Protecting the Heart Against Arrhythmias: Potassium Current Physiology and Repolarization Reserve

Hodgkin and Huxley’s classic experiments in the squid giant axon were the first to define a role for potassium efflux as a mechanism to return the membrane potential of an excitable cell to resting values.1 They showed that depolarization was caused by a rapid influx of sodium into the squid giant axon, an event which then initiated movement of potassium from inside the axon to the exterior. The resulting repolarizing current, termed I K, was identified decades later as a major contributor to repolarization in heart cells.2 I K appeared to not only drive normal repolarization but also respond to adrenergic activation. By the 1970s it was apparent that β-adrenergic stimulation markedly increases inward calcium current in myocytes3; this would prolong the QT interval on exercise were it not for a “balancing” effect of I K activation.4See p 1384 and 1392 In the late 1980s, there was some enthusiasm for the concept that arrhythmias could be suppressed by drugs that selectively delay repolarization (ie, without exerting other electrophysiological effects such as sodium channel block). A number of potent QT-prolonging agents were developed; in fact, 2—dofetilide and ibutilide—have reached clinical use. Studies of the molecular basis of such selective action potential prolongation led to the key discovery by Michael Sanguinetti, then at Merck, that “ I K” in guinea pig myocytes actually represented 2 distinct currents: a small drug-sensitive current that activated rapidly (hence, termed I Kr) and a large drug-resistant currrent that activated slowly, I Ks.5 I Kr block is now recognized as the overwhelmingly common mechanism whereby drugs produce QT prolongation. Work by many laboratories has defined key electrophysiological and pharmacological properties of I Kr. Notably, the Sanguinetti laboratory has proposed a structural basis for the peculiar “promiscuity” …