Model systems for the discovery and development of antiarrhythmic drugs.
Cardiovascular diseases are the leading cause of mortality worldwide and about 25% of cardiovascular deaths are due to disturbances in cardiac rhythm or "arrhythmias". Arrhythmias were traditionally treated with antiarrhythmic drugs, but increasing awareness of the risks of presently available antiarrhythmic agents has greatly limited their usefulness. Most common treatment algorithms still involve small molecule drugs, and antiarrhythmic agents with improved efficacy and safety are sorely needed. This paper reviews the model systems that are available for discovery and development of new antiarrhythmic drugs. We begin with a presentation of screening methods used to identify specific channel-interacting agents, with a particular emphasis on high-throughput screens. Traditional manual electrophysiological methods, automated electrophysiology, fluorescent dye methods, flux assays and radioligand binding assays are reviewed. We then discuss a variety of relevant arrhythmia models. Two models are widely used in testing for arrhythmogenic actions related to excess action potential prolongation, an important potential adverse effect of chemical entities affecting cardiac rhythm: the methoxamine-sensitized rabbit and the dog with chronic atrioventricular block. We then go on to review models used to assess potential antiarrhythmic actions. For ventricular arrhythmias, chemical induction methods, cardiac or neural electrical stimulation, ischaemic heart models and models of cardiac channelopathies can be used to identify effective antiarrhythmic agents. For atrial arrhythmias, potentially useful models include vagally-maintained atrial fibrillation, acute asphyxia with atrial burst-pacing, sterile pericarditis, Y-shaped atria surgical incisions, chronic atrial dilation models, atrial electrical remodelling due to sustained atrial tachycardia, heart failure-related atrial remodelling, and acute atrial ischaemia. It is hoped that the new technologies now available and the recently-developed models for arrhythmia-response assessment will permit the introduction of newer and more effective antiarrhythmic therapies in the near future.
Nattel
Stanley
S
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street, Montreal, Quebec, H1T 1C8 Canada. stanleynattel@aol.com <stanleynattel@aol.com>
Duker
Göran
G
Carlsson
Leif
L
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D055724:Electrophysiological Phenomena; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels