Toward specific cardiac IK1 modulators for in vivo application: Old drugs point the way

Abstract

a a Current knowledge of cardiac electrophysiology depends heavily on specific manipulation of individual ion channels and transporters whose combined functioning results in action potential formation. Whereas molecular interference introduces opportunities to modify currents by transgenesis and null mutation in genetically accessible animals such as mice, electrophysiologic studies in large animal models still rely heavily on specific pharmaceutical compounds. Many drugs in use that address the role of the main cardiac ion channels, such as sodium (e.g., lidocaine), calcium (e.g., verapamil), transient outward (e.g., 4-aminopyridine), and delayed rectifier (e.g., dofetilide, chromanol 293B), have no doubt proven their scientific importance. Unfortunately, o specific compound currently available addresses the hysiologic and pathophysiologic roles of KIR2.1, KIR2.2, and KIR2.3 carried cardiac inward rectifier current (IK1) in vivo. Existing blockers or activators of this ion current either are lethal when used in animal models or target other ion channels too. The primary functions of IK1 are to establish a negative and stable resting membrane potential and to contribute to the final phase of repolarization. Action potential modeling defines that action potential duration responses stronger to IK1 modulation than resting membrane potential and that the trial action potential responses stronger to IK1 modulation than that of the ventricle (Figure 1). In general, IK1 channels are formed by homotetramerization or heterotetramerization of KIR2.x isoforms that each contributes their specific charcteristics (e.g., single channel conductance, rectification trength). Whereas KIR2.1 is the strongest expressed iso-