Riluzole protects against cardiac ischaemia and reperfusion damage via block of the persistent sodium current
Date
2010
Authors
Weiss, Steven
Benoist, D
White, E
Teng, W
Saint, David Albert
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Nature Publishing Group
Abstract
Background and purpose: Current strategies to ameliorate cardiac ischaemic and reperfusion damage, including block of the sodium-hydrogen exchanger, are therapeutically ineffective. Here we propose a different approach, block of the persistent sodium current (INaP). Experimental approach: Left ventricular pressure was measured as an index of functional deficit in isolated, Langendorff perfused, hearts from adult rats, subjected to 30 min global ischaemia and reperfusion with vehicle only (control) or riluzole (1-10 μM) in the perfusate. Cell shortening and intracellular Ca2+ concentrations Ca2+i were measured in adult rat isolated myocytes subjected to hypoxia and re-oxygenation. The block of transient and persistent sodium currents by concentrations of riluzole between 0.01 and 100 μM were assessed in rat isolated myocytes using patch clamp techniques. Key results: In perfused hearts, riluzole produced a concentration-dependent cardioprotective action, with minor protection from 1 μM and produced rapid and almost complete recovery upon reperfusion from 3 and 10 μM. In isolated myocytes, riluzole at 3 and 10 μM greatly attenuated or prevented the hypoxia- and reperfusion-induced rise in Ca2+i and the contractile deficit. In patch clamp experiments, riluzole blocked the persistent sodium current with an IC50 of 2.7 μM, whereas the block of the transient sodium current was only apparent at concentrations above 30 μM. Conclusions and implications: Riluzole preferentially blocked INaP and was protective in cardiac ischaemia and reperfusion. Thus block of the persistent sodium current would be a viable method of ameliorating cardiac ischaemic and reperfusion damage.
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Keywords: calcium ion; riluzole; sodium ion; animal cell; animal experiment; animal model; animal tissue; article; attenuation; calcium cell level; cell hypoxia; controlled study; drug mechanism; heart contraction; heart index; heart left ventricle pressure; heart Cardioprotection; Ischaemia; Persistent sodium current (INaP); Reperfusion; Riluzole
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British Journal of Pharmacology
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Journal article
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2037-12-31
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