Voltage-gated calcium-channels and antiarrhythmic drug action.

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Calcium-channels, blockers have an established role in the management of cardiac arrhythmias [1–5]. They were identified empirically with the idea of achieving selective inhibition of voltage-gated calcium-channels and vasodilatation [6,7], but early laboratory studies of the hemodynamic and vascular effects of verapamil happened also to demonstrate efficacy against cardiac arrhythmias [1,8]. The importance of the landmark paper by Vaughan Williams and Singh [9] is that it proposed a novel discrete mechanism for the drug control of arrhythmias that did not rely on the three mechanisms viz. local anaesthetic, anti-sympathetic or delay in repolarization already described [10]. There were two major outcomes of this publication. First, the expanded and refined classification of antiarrhythmic drug actions heralded a period of development in antiarrhythmic drug strategies and encouraged critical thinking about the mechanisms of drug action. This contributed in turn to a more complete evaluation of antiarrhythmic drug therapy in general [11,12]. Second, intravenous verapamil entered clinical practice leading to a complete change in the treatment of acute paroxysmal supraventricular tachycardia [13–15]. The deployment of calcium-channel blockers in cardiac arrhythmias moved, of course, in parallel with increased use of this class of drug in coronary artery disease and hypertension [16,17]. This growth was unencumbered until more recently when it has been clouded by controversy [17–21]. This commentary will examine the cellular and molecular mechanisms of action and current applications of calcium-channel blockers in cardiac arrhythmias. We contend that there have been major advances in understanding the molecular mechanisms of action of these agents and this has substantially contributed to a greatly expanded knowledge of cardiac (and indeed non-cardiac) ion channel structure-function relationships [22]. This explosion of knowledge however has not yet resulted in any useful new drugs [23]. Despite this lack of progress …