Curtis M J, Pugsley M K, Walker M J
Department of Pharmacology, King's College, University of London, United Kingdom.
Cardiovasc Res. 1993 May;27(5):703-19. doi: 10.1093/cvr/27.5.703.
The causes of ventricular arrhythmias in the acute setting of coronary artery disease (myocardial ischaemia and reperfusion) may be approached using two paradigms. One, the electrophysiological paradigm (disturbance of ionic homeostasis, electrogenesis, and conduction) has not been addressed in detail here. Instead, we have focused on the concept of a chemical paradigm of arrhythmogenesis. Many endogenous chemical substances (derived from the myocardium, nerves, blood plasma, platelets, leucocytes, and endothelium) accumulate in the ischaemic tissue or are produced during reperfusion and many of these have been suggested to modulate ventricular arrhythmias. Some substances may be arrhythmogenic and others may be antiarrhythmic. Together they determine whether or not arrhythmias occur. Potentially arrhythmogenic substances include potassium, catecholamines, cAMP, histamine, 5-HT, lysophosphatidylcholine, palmitylcarnitine, platelet activating factor, prostaglandins, leukotrienes, thromboxane A2, angiotensin II, endothelin, opioids, protons, calcium, and free radicals. We have considered each of these, with the objective of evaluating which are important in arrhythmogenesis in acute ischaemia and reperfusion. Two alternative models of arrhythmogenesis are possible in the context of the chemical paradigm: a series model (where one substance or its effects determines the arrhythmogenicity of another) and a parallel model (where numerous substances operate independently to cause ventricular arrhythmias). It is not yet clear which model is most appropriate; a combination of the two is possible, so a working prototype has been constructed which accommodates both. A set of criteria (hitherto lacking) for establishing whether a substance is sufficient and necessary for arrhythmogenesis is proposed. Some generalisations are given on approaches to establishment of these criteria for putative arrhythmogenic substances. Finally, we have considered how arrhythmogenic drug development may be influenced by using the chemical paradigm as an alternative to the electrophysiological paradigm of arrhythmogenesis.
在冠心病急性发作（心肌缺血和再灌注）时，室性心律失常的病因可以通过两种模式来探讨。一种是电生理模式（离子稳态、电发生和传导紊乱），本文未详细讨论。相反，我们专注于心律失常发生的化学模式概念。许多内源性化学物质（源自心肌、神经、血浆、血小板、白细胞和内皮）在缺血组织中积聚或在再灌注期间产生，其中许多已被认为可调节室性心律失常。一些物质可能具有致心律失常作用，而其他物质可能具有抗心律失常作用。它们共同决定心律失常是否发生。潜在的致心律失常物质包括钾、儿茶酚胺、环磷酸腺苷、组胺、5-羟色胺、溶血磷脂酰胆碱、棕榈酰肉碱、血小板活化因子、前列腺素、白三烯、血栓素A2、血管紧张素II、内皮素、阿片类物质、质子、钙和自由基。我们已经对这些物质逐一进行了研究，目的是评估哪些物质在急性缺血和再灌注时的心律失常发生中起重要作用。在化学模式的背景下，可能存在两种心律失常发生的替代模型：串联模型（一种物质或其作用决定另一种物质的致心律失常性）和平行模型（多种物质独立起作用导致室性心律失常）。目前尚不清楚哪种模型最合适；两种模型可能结合，因此构建了一个同时包含这两种模型的工作原型。提出了一套（迄今缺乏的）用于确定一种物质对心律失常发生是否充分且必要的标准。对确定这些假定致心律失常物质标准的方法给出了一些一般性概括。最后，我们考虑了将化学模式作为心律失常发生电生理模式的替代方法可能如何影响致心律失常药物的研发。
