The impact of recent ion channel science on the development and use of antiarrhythmic drugs
- Marie-Noelle S. Langan MD
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In the past 20 years in the basic laboratory, tools have been developed to further our understanding of the mechanism of arrhythmias and of the effect of compounds on these or their substrates. Patch clamp studies have better defined the cardiac channels. A new classification of antiarrhythmic drugs was devised, coined the Sicilian Gambit. Drugs, aimed at blocking specific channels, are now being developed. With the cloning of channels, information about their molecular structure became available. One can begin to understand the molecular determinants of antiarrhythmic drug action on specific ion channels, and how this is modulated by effectors. Molecular and electrophysiologic techniques also have been used to collect information about the way disease states affect the cardiac channels, and how this can alter the response to ion channel blockers. This has proceeded utilizing a few technologies. Diseased heart cells from patients, from animal models of disease, or from transgenic mice are studied to examine the change in current expression and channel protein quantity in different stages of disease. Hopefully this new information will make drug therapy more target-oriented.
- Singh BN: Current antiarrhythmic drugs: An overview of mechanisms of action and potential clinical utility. J Cardiovasc Electrophysiol 1999, 10(2):283–301. CrossRef
- Cardiac Arrhythmia Suppression Trial (II) Investigators: Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992, 327:227–233. CrossRef
- Ackerman MJ, Clapham DE: Ion channels-basic science and clinical disease. N Engl J Med 1997, 336:1575–1586. CrossRef
- Vaughan-Williams E: Symposium on Cardiac Arrhythmias, edited by F.-J.E. Sandoe E, Olesen KH. Sodertalje: AB Astra; 1970:440–469.
- Task Force of the Working Group on Arrhythmias of the European Society of Cardiology The Sicilian Gambit: A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991, 84(4):1831–1851.
- Carmeliet E: Use-dependent block of the delayed K+ current in rabbit ventricular myocytes. Cardiovasc Drugs Ther 1993, 3:599–604 CrossRef
- Wang J, Feng J, Nattel S: Class III antiarrhythmic drug action in experimental atrial fibrillation: Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide. Circulation 1994, 90:20320–2040.
- Bosch RF, et al.: Effects of the chromanol 293B, a selective blocker of the slow component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc Res 1998, 38(2):441–450. CrossRef
- Nattel S, Liu L, St-Georges D: Effects of the novel antiarrhythmic agent on azimilide on experimental atrial fibrillation and atrial electrophysiologic properties. Cardiovasc Res 1998, 37:627–635. CrossRef
- Black SV, Butterfield JL, Lucchesi BR: Protection against programmed stimulation and sudden cardiac death by NE-10064, a class III antiarrhythmic drug. J Cardiovasc Pharmacol 1993, 22:810–818. CrossRef
- Ragsdale DS, et al.: Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 1994, 265(5179):1724–1728. CrossRef
- Yeola SW, et al.: Molecular analysis of a binding site for quinidine in a human cardiac delayed rectifier K+ channel: Role of S6 in antiarrhythmic drug binding. Circ Res 1996, 78(6):1105–1114.
- Nattel S: The molecular and ionic specificity of antiarrhythmic drug actions. J Cardiovasc Electrophysiol 1999, 10(2):272–282. CrossRef
- Keating M, et al.: Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991, 252(5006): 704–706. CrossRef
- Moss AJ, et al.: ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995, 92 2929–2934.
- Schwartz, PJ, et al.: Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: Implications for gene-specific therapy. Circulation 1995, 92:3381–3386.
- Zareba W, et al.: Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med 1998, 339(14):960–965. CrossRef
- An RH, et al.: Lidocaine block of LQT-3 mutant human Na+ channels. Circ Res 1996, 79:103–108.
- Compton SJ, et al.: Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation 1996, 94(5):1018–1022.
- Choy AM, et al.: Normalization of acquired QT prolongation in humans by IV potassium. Circulation 1997, 96(7):2149–2154.
- Keung EC, Aronson RS: Transmembrane action potentials and the electrocardiogram in rats with renal hypertension. Circ Res 1981, 15(11):611–614.
- Kaab S, et al.: Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res 1996 78(2):262–273.
- Pak PH, et al.: Repolarization abnormalities, arrhythmias and sudden death in canine tachycardia-induced cardiomyopathy. J Am Coll Cardiol 1997, 30(2):576 584. CrossRef
- Luc WM, Boyden PA: Abnormal electrical properties of myocytes from chronically infarcted canine heart. Alterations in Vmax and the transient outward current Circulation 1992, 85:1175–1188.
- Jeck CD, Pinto JM, Boyden PA: Transient outward currents in subendocardial Purkinje myocytes that surviving in the infarcted heart. Circulation 1995, 92(3):465–473.
- Boyden PA, Pinto JM: Reduced calcium currents in subendocardial Purkinje myocytes that survive in the 24- and 48-hour infarcted heart. Circulation 1994, 89(6):2747 2759.
- de Bakker JM, et al.: Slow conduction in the infarcted human heart: A zigzag course of activation. Circulation 1993, 88(3):915–926.
- Smith JH, et al.: Altered patterns of gap junction distribution in ischemic heart disease- an immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol 1991, 139:801–821.
- Fast VG, et al.: Anisotropic activation spread in heart cell monolayers assessed by high resolution and optical mapping. Role of tissue discontinuities. Circ Res 1996, 79(1):115–127.
- Peters NS, et al.: Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 1997, 95(4):988–996.
- The impact of recent ion channel science on the development and use of antiarrhythmic drugs
Current Cardiology Reports
Volume 1, Issue 4 , pp 302-307
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- 1. The Zena and Michael A. Wiener Cardiovascular Institute, Mt. Sinai Medical Center, 1 Gustave L. Levy Place, 10029, New York, NY, USA