European Heart Journal Supplements (2006) 8 (Supplement A), A10–A13

doi:10.1093/eurheartj/sui091

The mechanism of ranolazine action to reduce

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ischemia-induced diastolic dysfunction
Luiz Belardinelli*, John C. Shryock, and Heather Fraser
Pharmacology and Translational Biomedical Research, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto,
CA 94304, USA

KEYWORDS Ischaemia of myocardium is associated with increases in the late sodium current
Late INa; (INa), intracellular sodium and calcium concentrations, calcium overload, and
Ischaemia; impairment of contractile relaxation (i.e. increased diastolic wall tension). An
Diastole; increase in diastolic wall tension compresses the vasculature and reduces nutritive
Angina;
blood flow, creating a positive feedback system that further impairs myocardial
Calcium overload;
oxygenation and contractile function. Ranolazine reduces the late INa and, is
Persistent sodium current;
Ranolazine
expected to decrease sodium entry into ischaemic myocardial cells. As a conse-
quence, ranolazine is proposed to reduce calcium uptake indirectly via the
sodium/calcium exchanger and to preserve ionic homeostasis and reverse ischae-
mia-induced contractile dysfunction.

Introduction Sodium channels and the action of

Ranolazine improves exercise tolerance and reduces
the frequency of angina attacks in patients with
ischaemic heart disease.1–3 The beneficial effects of
ranolazine are proposed to be a consequence of its
action to reduce sodium entry into myocardial cells
through sodium channels that either fail to inactivate
or that re-open.4,5 In the following review, the role
of sodium as mediator of ischaemia-induced patho-
logical changes in calcium homeostasis and diastolic
heart function is described. Moreover, the preclinical
evidence suggests that ranolazine reduces sodium
entry into cardiac cells, thereby maintaining sodium
and calcium homeostasis and preventing ischaemia-
induced diastolic dysfunction. The substantial effects
of ranolazine to attenuate electrical dysfunction
(i.e. afterdepolarizations, increased heterogeneity of
ventricular repolarization, and arrhythmic activity)
caused by excessive entry of sodium through non-
inactivated sodium channels are not presented here,
and have been reviewed elsewhere.4,6
* Corresponding author. Tel: þ1 650 384 8526; fax: þ1 650 475 0450.
E-mail address: luiz.belardinelli@cvt.com
ranolazine
Electrical excitation causes sodium ions to enter cardiac
cells through membrane sodium channels. The passage
of sodium ions through sodium channels and into a
myocardial cell generates the rapid depolarization or
‘upstroke’ of the action potential. Sodium channel
‘openings’ are very brief and, after opening, channels
inactivate rapidly and stay closed during the plateau
phase of the action potential. Channel inactivation
appears to involve a ‘plugging’ of the channel pore by a
cytoplasmic loop of the channel.7 Upon repolarization
of the cell membrane, sodium channels transform from
the inactivated to a resting state and do not open again
until the next membrane depolarization.7–9 However, a
small fraction of sodium channels may not fully inactivate
after opening. These channels may continue to open and
close spontaneously throughout the plateau phase of the
action potential at a time when sodium channels typically
remain closed. The late openings of these channels allow
a sustained/persistent current of sodium ions (referred to
as late INa) to enter the myocardial cell throughout
systole.
The nature of the modification(s) of the sodium
channel that leads to an increase in late INa is largely

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Mechanism of ranolazine action
Figure 1 Positive feedback during ischaemia increases the imbalance
between myocardial oxygen supply and demand. In this deleterious posi-
tive feedback cycle, the [Naþ]i-dependent calcium overload caused by
the imbalance between O2 supply and demand results in a further
decrease in O2 supply and increase in O2 demand (see text for details).
unknown. However, late INa is increased in myocytes
exposed to hypoxia,10 ischaemic metabolites,11,12 and
reactive oxygen species,13 and it is increased in post-
ischaemic ‘remodelled’ ventricular myocytes.14 Nitric
oxide is also reported to induce late INa by direct chemi-
cal modification of a thiol group either in the sodium
channel or in a closely associated protein.15
Ischaemia creates an imbalance between myocardial
oxygen supply and demand (Figure 1). The pathological
milieu during ischaemia (e.g. hypoxia and formation
of reactive oxygen species, palmitoyl carnitine, and
lysophosphatidylcholine) is associated with an eleva-
tion of the intracellular sodium concentration in
myocytes.10–14,16,17 An increase in the late INa contributes
to the elevation of intracellular sodium that is observed
during ischaemia.10,16,17 By virtue of the coupled exchange
of sodium and calcium that is facilitated by the cell
membrane Naþ/Ca2þ exchanger (NCX), an elevation of
the intracellular sodium concentration leads to an
increased exchange of intracellular sodium for extracellu-
lar calcium (i.e. activity of NCX in the reverse mode,
with sodium exit and calcium entry), and a reduced
exchange of intracellular calcium for extracellular
sodium (i.e. activity of NCX in the forward mode, with
calcium exit and sodium entry). An excessive or prolonged
increase of the intracellular sodium concentration,
thereby leads to intracellular calcium ([Ca2þ]i) overload.16
In several preclinical models, ranolazine has been
shown to reduce late INa.4–6 The action of ranolazine
to inhibit late INa is concentration-, voltage- and
frequency-dependent.4–6 During ischaemia, a decrease
of late INa by ranolazine would be expected to attenuate
the ischaemia-induced increase in the cytosolic sodium
concentration, and to reduce reverse mode NCX and
calcium loading. Thus, ranolazine may act to preserve
ionic homeostasis in the ischaemic myocardium.
Consequences of altered sodium/calcium
homeostasis and the effect of ranolazine
The failure of myocardial cells to maintain calcium
homeostasis has adverse consequences. Cellular calcium
A11
overloading causes increased actin/myosin filament
interaction and an increase in the left ventricular (LV)
diastolic tension (i.e. ‘stiffness,’ a failure to relax nor-
mally).18 As a result, myocardial contractile work,
oxygen consumption, and compression of the vascular
space during diastole may become abnormally elevated.
Compression of the vascular space causes a reduction in
myocardial blood flow.19 Consequently, oxygen supply is
reduced (especially in the subendocardial region of the
left ventricle), whereas the demand for oxygen to
support contraction is further increased. This pattern of
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cause and effect has the characteristics of a deleterious
positive feedback system, wherein ischaemia leads to
further ischaemia (Figure 1).
The effect of ranolazine to block late INa has the poten-
tial to disrupt this cycle by reducing intracellular calcium
accumulation and the accompanying increase in ventricu-
lar wall tension. This can be expected to have at least
two beneficial consequences. First, the reduction in
wall tension during diastole should reduce the consump-
tion of oxygen and ATP for contractile work, and thus
oxygen demand. Secondly, the reduction of wall tension
should reduce vascular compression. Because vascular
compression causes closure of small vessels and reduction
of blood flow, a reduction in compression may lead to
increased myocardial nutritive blood flow and oxygen
supply to the myocardium during diastole.
Preclinical evidence for ranolazine
Ranolazine improves sodium and calcium homeostasis
and contractile function in experimental models in
which sodium overloading is caused by increased late
INa. Ranolazine, at concentrations within the proposed
therapeutic range of 1–10 mM, attenuates an increase
in late INa caused by the sea anemone toxin ATX-II, an
enhancer of late INa.4 ATX-II mimics the effects of ischae-
mia to increase [Naþ]4i and [Ca2þ]i.20 Ranolazine has been
shown to significantly reverse and/or prevent the sus-
tained rises in diastolic and systolic [Ca2þ]i caused by
ATX-II.20 The attenuation by ranolazine of the rise in
[Ca2þ]i caused by ATX-II is accompanied by a reduction
in the ATX-II-induced rise in LV end-diastolic pressure
and decrease in peak LV 2dP/dt, a reversal of the
decreases in LV systolic pressure and peak LV þdP/dt,
and a reduction in the ATX-II-induced increase in myocar-
dial lactate release.21 Equally importantly, ranolazine
also reverses the decrease of coronary flow caused by
ATX-II (unpublished data). This finding suggests that rano-
lazine is capable of reversing the ATX-II-induced increase
in extravascular compression that may be the proximate
cause of the decrease in myocardial blood flow when ven-
tricular wall tension is increased. Furthermore, ranola-
zine was found to improve diastolic ventricular
relaxation during ischaemia/reperfusion,22,23 in the pre-
sence of ischaemic metabolites,24 in the presence of
reactive oxygen species,25 and in ventricular myocytes
from dogs with ischaemic heart failure.5
The actions of ranolazine on in vitro cardiac prep-
arations are similar to those of the sodium channel
A12
blockers R56865 and KC1121.26–29 R56865 and KC1121
have been shown to inhibit late INa, decrease calcium
overload, and improve LV diastolic function during
ischaemia, hypoxia, and other conditions known to
increase [Naþ]i.26–31 R56865 significantly attenuated the
impairment of LV relaxation (i.e. R56865 improved dias-
tolic compliance) during pacing-induced ischaemia in
dogs.31 This latter observation is consistent with studies
in dogs that describe the effects of coronary artery steno-
sis and associated LV diastolic dysfunction.31–37 These
studies demonstrate that pacing-induced ischaemia is
accompanied by an impairment of LV diastolic relaxation,
including increases in LV end-diastolic pressure and dias-
tolic stiffness, a decrease in LV peak 2dP/dt and an
upward shift in the diastolic pressure–volume relation-
ship.31–37 The impairment of LV diastolic relaxation is
attributed to the sustained increase in myocardial
[Ca2þ]i (i.e. cellular calcium overload) that occurs
during ischaemia.
Clinical evidence for ranolazine
A substantial body of clinical data supports the concept that
exercise- or pacing-induced ischaemia (acute and chronic)
impairs LV relaxation and reduces diastolic compliance.38–44
During episodes of angina pectoris, LV diastolic relaxation is
impaired, myocardial stiffness is increased, and LV diastolic
compliance is reduced.38–41,43,44 Pacing-induced ischaemia
(with angina pectoris) in patients is associated with a
decrease in LV peak 2dP/dt,38,41,43 and with an upward
shift in the diastolic pressure–volume relationship,39,40,44
indicative of a decrease in LV diastolic compliance.
Combined haemodynamic and echocardiographic studies
in patients with ischaemic heart disease revealed that
during pacing-induced angina, there is an increase in
regional LV myocardial ‘active’ stiffness.44 Thus, clinical
data support the concept that LV diastolic function is
impaired during episodes of angina pectoris (i.e. pain
induced by myocardial ischaemia).
In patients with ischaemic heart disease, ranolazine
was reported to cause a downward shift of the LV
pressure–volume relationship, to increase peak
filling rate and to increase wall lengthening during
isovolumic relaxation of ischaemic regions of the LV.1,45
These responses are consistent with an effect of
ranolazine to improve LV diastolic function associated
with ischaemic heart disease. Thus, the concept that
acute and chronic ischaemia leads to impairment of LV
diastolic relaxation (reduced diastolic compliance), and
that diastolic dysfunction leads to angina, is also sup-
ported by observations that ranolazine improves both
LV diastolic function and reduces the severity of angina.
Conclusion
The results of experiments with various cardiac prep-
arations support the concept that accumulation of intra-
cellular sodium, due in part to an impaired inactivation
of sodium channels (i.e. increase in late INa), leads to
L. Belardinelli et al.
cellular calcium overload. Calcium overload in turn
causes abnormal LV relaxation and diastolic dysfunction.
Both preclinical and clinical data support the hypothesis
that ranolazine reduces the severity of ischaemic and
post-ischaemic LV diastolic dysfunction by decreasing
the intracellular calcium overload that is secondary to
an inhibition of the late INa. The improvement in diastolic
function by ranolazine occurs without a decrease in
systolic function, because ranolazine does not reduce
either the peak inward sodium current or the peak
inward calcium current. In contrast, both calcium
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channel blockers and beta-adrenergic receptor blockers
can decrease cardiac systolic function; the former
directly decrease cardiac excitation–contraction coup-
ling, whereas the latter attenuate the cardio-stimulatory
effects of sympathetic nervous activity. Thus, both the
mechanism of action and the effects of ranolazine are
different from those of currently available anti-anginal
and anti-ischaemic drugs.
Conflict of interest: All authors are employees of CV
Therapeutics, Inc., and CV Therapeutics has patent rights
related to Ranolazine.
References
1. Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of
ranolazine on left ventricular regional diastolic function in
patients with ischemic heart disease. Cardiovasc Drugs Ther
1994;8:741–747.
2. Chaitman BR, Pepine CJ, Parker JO et al. Effects of ranolazine with
atenolol, amlodipine, or diltiazem on exercise tolerance and angina
frequency in patients with severe chronic angina: a randomized con-
trolled trial. JAMA 2004;291:309–316.
3. Chaitman BR, Skettino SL, Parker JO et al. Anti-ischemic effects and
long-term survival during ranolazine monotherapy in patients with
chronic severe angina. J Am Coll Cardiol 2004;43:1375–1382.
4. Song Y, Shryock JC, Wu L, Belardinelli L. Antagonism by ranolazine of
the pro-arrhythmic effects of increasing late INa in guinea pig ventri-
cular myocytes. J Cardiovasc Pharmacol 2004;44:192–199.
5. Undrovinas AI, Undrovinas NA, Belardinelli L. Ranolazine inhibits late
sodium current in isolated left ventricular myocytes of dogs with
heart failure. J Am Coll Cardiol 2004;43:178A.
6. Antzelevitch C, Belardinelli L, Zygmunt AC et al. Electrophysiological
effects of ranolazine, a novel antianginal agent with antiarrhythmic
properties. Circulation 2004;110:904–910.
7. Catterall WA. From ionic currents to molecular mechanisms: the
structure and function of voltage-gated sodium channels. Neuron
2000;26:12–25.
8. Roden DM. Cardiac membrane and action potentials. In: Spooner PM,
Rosen MR, eds. Foundations of Cardiac Arrhythmias: Basic Concepts
and Clinical Approaches. New York: Marcel Dekker; 2001. p21–41.
9. Clancy CE, Kass RS. Defective cardiac ion channels: from mutations to
clinical syndromes. J Clin Invest 2002;110:1075–1077.
10. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium
current in rat ventricular myocytes. J Physiol 1996;497:337–347.
11. Undrovinas AI, Fleidervish IA, Makielski JC. Inward sodium current
at resting potentials in single cardiac myocytes induced by the
ischemic metabolite lysophosphatidylcholine. Circ Res 1992;71:
1231–1241.
12. Wu J, Corr PB. Palmitoyl carnitine modifies sodium currents and
induces transient inward current in ventricular myocytes. Am J
Physiol 1994;266:H1034–H1046.
13. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen
peroxide in rat ventricular myocytes. J Physiol 1997;500:631–642.
14. Huang B, El Sherif T, Gidh-Jain M et al. Alterations of sodium channel
kinetics and gene expression in the postinfarction remodeled myo-
cardium. J Cardiovasc Electrophysiol 2001;12:218–225.
Mechanism of ranolazine action
15. Ahern GP, Hsu SF, Klyachko VA, Jackson MB. Induction of a persistent
sodium current by exogenous and endogenous nitric oxide. J Biol
Chem 2000;275:28810–28815.
16. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays
the ischemia-induced rise in cytosolic free calcium. Circ Res 1991;
68:1250–1258.
17. Jansen MA, van Emous JG, Nederhoff MG, van Echteld CJ. Assessment
of myocardial viability by intracellular 23Na magnetic resonance
imaging. Circulation 2004;110:3457–3464.
18. Bing OHL, Keefe JF, Wolk MJ et al. Tension prolongation during recov-
ery from myocardial hypoxia. J Clin Invest 1971;50:660–666.
19. Bache RJ, Vrobel TR, Arentzen CE, Ring WS. Effect of maximal
coronary vasodilation on transmural myocardial perfusion during
tachycardia in dogs with left ventricular hypertrophy. Circ Res 1981;
49:742–750.
20. Fraser H, Belardinelli L, Wang L et al. Inhibition of late INa by ranola-
zine reduces Ca2þ overload and LV mechanical dysfunction in ejecting
rat hearts. Eur Heart J 2005;26(abstract suppl.):414.
21. Fraser H, McVeigh JJ, Belardinelli L. Inhibition of late INa by ranola-
zine improves left ventricular relaxation in a model of Naþ-induced
Ca2þ overload. Eur Heart J 2005, in press.
22. Gralinski MR, Black SC, Kilgore KS et al. Cardioprotective effects
of ranolazine (RS-43285) in the isolated perfused rabbit heart.
Cardiovasc Res 1994;28:1231–1237.
23. Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late
(sustained/persistent) sodium current: a potential drug target to
reduce intracellular sodium-dependent calcium overload and its
detrimental effects on cardiomyocyte function. Eur Heart J
2004;6(Suppl. I):I3–I7.
24. Maruyama K, Hara A, Hashizume H et al. Ranolazine attenuates
palmitoyl-L -carnitine-induced mechanical and metabolic derange-
ment in the isolated, perfused rat heart. J Pharm Pharmacol
2000;52:709–715.
25. Matsumura H, Hara A, Hashizume H et al. Protective effects of rano-
lazine, a novel anti-ischemic drug, on the hydrogen peroxide-induced
derangements in isolated, perfused rat heart: comparison with
dichloroacetate. Jpn J Pharmacol 1998;77:31–39.
26. Ver Donck L, Borgers M. Myocardial protection by R56865: a new prin-
ciple based on prevention of ion channel pathology. Am J Physiol
1991;261:H1828–H1835.
27. Ver Donck L, Borgers M, Verdonck F. Inhibition of sodium and calcium
overload pathology in the myocardium: a new cytoprotective prin-
ciple. Cardiovasc Res 1993;27:349–357.
28. Tamareille S, Le Grand B, John GW et al. Anti-ischemic compound
KC12291 prevents diastolic contracture in isolated atria by blockade
of voltage-gated sodium channels. J Cardiovasc Pharmacol 2002;
40:346–355.
29. Decking UK, Hartmann M, Rose H et al. Cardioprotective actions of KC
12291. I. Inhibition of voltage-gated Naþ channels in ischemia delays
myocardial Naþ overload. Naunyn Schmiedebergs Arch Pharmacol
1998;358:547–553.
A13
30. Haigney MC, Lakatta EG, Stern MD, Silverman HS. Sodium channel
blockade reduces hypoxic sodium loading and sodium-dependent
calcium loading. Circulation 1994;90:391–399.
31. Vandeplassche G, Hermans C, Wouters L, Borgers M. Effects of
R56,865, a preventer of cellular calcium overload, on left ventricular
diastolic properties during pacing-induced ischemia in dogs.
J Cardiovasc Pharmacol 1991;17:621–626.
32. Paulus WJ, Serizawa T, Grossman W. Altered left ventricular
diastolic properties during pacing-induced ischemia in dogs with
coronary stenoses: potentiation by caffeine. Circ Res 1982;50:
218–227.
33. Bourdillon PD, Paulus WJ, Serizawa T, Grossman W. Effects
of verapamil on regional myocardial diastolic function in pacing-
induced ischemia in dogs. Am J Physiol 1986;251: H834–H840.
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/8/suppl_A/A10/429085 by guest on 15 June 2020
34. Serizawa T, Mirsky I, Carabello BA, Grossman W. Diastolic myocardial
stiffness in gradually developing left ventricular hypertrophy in dog.
Am J Physiol 1982;242:H633–H637.
35. Sasayama S, Takahashi M, Nakamura M et al. Effect of diltiazem on
pacing-inducing ischemia in conscious dogs with coronary stenosis:
improvement of postpacing deterioration of ischemic myocardial
function. Am J Cardiol 1981;48:460–467.
36. Paulus WJ, Grossman W, Serizawa T et al. Different effects of two
types of ischemia on myocardial systolic and diastolic function.
Am J Physiol 1985;248:H719–H728.
37. Serizawa T, Carabello BA, Grossman W. Effect of pacing-induced
ischemia on left ventricular diastolic pressure-volume relations in
dogs with coronary stenoses. Circ Res 1980;46:430–439.
38. McLaurin LP, Rolett EL, Grossman W. Impaired left ventricular-
relaxation during pacing-induced ischemia. Am J Cardiol 1973;
32:751–757.
39. Dwyer EM Jr. Left ventricular pressure-volume alterations and
regional disorders of contraction during myocardial ischemia
induced by atrial pacing. Circulation 1970;42:1111–1122.
40. Barry WH, Brooker JZ, Alderman EL, Harrison DC. Changes in diastolic
stiffness and tone of the left ventricle during angina pectoris.
Circulation 1974;49:255–263.
41. Grossman W, Mann JT. Evidence for impaired left ventricular
relaxation during acute ischemia in man. Eur J Cardiol 1978;
7(suppl.):239–249.
42. Flessas AP, Connelly GP, Handa S et al. Effects of isometric exercise
on the end-diastolic pressure, volumes, and function of the left
ventricle in man. Circulation 1976;53:839–847.
43. Mann T, Goldberg S, Mudge GH Jr, Grossman W. Factors contributing
to altered left ventricular diastolic properties during angina pectoris.
Circulation 1979;59:14–20.
44. Bourdillon PD, Lorell BH, Mirsky I et al. Increased regional myocardial
stiffness of the left ventricle during pacing-induced angina in man.
Circulation 1983;67:316–323.
45. Rousseau MF, Cocco G, Bouvy T et al. Effects of a novel metabolic
modulator, ranolazine, on exercise tolerance and left ventricular
filling dynamics in patients with angina pectoris. Circulation
1992;86(Suppl. 1):I716.