Abstract
BACKGROUND: Ectopic activity arising from the pulmonary veins (PV) plays a prominent role in the development of atrial fibrillation (AF). OBJECTIVE: This study sought to determine the electrophysiological effects of ranolazine in canine PV sleeve preparations. METHODS: Transmembrane action potentials were recorded from canine superfused left superior or inferior PV sleeves using standard microelectrode techniques. Acetylcholine (ACh, 1 microM), isoproterenol (1 microM), high calcium ([Ca(2+)](o) = 5.4 mM) or a combination was used to induce early or delayed afterdepolarizations (EADs or DADs) and triggered activity. RESULTS: Ranolazine (10 microM) significantly accentuated use-dependent depression of maximal rate of increase of action potential upstroke (V(max)). Reducing basic cycle length (BCL) from 2000 to 200 ms resulted in a decrease of V(max) from 279 +/- 58 to 146 +/- 23 V/s (47.7%) in control subjects and from 241 +/- 71 to 72 +/- 63 V/s (70.2%) after 10 microM ranolazine (n = 4, P <.05). Ranolazine slightly abbreviated action potential duration, but induced significant rate-dependent prolongation of effective refractory period due to development of postrepolarization refractoriness (n = 6, P <.05). Ranolazine (10 microM) caused loss of excitability resulting in 2:1 activation failure at BCLs