L-Type Calcium Channel Gating Modifiers as a New Class of Antiarrhythmic Drugs

Abstract

Pharmacological treatment of cardiac arrhythmias includes the use of Ca2+ channel blockers (Class IV antiarrhythmics), that while suppressing arrhythmias, also block peak ICa,L, compromising EC coupling and contractility. To circumvent these limitations, we are studying and testing the properties of L-type Ca channel gating modifiers, rather than blockers, to selectively reduce the non-inactivating component (late ICa,L), leaving peak ICa,L minimally affected, thus preserving cardiac contractility. This strategy is based on our discovery that the selective reduction of late ICa,L potently suppress early afterdepolarizations (EADs) of the cardiac action potential (AP), recognized cellular triggers of arrhythmias (Madhvani et al., 2015). We previously reported that roscovitine, a purine analog known to reduce late ICa,L, potently suppressed H2O2-mediated EADs in rabbit ventricular myocytes. We are evaluating the robustness of this pharmacological intervention in a new model of EAD favoring condition using 600μM H2O2+1-2μM Isoproterenol. H2O2 alone (n=7) caused EADs in 83.2±5.39% APs and 85.7±7.83% APs in presence of H2O2+Isoproterenol (n=5); the perfusion of roscovitine (20 µM) efficiently suppressed EAD occurrence restoring normal AP duration in all myocytes tested. This antiarrhythmic effect was achieved without significantly perturbing calcium transients and cell shortening, indicating maintenance of normal EC coupling. We also tested roscovitine ability to suppress EAD-triggered ventricular fibrillation (VF) in isolated-perfused aged rat and rabbit hearts. We found that roscovitine suppressed VF induced by H2O2 (8/8 rat hearts, average time: 13±2.8 min) and H2O2+Isoproterenol (4/4 rabbit hearts, average time: 21±7 min), restoring sinus rhythm. Roscovitine had no significant effect on the rate-pressure product (RPP) as a measure of myocardial workload in isolated rat hearts (n=5). We propose that these findings establish roscovitine as a pilot compound to drive the development of a new class of antiarrhythmics based on Ca channel gating modification.