Selective inhibition by riluzole of voltage-dependent sodium channels and catecholamine secretion in adrenal chromaffin cells

The examined the effects of riluzole, a neuroprotective drug, on voltage-dependent Na channels, nicotinic receptors, and voltage-dependent Ca channels, as well as catecholamine secretion, in comparison with those of verapamil and nicardipine, in primary cultures of bovine adrenal chromaffin cells. Riluzole inhibited veratridine-induced Na-22 influx via voltage-dependent Na channels even in the presence of ouabain. an inhibitor of Na,K-ATPase. Blockade of Na channels by riluzole was concentration-dependent with an IC50 of 5.3 mu M. It was associated with a similar concentration-related reduction of veratridine-induced Ca-45 influx via voltage-dependent Ca channels, and of catecholamine secretion. Riluzole had no effect on Ca-45 influx caused by high K, which directly activates voltage-dependent Ca channels, and on nicotine-induced Na-22 influx, which passes through the nicotinic receptors. Verapamil and nicardipine attenuated Na-22 influx caused by veratridine or nicotine at the same concentrations as they suppressed high K-induced Ca-45 influx. The inhibitory effect of riluzole on veratridine-induced Na-22 influx disappeared at high concentrations of veratridine. A potentiation of veratridine (site 2 toxin)-induced Na-22 influx caused by alpha-scorpion venom (site 3 toxin), beta-scorpion venom (site 4 toxin), or brevetoxin PbTx-3 (site 5 toxin), occurred in the presence of riluzole in the same manner as in control cells. These results suggest that riluzole binds to the veratridine site in voltage-dependent Na channels. It does not impair the cooperative interaction between the functional peptide segments of Na channels, but selectively inhibits gating of Na channels, thereby reducing Ca influx via Ca channels and catecholamine secretion. In contrast, verapamil and nicardipine suppress Na influx both Na channels and nicotinic receptors.