,Future perspective,Sick Sinus Syndrome,Cardiac electrical activity,ECGSick Sinus Syndrome,Bradycardiac and tachycardia are seen in Sick Sinus Syndrome,Atriaficial pacemaker,Threshold potential,Diastolic potential(60 mV),0,3,4,Pacemaker
17、 cell action potentials,ICa,IK,If,Sinoatrial node(SA node),Pacemaker potential and If,5 mV,From Difrancesco:Cardiovasc Res 1995;29:449-456,Modulation of If,A,C,B,From Difrancesco:Cardiovasc Res 1995;29:449-456,If and cloned HCN channels,From Ludwig et al.:Nature 1998;393:587-591,HCN:Hyperpolarization-activated,cyclic nucleotide-gated channels,the HCN family includes the members HCN1-HCN4.,
