Riluzole protects against cardiac ischaemia and reperfusion damage via block of the persistent sodium current.

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 microM) in the perfusate. Cell shortening and intracellular Ca2+ concentrations Ca2+ 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 microM 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 microM and produced rapid and almost complete recovery upon reperfusion from 3 and 10 microM. In isolated myocytes, riluzole at 3 and 10 microM greatly attenuated or prevented the hypoxia- and reperfusion-induced rise in Ca2+ and the contractile deficit. In patch clamp experiments, riluzole blocked the persistent sodium current with an IC(50) of 2.7 microM, whereas the block of the transient sodium current was only apparent at concentrations above 30 microM.

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.