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 <or= 200 ms (n = 3) and suppressed late phase 3 EADs, DADs, and triggered activity elicited by exposure of the PV sleeves to Ach + isoproterenol, or high [Ca(2+)](o) + rapid pacing (n = 11). CONCLUSION: Ranolazine causes marked use-dependent inhibition of sodium channel activity leading to prolongation of effective refractory period, conduction slowing, and block as well as suppression of late phase 3 EAD and DAD-mediated triggered activity in canine PV sleeves. Our data suggest that ranolazine may be useful in suppressing AF triggers arising from the PV sleeves.
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 <or= 200 ms (n = 3) and suppressed late phase 3 EADs, DADs, and triggered activity elicited by exposure of the PV sleeves to Ach + isoproterenol, or high [Ca(2+)](o) + rapid pacing (n = 11). CONCLUSION:Ranolazine causes marked use-dependent inhibition of sodium channel activity leading to prolongation of effective refractory period, conduction slowing, and block as well as suppression of late phase 3 EAD and DAD-mediated triggered activity in canine PV sleeves. Our data suggest that ranolazine may be useful in suppressing AF triggers arising from the PV sleeves.
Authors: M Haïssaguerre; P Jaïs; D C Shah; S Garrigue; A Takahashi; T Lavergne; M Hocini; J T Peng; R Roudaut; J Clémenty Journal: Circulation Date: 2000-03-28 Impact factor: 29.690
Authors: Charles Antzelevitch; Luiz Belardinelli; Lin Wu; Heather Fraser; Andrew C Zygmunt; Alexander Burashnikov; José M Di Diego; Jeffrey M Fish; Jonathan M Cordeiro; Robert J Goodrow; Fabiana Scornik; Guillermo Perez Journal: J Cardiovasc Pharmacol Ther Date: 2004-09 Impact factor: 2.457
Authors: Charles Antzelevitch; Luiz Belardinelli; Andrew C Zygmunt; Alexander Burashnikov; José M Di Diego; Jeffrey M Fish; Jonathan M Cordeiro; George Thomas Journal: Circulation Date: 2004-08-09 Impact factor: 29.690