Suppression of ventricular arrhythmias by targeting late L-type Ca(2+) current

Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca(2+) channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of I(Ca,L), compromising inotropy. However, computational studies have recently demonstrated that selective reduction of late I(Ca,L) (Ca(2+) influx during late phases of the action potential) is sufficient to potently suppress EADs, suggesting that effective antiarrhythmic action can be achieved without blocking the early peak I(Ca,L), which is essential for proper excitation–contraction coupling. We tested this new strategy using a purine analogue, roscovitine, which reduces late I(Ca,L) with minimal effect on peak current. Scaling our investigation from a human Ca(V)1.2 channel clone to rabbit ventricular myocytes and rat and rabbit perfused hearts, we demonstrate that (1) roscovitine selectively reduces I(Ca,L) noninactivating component in a human Ca(V)1.2 channel clone and in ventricular myocytes native current, (2) the pharmacological reduction of late I(Ca,L) suppresses EADs and EATs (early after Ca(2+) transients) induced by oxidative stress and hypokalemia in isolated myocytes, largely preserving cell shortening and normal Ca(2+) transient, and (3) late I(Ca,L) reduction prevents/suppresses ventricular tachycardia/fibrillation in ex vivo rabbit and rat hearts subjected to hypokalemia and/or oxidative stress. These results support the value of an antiarrhythmic strategy based on the selective reduction of late I(Ca,L) to suppress EAD-mediated arrhythmias. Antiarrhythmic therapies based on this idea would modify the gating properties of Ca(V)1.2 channels rather than blocking their pore, largely preserving contractility.