Mechanism of action of the new anti-ischemia drug ranolazine

G Hasenfuss, L S Maier, G Hasenfuss, L S Maier

Abstract

Myocardial ischemia is associated with reduced ATP fluxes and decreased energy supply resulting in disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased persistent (late) sodium current was suggested to contribute to disturbed ion homeostasis by elevating intracellular sodium concentration with subsequent elevation of intracellular calcium. The new anti-ischemia drug ranolazine, a specific inhibitor of late sodium current, reduces sodium overload and hence ameliorates disturbed ion homeostasis. This is associated with symptomatic improvement of angina in patients. Moreover, ranolazine was shown to exhibit anti-arrhythmic effects. In the present article, we review the relevant pathophysiological concepts for the role of late sodium inhibition and summarize the most recent data from basic as well as clinical studies.

Figures

Fig. 1
Fig. 1
Ranolazine, structure
Fig. 2
Fig. 2
Scheme for the pathophysiology of myocardial ischemia and the role of late INa inhibition with ranolazine
Fig. 3
Fig. 3
Late INa under normal and increased late INa under pathophysiological conditions

References

    1. Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110:904–910. doi: 10.1161/01.CIR.0000139333.83620.5D.
    1. Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110:904–910. doi: 10.1161/01.CIR.0000139333.83620.5D.
    1. Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late (sustained/persistent) sodium current: a potential drug target to reduce intracellular sodium-dependent clcium overload and its detrimental effects on cardiomyocyte function. Europ Heart J. 2004;6(Suppl I):13–17. doi: 10.1093/eurheartj/6.suppl_i.i13.
    1. Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C. Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation. 2007;116:1449–1457. doi: 10.1161/CIRCULATIONAHA.107.704890.
    1. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, alodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. J Am Med Assoc. 2004;291:309–316. doi: 10.1001/jama.291.3.309.
    1. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survivial during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–1382. doi: 10.1016/j.jacc.2003.11.045.
    1. Clanachan AS (2004) Assessment of Ranolazine’s Effects on Mechanical Function and [Ca2+]i Accumulation in Ejecting Rat Hearts (CVT Technical Report Number CVT303.093-P)
    1. Clancy CE, Kass RS. Defective cardiac ion channels: from mutations to clinical syndromes. J Clin Invest. 2002;110:1075–1077.
    1. Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new mebatolic modulator, ranolazine on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol. 1992;20:131–138. doi: 10.1097/00005344-199207000-00017.
    1. Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan ASD. Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts. J Mol Cell Cardiol. 2006;41:1031–1038. doi: 10.1016/j.yjmcc.2006.08.012.
    1. 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. doi: 10.1093/cvr/28.8.1231.
    1. Hayashida W, 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. doi: 10.1007/BF00877121.
    1. Heusch G, Schulz R. Perfusion-contraction match and mismatch. Basic Res Cardiol. 2001;96:1–10. doi: 10.1007/s003950170072.
    1. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497(Pt2):337–347.
    1. Maier LS, Hasenfuss G. Role of [Na+]i and the emerging involvement of the late Na current (INa,late) in the pathophysiology of cardiovascular disease. Eur Heart J. 2006;8(Suppl A):A6–A9. doi: 10.1093/eurheartj/sui090.
    1. Messerli FH, Mancia G, Conti CR, Pepine CJ. Eur Heart J. 2006;27(23):2902–2903. doi: 10.1093/eurheartj/ehl308.
    1. Meyer M, Keweloh B, Guth K, Holmes JW, Pieske B, Lehnart SE, Just H, Hasenfuss G. Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations. J Mol Cell Cardiol. 1998;30(8):1459–1470. doi: 10.1006/jmcc.1998.0706.
    1. Morrow DA, Scirica BM, Karwatoswska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff A, Skene A, McCabes CH, Braunwald E. Effects of Ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes. The MERLIN-TIMI 36 Randomized Trial. JAMA. 2007;297(16):1775–1783. doi: 10.1001/jama.297.16.1775.
    1. Okada Y, Ogawa S, Sadanaga T, et al. Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-h Holter electrocardiography. J Am Coll Cardiol. 1996;27:84–89. doi: 10.1016/0735-1097(95)00424-6.
    1. Pepine CJ, Wolff AA. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Am J Cardiol. 1999;84:46–50. doi: 10.1016/S0002-9149(99)00190-3.
    1. Pieske B, Maier LS, Piacentino V, III, Weisser J, Hasenfuss G, Houser S. Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation. 2002;106:447–453. doi: 10.1161/01.CIR.0000023042.50192.F4.
    1. Roden DM (2001) Cardiac membrane and action potentials. In: Spooner PM, Rosen MR et al. (eds) foundations of cardiac arrhythmias: basic concepts and clinical approaches. Marcel Dekker, New York, p. 21
    1. Rousseau MF, Visser FG, Bax JJ. Ranolazine: antianginal therapy with a novel mechanism: placebor controlled comparison versus atenolol. Eur Heart J. 1994;15(Suppl):95.
    1. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, Molhoek P, Verheugt FW, Gersh BJ, McCabe CH, Braunwald E. Effect of Ranolazine, an Antianginal Agent With Novel Electrophysiological Properties, on the Incidence of Arrhythmias in Patients With Non ST-Segment Elevation Acute Coronary Syndrome: Results From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial. Circulation. 2007;116(15):1647–1652. doi: 10.1161/CIRCULATIONAHA.107.724880.
    1. Song Y, Shryock JC, Wagner S, Maier LS, Belardinelli L. Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction. J Pharmacol Exp Ther. 2006;318:214–222. doi: 10.1124/jpet.106.101832.
    1. Song Y, Shryock JC, Wu L, et al. Antagonism by ranolazine of the proarrhythmic effects of increasing late INa in guinea pig ventricular myocytes. J Cardiovasc Pharmacol. 2004;44:192–199. doi: 10.1097/00005344-200408000-00008.
    1. Sossalla S, Rasenack ECL, Wagner S, Ruff H, Tenderich G, Hasenfuss G, Belardinelli L, Maier LS. Inhibition of late sodium current by ranolazine improves diastolic dysfunction in human heart failure. Z Kardiol. 2007;96(Suppl 1):P837.
    1. Undrovians 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.
    1. Wagner S, Dybkova N, Rasenack ECL, Jacobshagen C, Fabritz L, Kirchhof P, Maier SKG, Zhang T, Hasenfuss G, Heller Brown J, Bers DM, Maier LS. Ca/calmodulin-dependent protein kinase II regulates cardiac Na channels. J Clin Invest. 2006;116:3127–3138. doi: 10.1172/JCI26620.
    1. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol. 1997;500(Pt 3):631–642.
    1. Wu J, Corr PB. Palmitoyl caritine modifies sodium currents and induces transient inward current in ventricular myocytes. Am J Physiol. 1994;266:H1034–H1046.
    1. Wu L, Shryock JC, Song Y, et al. Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther. 2004;310:599–605. doi: 10.1124/jpet.104.066100.

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