Antiarrhythmic Effects of Ranolazine in a Guinea Pig in Vitro Model of Long-QT Syndrome

Abstract

Prolongation of the QT interval of the ECG is associated with increased risk of torsades de pointes ventricular tachycardia. Ranolazine, a novel antianginal agent, is reported to decrease the delayed rectifier potassium current, I Kr , and to increase action potential duration (APD) and the QT interval. However, ranolazine is also reported to reduce late sodium current (late I Na) , a depolarizing current that contributes to prolongation of the plateau of the ventricular action potential. We hypothesized that ranolazine would decrease APD and the occurrence of arrhythmias when late I Na is increased. Therefore, we measured the effects of ranolazine alone and in the presence of anemone toxin (ATX)-II, whose action mimics the sodium channelopathy associated with long-QT3 syndrome, on epicardial monophasic action potentials and ECGs recorded from guinea pig isolated hearts. Ranolazine (0.1-50 M) prolonged monophasic APD at 90% repolarization (MAPD 90 ) by up to 22% but did not cause either early afterdepolarizations (EADs) or ventricular tachycardia (VT). ATX-II (1-20 nM) markedly increased APD and caused EADs and VT. Ranolazine (5-30 M) significantly attenuated increases in MAPD 90 and reduced episodes of EADs and VT produced by ATX-II. Ranolazine also attenuated the synergistic effect of MAPD 90 increase caused by combinations of ATX-II and blockers of I K [E-4031; 1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)piperidine]. Thus, although ranolazine alone prolonged APD, it reduced APD and ventricular arrhythmias caused by agents that increased late I Na and decreased I K .Prolongation of the duration of the ventricular action potential (indicated on the surface electrocardiogram as an increase of the QT interval) due to inhibition of the rapid delayed-rectifier potassium current, I Kr , is caused by drugs from many therapeutic classes and is associated with an increased risk of ventricular tachyarrhythmias such as torsades de pointes (TdP) (Belardinelli et al., 2003). However, QT interval prolongation per se may not be proarrhythmic (Hondeghem et al., 2001). Ranolazine is a novel antianginal drug (Pepine and Wolff, 1999;Louis et al., 2002;Chaitman et al., 2004), and it prolongs the QT interval but is not known to increase the incidence of ventricular tachycardias (VTs) and may reduce the incidence of ischemia-related arrhythmias (Gralinski et al., 1996). At a cellular level, ranolazine has been found to reduce the peak outward current conducted by the delayed rectifier potassium channel I Kr with a potency (IC 50 value) of 11.5 M (Zygmunt et al., 2002) and to reduce the late inward sodium current (late I Na ) with an IC 50 of 5 to 21 M, depending on pacing frequency and membrane potential (Zygmunt et al., 2002;Song et al., 2004).Inhibitions of I Kr and late I Na by ranolazine would be expected to have opposite effects on the duration of the QT interval. Whereas inhibition of I Kr prolongs action potential duration (APD), inhibition of late I Na decreases APD. Thus, the effect of ranolazine o...

Influence of heart failure on nucleolar organization and protein expression in human hearts

“…The rate-dependence yielded 110 and 190 ms maximal APD 90 prolongation in normal conditions versus I NaL increased by 4-fold, respectively. Similar observations were reported by others [20,24] in rabbit ventricular myocytes under the effects of I NaL activators, as well as in isolated perfused rabbit heart [22]. When considering HF conditions (squares), the rate-dependence is also increased with respect to normal conditions.…”

“…Also 40% and 60% inhibition of the rapid component of the delayed rectifier K + current (I Kr ) in failing myocytes were simulated with different degrees of I NaL enhancement (see Figure 6B). Indeed, the concomitant alteration of I NaL and I Kr has been reported to have important effects on arrhythmogenicity [20][21][22][23][24]. An important result obtained in our simulations, as shown in Figure 6A, is the reverse rate-dependence effect on APD 90 exerted by I NaL enhancement for normal conditions (compare circles with stars).…”

“…Experimental studies have shown that the I NaL is involved in the generation of EADs in myocytes [17,18] and life-threatening arrhythmias, such as torsade de pointes (TdP) [20], especially under conditions of reduced repolarization reserve in several animal species [21][22][23]. Other changes in biomarkers for arrhythmic risk such as the increase in the reverse rate-dependent APD prolongation [20,23,24] have been attributed to an increase in I NaL concomitant with inhibition of outward K + currents. Thus, the goal of our study was to analyze, using computer simulations, the role of the I NaL in the setting of human HF.…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…The importance of I Na,late for APD prolongation and the incidence of EADs are supported by the finding that inhibition of I Na,late by ranolazine reduces APD and EAD occurrence in various settings where I Na,late is enhanced. 22,[37][38][39] Early afterdepolarizations, depending on the membrane potential at which they occur, can trigger APs and ectopic activity that, if propagated, appears as extra beats on the electrocardiogram. 40 Hearts from mutant mice, delta KPQ SCN5a, which express a ''gain of function'' Na þ channel, mimicking human LQT3 syndrome, display EADs and ventricular tachycardia, highlighting the contribution of Na þ influx to this arrhythmogenic mechanism.…”

Torsades de Pointes in the Guinea-Pig Heart

“…The combined blockade of I Ks and I Kr in anaesthetized guinea pigs was not proarrhythmic, but a concomitant administration of adrenaline triggered TdP [25]. Moreover, pharmacological gain of I Na function has been used successfully to reduce repolarization reserve and induce TdP in ex-vivo studies [12,26,27]. Thus, co-administration of drugs attenuating repolarization strength or augmenting depolarizing currents increase sensitivity to TdP; however, it may also lower specificity of the model considerably, and additional studies are prompted to optimize experimental conditions of pharmacologically-primed proarrhythmia in the guinea pig [28].…”