The mammalian heart operates as an electromechanical pump, the proper functioning of which depends critically on the sequential activation of cells throughout the myocardium and the coordinated activation of the ventricles (Fig. 1). Electrical signaling in the heart is mediated through regenerative action potentials that reflect the synchronized activity of multiple ion channels that open, close, and inactivate in response to changes in membrane potential (Fig. 1). The rapid upstroke of the action potential (phase 0) in ventricular and atrial cells, for example, is attributed to inward currents through voltage-gated Na+ (Nav) channels. Phase 0 is followed by a rapid phase of repolarization (phase 2), reflecting Nav channel inactivation and the activation of voltage-gated outward K+ (Kv) currents (Fig. 1). In ventricular cells, this transient repolarization or notch influences the height and duration of the action potential plateau (phase 2), which depends on the balance of inward (Ca2+ and Na+) currents and outward (K+) currents. The main contributor of inward current during the plateau phase is Ca2+ influx through high threshold, L-type voltage-gated Ca2+ (Cav) channels. The (L-type Ca2+) channels undergo Ca2+ and voltage-dependent inactivation and, as these channels inactivate, the outward K+ currents predominate resulting in a second, rapid phase (phase 3) of repolarization back to the resting potential (Fig. 1). The height and duration of the plateau, as well as the time-and voltage-dependent properties of the underlying Na+, Ca2+, and K+ channels determine action potential durations in individual cardiac cells. Changes in the properties or the densities of any of these channels, owing to underlying cardiac disease or as a result of the actions of cardiac and noncardiac drugs, therefore, is expected to have dramatic effects on action potential waveforms, refractory periods, and cardiac rhythms.

Original languageEnglish
Title of host publicationCardiac Safety of Noncardiac Drugs
Subtitle of host publicationPractical Guidelines for Clinical Research and Drug Development
PublisherHumana Press
Number of pages24
ISBN (Print)9781588295156
StatePublished - 2005


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