Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent

Abstract

Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 microM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks I(Kr) (IC(50) = 12 microM), late I(Na), late I(Ca), peak I(Ca), I(Na-Ca) (IC(50) = 5.9, 50, 296, and 91 microM, respectively) and I(Ks) (17% at 30 microM), but causes little or no inhibition of I(to) or I(K1). In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block I(Kr) and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early after depolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 microM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late I(Na), I(Kr), I(Ks), and I(Ca)). Ranolazine's actions to reduce TDR and suppress early after depolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.

Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations

“…8 Other potassium (I Ks , I to , I K1 ) and calcium (peak I Ca ), as well as Na/Ca exchanger, currents are not affected by ranolazine or are only reduced at much higher concentrations that are beyond the therapeutic range of the drug (2-10 µmol/L). 8 Previous studies have also shown that ranolazine blocks I Na with IC 50 of 294 µmol/L in canine ventricular myocytes (at 0.1 Hz) 20 and reduces V max with an IC 50 of > 100 µmol/L in Purkinje fibers and M cell preparations paced at a BCL of 500 ms. 8,9 In marked contrast to the lack of an effect of ranolazine at therapeutic concentrations on peak I Na in ventricular myocardium and Purkinje fibers, the drug has recently been shown to exert potent use-dependent block of peak I Na (estimated from depression of V max ) in canine atrial tissues. The atrial selective-effects of ranolazine to depress peak I Na and associated parameters, such as impulse conduction velocity, excitability, and post-repolarization refractoriness 21-23 , were shown to result from a more negative steady-state inactivation relationship for I Na in atrial than ventricular cells.…”

Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels

“…Ranolazine, an antiangina agent, has been recently shown to inhibit persistent Na ϩ currents associated with cardiac ischemia and to suppress early afterdepolarization (EAD)-triggered arrhythmias in an experimental model of LQT3 by blocking the persistent Na ϩ current (2,52). Ranolazine has recently been successfully used to treat LQTS patients harboring Na v 1.5 ⌬KPQ mutations (14,34).…”

Ranolazine Attenuates the Enhanced Reverse Na+-Ca2+ Exchange Current via Inhibiting Hypoxia-Increased Late Sodium Current in Ventricular Myocytes

“…In addition, little information is available about the inhibition of RAN (< 10 mΜ) on hypoxia-increased reverse I NCX before this investigation. Although RAN has been reported to inhibit reverse I NCX at high concentration (100 mΜ), whether it directly attenuates the hypoxia-enhanced reverse I NCX or not at therapeutically relevant concentrations (< 10 mΜ) in ventricular myocytes remains to be determined conclusively (29,30). In this study, I Na.L and I NCX were recorded simultaneously and alternately at an interval of 5 s in the same cell during hypoxia, and then the myocytes were treated with RAN (< 10 mΜ) or TTX (2 mΜ) to observe their effects on the two aforementioned currents.…”