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. 2006 Mar 6;148(1):4–6. doi: 10.1038/sj.bjp.0706713

Ranolazine and late cardiac sodium current – a therapeutic target for angina, arrhythmia and more?

Jonathan C Makielski 1,*, Carmen R Valdivia 1
PMCID: PMC1617040  PMID: 16520741

Abstract

Ranolazine is a new antianginal drug approved for clinical use in the United States in January 2006. A study published in this same issue of the British Journal of Pharmacology characterizes ranolazine block of late sodium current caused by the long QT syndrome 3 mutations. This commentary discusses the implications of that study and the background and implications for block of late cardiac sodium current in general.

Keywords: SCN5A, local anesthetic drugs, antiarrhythmic drugs

Ranolazine – a selective blocker of late Na current (INaL)

The paper by Fredj et al. (2006), in this issue of British Journal of Pharmacology uses cloned and expressed cardiac Na channels (SCN5A) in HEK cells, and in native cardiac myocytes from a transgenic mouse arrhythmia model, to further our knowledge of the interaction of ranolazine with SCN5A. The major new finding is the evidence that ranolazine interacts with SCN5A at the same site on the domain IV S6 as other local anesthetic and antiarrhythmic drugs (Ragsdale et al., 1994). This places ranolazine firmly in the category of typical Na channel blocking drugs, but with a distinct profile in regard to that it preferential block of INaL relative to peak sodium current (INa). Ranolazine block of INaL was 10 times more potent than block of peak INa for two different SCN5A mutations that cause inherited long QT syndrome (LQTS) type 3 (LQT3) (Fredj et al., 2006). These results extend previously published results showing a relatively selective ranolazine block of INaL in myocytes using ATX-II to induce INaL (Antzelevitch et al., 2004; Song et al., 2004). Selective block of INaL over peak INa has been shown previously for drugs such as mexiletine (Dumaine et al., 1996) and flecainide (Nagatomo et al., 2000), but ranolazine appears to be even more selective. For example, flecainide was only three times more potent in blocking INaL compared to peak INa (Nagatomo et al., 2000). Ranolazine also shortened action potential duration (APD) in native cardiac myocytes just as it did for the ATX-II model (Antzelevitch et al., 2004; Song et al., 2004). These data provide support for a possible role for ranolazine in treating LQT3 patients where INaL may play a role in triggered cardiac arrhythmia, and also perhaps in acquired arrhtymia symdromes in which INaL may play a role.

Ranolazine as antianginal drug

Ranolazine was developed and will soon come into clinical use as an antianginal medication (Chaitman et al., 2004a, 2004b). Clinically, ranolazine has been shown to be distinct from other conventional antianginal agents such as beta blockers, calcium channel blockers, and nitrates in that it did not have a clinically significant effect on heart rate or blood pressure (Chaitman et al., 2004a, 2004b). This implies a molecular mechanism of action that may be distinct from these conventional agents. Initial attention was directed at investigations of ranolazine to partially decrease fatty acid oxidative metabolism (pFOX inhibition) (McCormack et al., 1998). This effect, however, occurred at levels greater than the therapeutic range (>10 μM). Later investigations of the electrophysiological effects of ranolazine found a potent and selective block of INaL in heart at concentrations (∼6 μM), well within the therapeutic range (Antzelevitch et al., 2004). This concentration was also lower than the blocking effects of ranolazine for other cardiac ion channels (Antzelevitch et al., 2004) and lower than the concentration required for the pFOX effects (McCormack et al., 1998). Could this block of INaL be a mechanism of action for the antianginal effects?

Changes in ion homeostasis in acute ischemia are immediate, and the mechanisms are complex. Intracellular sodium and intracellular calcium rise in parallel along with internal protons and extracellular potassium (Steenbergen et al., 1993). The increase in calcium may be caused at least in part by sodium induced calcium overload through a decreased activity or actual reversal of the sodium–calcium exchanger, although the role for internal sodium in this process has been questioned recently (Imahashi et al., 2005), and protons and sodium–hydrogen exchange may also play an important role (Anderson et al., 1990). In any event, the rise in intracellular calcium in myocardial cells increases diastolic wall tension and increases end-diastolic pressure, which increases oxygen demand while at the same time decreases oxygen supply because of decreased diastolic flow. In the laboratory setting, cardiac INaL has been shown to be acutely increased in conditions found in ischemia such as hypoxia (Ju et al., 1996) and increased concentrations of ischemic metabolites such as lysophosphatidylcholine (Undrovinas et al., 1992; Shander et al., 1996). Belardinelli et al. (2004) proposed that ranolazine block of late INaL ameliorates ischemia induced accumulation of intracellular Na, preventing Na-induced calcium overload and the subsequent deleterious effects on left ventricular end-diastolic pressure that exacerbates angina.

Ranolazine as antiarrhythmic drug?

The potential for ranolazine as an antiarrhythmic agent is apparent from its Vaughan Williams Class I sodium channel blocking properties. Block of INaL by ranolazine would be expected to shorten APD and the QT interval on ECG, but ranolazine has a minor prolonging effect on APD under control conditions (Antzelevitch et al., 2004; Fredj et al., 2006), and studies have reported a small prolongation of the QT interval in experimental models (Antzelevitch et al., 2004) and in patients (Chaitman et al., 2004a, 2004b). As ranolazine has no effect on the QRS duration (Chaitman et al., 2004a, 2004b), it would probably best be placed in the Class 1B Harrison modification (Harrison, 1983). The small amount of prolongation observed probably results from the block of the delayed rectifier potassium channels (Antzelevitch et al., 2004), and the prolonging effect of potassium channel block is mitigated by INaL block. It is important to note that ranolazine even at high doses does not induce early after depolarizations (EADs) that may underlie triggered tachyarrhythmia (Song et al., 2004) and no torsades de pointes has been observed in experimental tissue models (Antzelevitch et al., 2004; Schram et al., 2004) or so far in patients (Chaitman et al., 2004a, 2004b). The negligible blocking effects of ranolazine on peak and early INa at therapeutic concentrations also suggests that a ‘loss of function' mechanism for proarrhythmia would not apply. Clinical and basic data suggest no proarrhythmic effects for ranolazine, but what about antiarrhythmic effects? When EADs are induced by increased INaL in the presence of ATX-II, ranolazine shortens APD and eliminates EADs (Antzelevitch et al., 2004; Song et al., 2004; Wu et al., 2004). Although no EADs were observed in the present study (Fredj et al., 2006), ranolazine did shorten APD in the transgenic mouse LQT3 myocyte model. How useful might INaL block be in acquired arrhythmia? As mentioned above, INaL is increased in acute ischemia and the resultant electrophysiological abnormality may cause arrhythmia. Moreover, cardiac INaL is increased in heart failure (Undrovinas et al., 1999; Valdivia et al., 2005), where it has been proposed to be arrhythmogenic. Ranolazine did offer protection from ventricular fibrillation in an animal pharmacological model (Gralinski et al., 1994).

Remaining questions and further studies

The antiarrhythmic efficacy of ranolazine in humans is unknown, but it is an intriguing possibility in LQT3 patients as demonstrated by this study (Fredj et al., 2006), but it is also an intriguing possibility for acquired arrhythmia in ischemia and heart failure. Further clinical studies are needed to address this issue. In animal models, a potential for myocardial protection has been suggested (Black et al., 1994). An ongoing study of ranolazine in acute coronary syndrome addresses this issue (Marzilli, 2005) may test this in humans.

At the basic and preclinical level, Fredj et al. (2006) have shown the site of interaction of ranolazine on SCN5A, but we do not yet know the mechanism of the preferential block of INaL in general, or for the special potency of ranolazine realitive to other SCN5A blocking drugs in particular. The existing studies have used ATX-II as a model for increase INaL, and now in this study the relatively uncommon LQT3 mutations. These studies do provide ‘proof of principle', but additional studies of ranolazine in even more clinically relevant models such as ischemia and heart failure (Undrovinas et al., 2005) will be important. It has only been two short years since block of INaL has emerged as an established hypothesis for ranolazine action. The study by Fredj et al. (2006) represents an important advance in our knowledge of the mechanism of action of this drug and its interesting therapeutic potential. Additional study at the basic, preclinical and clinical levels is warranted to reveal its full potential and underlying mechanism of action.

Acknowledgments

J.C.M. and C.R.V. are by NIH HL71092 (JCM PI), and also by a sponsored research agreements with Cardiovascular Therapeutics, the maker of ranolazine. J.C.M. also serves as an ad hoc consultant and is on the Speakers Bureau for Cardiovascular Therapeutics.

Abbreviations

INa

sodium current

INaL

late sodium current

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