Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations

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 <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.

Conflict of interest statement

Conflict of interest: Dr. Antzelevitch received research support and is a consultant to CV Therapeutics. Dr Belardinelli is an employee of CV Therapeutics.

Figures

Figure 1

Rate-dependent effects of ranolazine on maximum rate of rise of action potential upstroke (Vmax) and take-off potential (TOP) of action potentials recorded from PV sleeve preparations (n = 4). A and B: Representative examples of action potentials recorded at various basic cycle lengths (BCLs) in the absence (control, panel A) and presence of 10 µM ranolazine (panel B). C and D: Summary of the rate-dependent effects of ranolazine on Vmax and TOP. Ranolazine induced a marked decrease in Vmax and a small (2 to 5 mV) depolarization of TOP. Data are expressed in mean ± SD, * p<0.05 ranolazine vs. control.

Figure 2

Effects of ranolazine (10 µM) on maximum upstroke velocity of the action potential (Vmax) following an abrupt change in basic cycle length (BCL) in a PV sleeve preparation. Upper panel: Recordings of APs and Vmax following a change in BCL from 2000 to 200 ms (A, control; B, Ranolazine) and from 2000 to 170 ms (C, control; D, Ranolazine). Lower panel: Plot of beat to beat changes in Vmax (E, control; F, Ranolazine).

Figure 3

Ranolazine (10 µM)–induced postrepolarization refractoriness in PV sleeve preparations (n = 6). Ranolazine induced a rate-dependent decrease in APD85, but an increase in ERP leading due to development of PRR (the difference between ERP and APD85); n = 6. Data are expressed in mean + SD. *p < 0.05; ERP vs APD85.

Figure 4

Ranolazine (10 µM)–induced impulse conduction block in a PV sleeve preparation. Simultaneous recordings of two actions potentials (AP1 and AP2) along a PV sleeve preparation (interelectrode distance = 16 mm). The 1:1 conduction observed at basic cycle length (BCL) of 170 ms (first 6 beats) deteriorates to 2:1 conduction at a BCL of 150 ms.

Figure 5

Ranolazine suppresses delayed afterdepolarizations (DADs) and triggered activity (TA) induced by isoproterenol in a PV sleeve preparation. Upper panel: effect of isoproterenol (1 µM). DAD activity is apparent following a train of 20 beats at basic cycle length (BCL) of 200 ms, and increases in amplitude as BCL is reduced to 150 and 120 ms. The DAD reaches threshold as the train was extended to 35 beats, giving rise to a triggered beat (arrow) followed by a small DAD. Lower panel: ranolazine abolished the DAD and DAD-induced TA.

Figure 6

Ranolazine reduces the amplitude of ACh and high calcium ([Ca2+]o = 5.4 mM)-induced delayed afterdepolarization (DAD) in a PV sleeve preparation. A and B: ACh/high calcium induces DAD activity at basic cycle length (BCL) of 70 and 80 ms, respectively. C: ranolazine markedly reduced DAD amplitude at a BCL of 85 ms (fastest rate permitting 1:1 activation).

Figure 7

Ranolazine abolishes late phase 3 EADs and triggered activity (TA) induced by ACh and high calcium ([Ca2+]o = 5.4 mM) in a PV sleeve preparation. Basic cycle length (BCL) = 1000 ms. A. control. B. ACh/high calcium induced late phase 3 EADs (first 2 beats) and late-phase 3 EAD-induced triggered activity (TA) (third beat). C. Ranolazine (10 µM) abolished late phase 3 EADs and TA. D. Upon washout of ranolazine (30 minutes), late phase 3 EADs and TA reappear.