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Inhibition des späten Natriumeinstroms (INa,late) als neuartige kardioprotektive Therapieoption

Inhibition of the late sodium current (INa,late) as an innovative cardioprotective treatment option

  • Klinische Pharmakologie
  • Published:
Der Kardiologe Aims and scope

Zusammenfassung

In den letzten Jahren konnte gezeigt werden, dass der späte Natriumeinstrom (INa,late) über die sarkolemmalen Natriumkanäle der Herzmuskelzelle bei der Pathophysiologie der myokardialen Ischämie eine wichtige Rolle spielt. Dabei kommt es durch einen vermehrten INa,late zu einer Erhöhung der intrazellulären Natriumkonzentration. Über den sarkolemmalen Na+/Ca2+-Austauscher (NCX) versucht die Zelle, Natrium aus dem Zytosol zu eliminieren, weshalb es im Gegenzug zu einer intrazellulären Kalziumüberladung mit konsekutiver kontraktiler Dysfunktion kommt. Mittels spezifischer Inhibition des INa,late wird diese pathologische Kaskade frühzeitig unterbrochen. Die daraus resultierende Abnahme des Natriumeinstroms führt zu einer verminderten intrazellulären Natriumkonzentration und konsekutiv verringerter NCX-bedingten Kalziumüberladung der Herzmuskelzelle. Experimentelle Daten weisen darauf hin, dass die Inhibition des INa,late die Infarktgröße reduziert sowie die linksventrikuläre Funktion nach akuter Ischämie und bei chronischer Herzinsuffizienz verbessert. Ranolazin als potenter und selektiver Inhibitor des INa,late führt zu einer symptomatischen Verbesserung von Anginapatienten, ohne den Blutdruck oder die Herzfrequenz zu beeinflussen. Neueste klinische Studien weisen zusätzlich auf antiarrhythmische Eigenschaften dieses neuartigen therapeutischen Ansatzes hin. Diese Übersichtsarbeit befasst sich mit den relevanten pathophysiologischen Konzepten, bei denen der INa,late eine Rolle spielt, und fasst die aktuelle Datenlage grundlagenwissenschaftlicher und klinischer Studien zusammen.

Abstract

Over the last few years, it has been shown that the late sodium current (INa,late) mediated by voltage-gated cardiac sodium channels plays an important role in the pathophysiology of myocardial ischemia. A rise in INa,late increases the intracellular sodium concentration. In consequence, the myocyte eliminates sodium ions through the sarcolemmal Na/Ca exchanger (NCX), leading to calcium overload and hence contractile dysfunction. By specifically inhibiting INa,late, this pathological cascade can be interrupted by improving the intracellular sodium concentration and hence the NCX-dependent calcium overload. Experimental data suggest that inhibition of INa,late decreases infarct size and improves left ventricular function after acute ischemia and during chronic heart failure. As a potent inhibitor of INa,late, ranolazine improves angina pectoris symptoms without changing blood pressure or heart rate. New clinical studies even point to beneficial antiarrhythmic effects. This review focuses on relevant pathophysiological concepts in which INa,late plays a role and summarizes the latest basic and clinical data.

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Danksagung

Dr. Maier wurde von der Deutschen Forschungsgemeinschaft (DFG) im Rahmen eines Emmy Noether-Stipendiums unterstützt (MA 1982/1–5) und ist mittlerweile DFG Heisenberg-Stipendiat (MA 1982/3–1). Drs. Hasenfuss und Maier sind Projektleiter in der DFG Klinischen Forschergruppe 155.

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung hin: Die Autoren werden im Rahmen eines wissenschaftlichen Projekts von CV Therapeutics unterstützt, dem Hersteller von Ranolazin in den USA.

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  1. Abt. Kardiologie & Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Deutschland

    S. Sossalla, G. Hasenfuss &  L.S. Maier

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  1. S. Sossalla
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  2. G. Hasenfuss
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  3. L.S. Maier
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Correspondence to L.S. Maier.

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Sossalla, S., Hasenfuss, G. & Maier, L. Inhibition des späten Natriumeinstroms (INa,late) als neuartige kardioprotektive Therapieoption. Kardiologe 2, 142–148 (2008). https://doi.org/10.1007/s12181-008-0070-4

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  • DOI: https://doi.org/10.1007/s12181-008-0070-4

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