A New Class of Antiarrhythmics for Late ICA,L

Abstract

Early Afterdepolarizations (EADs) of the cardiac action potential (AP) are membrane potential oscillations arising during phase 2-3 and well-recognized cellular triggers of lethal cardiac arrhythmias. The L-type Ca2+ current (ICa,L) is a major regenerative inward current during these phases of the AP, and is therefore highly relevant to EAD upstroke and propagation at the tissue level. We recently discovered that late ICa,L reduction produced by minimally altering specific ICa,L biophysical properties (smaller pedestal ICa,L or more depolarized steady-state activation), potently suppresses EAD occurrence in rabbit ventricular myocytes under dynamic clamp. Based on these findings, we hypothesize that drugs able to mimic these late ICa,L modifications could constitute a new Class of antiarrhythmics that do not compromise inotropy. We are studying the antiarrhythmic effects of two pilots drugs, roscovitine and pregabalin, that we found to reduce late ICa,L in rabbit ventricular myocytes via two distinct mechanisms. Specifically, roscovitine reduced the non-inactivating (pedestal) ICa,L while leaving peak ICa,L intact and pregabalin induced a depolarizing shift of the steady-state activation. In this study we assessed the antiarrhythmic potential of these pilot compounds that reduce late ICa,L. We tested the ability of these drugs to suppress EADs in ventricular myocytes induced by oxidative stress (H2O2). The perfusion of roscovitine (20µM) or pregabalin (1mM) dramatically suppressed EAD occurrence (roscovitine: from 81.37%±8.1% to 0% APs with EADs; pregabalin from 64.5±17.7% to 6.6±3.8%) and restored normal AP duration. Moreover, both drugs suppressed EAD-mediated VT/VF in isolated perfused aged rat hearts, restoring sinus rhythm (roscovitine: 5/6; pregabalin: 2/2 hearts). These studies set the basis for the development of a conceptually new Class of antiarrhythmics (L-type Ca2+ channel gating modifiers) that selectively reduce late ICa,L, avoiding the negative inotropy caused by traditional CaV channel blockers used as Class IV Antiarrhythmics.