Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations

J Gen Physiol. 2015 May;145(5):395-404. doi: 10.1085/jgp.201411288.

Abstract

Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca(2+) current (ICa,L) plays a key role in both AP prolongation and EAD formation, L-type Ca(2+) channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation-contraction coupling. Isolated rabbit ventricular myocytes were first exposed to H2O2 or moderate hypokalemia to induce EADs, after which their endogenous ICa,L was replaced by a virtual ICa,L with tunable parameters, in dynamic-clamp mode. We probed the sensitivity of EADs to changes in the (a) amplitude of the noninactivating pedestal current; (b) slope of voltage-dependent activation; (c) slope of voltage-dependent inactivation; (d) time constant of voltage-dependent activation; and (e) time constant of voltage-dependent inactivation. We found that reducing the amplitude of the noninactivating pedestal component of ICa,L effectively suppressed both H2O2- and hypokalemia-induced EADs and restored APD. These results, together with our previous work, demonstrate the potential of this hybrid experimental-computational approach to guide drug discovery or gene therapy strategies by identifying and targeting selective properties of LTCC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials*
  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Cells, Cultured
  • Heart Ventricles / cytology
  • Heart Ventricles / metabolism
  • Male
  • Membrane Potentials
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology*
  • Rabbits

Substances

  • Calcium Channels, L-Type